EDGAR 10-K Filing

Company CIK: 1603207
Filing Year: 2024
Filename: 1603207_10-K_2024_0001493152-24-014342.json

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ITEM 1. BUSINESS
Item 1. BUSINESS
On October 16, 2023, pursuant to the previously announced Agreement and Plan of Merger, dated February 22, 2023, (the “Merger Agreement”), by and among Notable Labs, Ltd., an Israeli corporation previously known as Vascular Biogenics, Ltd. (the “Company”), Vibrant Merger Sub Inc., a Delaware corporation and a wholly owned subsidiary of the Company (“Merger Sub”), and Notable Labs, Inc., a Delaware corporation previously known as Notable Labs, Inc. (“Notable”), Merger Sub was merged with and into Notable, with Notable continuing after the merger as the surviving entity and a wholly owned subsidiary of the Company (the “Merger”). In this Annual Report on Form 10-K, unless the context otherwise requires, references to “we,” “us,” “our,” “our company” and “Notable” refer to Notable Labs, Ltd. and its subsidiaries. References to “VBLT” refer to Vascular Biogenics, Ltd. prior to the Merger. For more information on the merger, see “Business - Notable Background and Corporate History - Merger” below.
Business Overview
Notable is a clinical-stage platform therapeutics company developing predictive precision medicines for patients with cancer. Through its proprietary Predictive Precision Medicines Platform or PPMP, Notable bio-simulates a patient’s cancer treatment ex vivo (outside of the body) and seeks to precisely predict whether or not an individual patient will clinically respond to their actual treatment. In four independent clinical validation trials with recognized medical centers, PPMP predicted responders with 83-100% precision. To pursue improved medical outcomes compared to traditional precision medicines, PPMP does not depend on genetic or other biomarkers. Instead, PPMP generates multi-dimensional measures of biological response of cells to drugs and then integrates and translates these data by computational algorithms into a patient response predictor.
PPMP is designed to enable Notable to identify and select patients expected to be clinically responsive prior to the initiation of their treatment and potentially enable fast-track therapeutic development in this patient population. Notable utilizes its PPMP to evaluate investigational compounds for in-licensing and development or co-development that have shown clinical activity, with the goal of improving patient response and the success, speed and value of developing these compounds, compared with traditional drug development.
Using PPMP, Notable targets in-licensing assets that have already demonstrated compelling clinical activity but have been abandoned because the activity was limited to a subset of 10% to 30% of treated patients, a likely hurdle to successful development, regulatory approval, and commercialization. Notable has screened and evaluated hundreds of assets on its PPMP platform, and for many of these assets, believes it can predict with relatively high precision which patients will clinically respond. This provides Notable with the opportunity to selectively enroll predicted responders into clinical trials, and thus to fast-track development of these assets selectively in clinical responders delivering higher response rates.
Notable is seeking to create a growing portfolio of predictive precision medicines using its PPMP. PPMP has already guided Notable in the selection of its first two candidate predictive precision medicines, two clinical-stage candidates for development in platform-predicted responders with acute myeloid leukemia (“AML”). Notable’s lead asset derived from PPMP is Volasertib, a polo like kinase 1 (“PLK1”) inhibitor proven to induce cell cycle arrest and apoptosis in various cancer cells. Notable expects to initiate a Phase 2 trial evaluating Volasertib in adult AML in the second quarter of 2024, which includes a dose optimization prelude targeting 6 patients. The results of these first 6 patients are expected in the fourth quarter of 2024, and the enrollment of the first PPMP-predicted responder is expected in the same quarter. In addition, Notable is co-developing, with CicloMed LLC (“CicloMed”), Fosciclopirox for patients with AML. This co-development partnership resulted from a successful pre-clinical application of PPMP for Fosciclopirox. Notable is also using PPMP to identify additional compelling assets for in-licensing and fast-tracking additional assets as it builds out its development pipeline.
By continually advancing and expanding the reach of the PPMP across patient segments, diseases and predicted medical outcomes, Notable aims to be the leader in predictive precision medicine and revolutionize the way in which patients seek and receive treatments that are most likely to work best for them - with major impact for patients and the healthcare community.
Predictive Precision Medicines Platform (“PPMP”)
Overview
Notable’s proprietary PPMP is a diagnostic platform that predicts - before treatment - an individual patient’s clinical response to a given treatment or treatment combination by measuring the biological response of the patient’s cancer and normal cells to that treatment or treatment combination ex vivo. Notable’s PPMP has been developed exclusively by teams of internal biologists, engineers and data scientists and, while currently fully functional, continues to evolve and improve, both from an efficiency as well as a predictive performance perspective.
Since Notable’s PPMP measures the cellular and cell-functional response of cancer cells to a treatment, it does not depend on and is not constrained by genetic biomarkers as opposed to traditional precision medicines that are designed to target a genetic mutation. For each patient sample analyzed, Notable’s PPMP produces a binary result - predicted responder or predicted non-responder. In four independent collaborative studies in collaboration with recognized academic institutions, Notable’s PPMP platform has demonstrated an 83-100% predictive precision (also referred to as, positive predictive value (“PPV”)), in identifying clinically responding patients. A predictive precision of 83-100% means that if a clinical trial selectively enrolled predicted responders, the study can be expected to yield an 83-100% response rate. In addition, Notable’s PPMP predicted the clinical outcome of a fosciclopirox Phase 2a trial with 100% accuracy.
Notable’s strategic focus is to acquire treatments that have already shown compelling efficacy through other companies, but only in a 10-30% patient subset that other companies could not further enrich, deemed not suitable for their portfolio, and therefore declined to pursue further development. Using its proprietary PPMP, Notable targets and tests these compelling yet abandoned assets on its platform, and if its PPMP has been shown to identify this patient subset, in- licenses these compounds and fast-tracks their remaining development selectively for these patients. Using this strategy, Notable is seeking to particularly improve patient outcomes for patients with the highest medical needs (e.g., response rates of 0-50% by current standard of care).
Notable’s PPMP combines the power of biology with the power of technology, including engineering, digital technology, and computational data science. Instead of focusing on one genetic pathway or one other feature, PPMP measures the ex vivo biological response of cancer and normal cells to drugs across many signals and dimensions. Hundreds of thousands of data points per patient sample are then integrated and translated by computational algorithms into a patient response predictor that describes whether a patient is likely to respond to their actual treatment. Notable’s PPMP has been designed as a high-throughput, automated platform that enables virtuous learning cycles and continuous optimization, patient sample by patient sample. Notable’s laboratory is accredited by the College of American Pathologies (“CAP”).
For patients and physicians, the use of Notable’s PPMP is simple: A blood or bone marrow sample containing cancer cells and normal cells is shipped to Notable and is co-processed with a given drug or drugs under its optimized proprietary conditions. PPMP measures the differential behavior and response of the patient’s cancer cells versus normal cells down to the single cell level, and computational algorithms translate those hundreds of thousands of data points into a patient response predictor. PPMP establishes a patient’s predicted response within 3-5 days from sample receipt, and thus, within a clinically actionable timeframe.
Notable’s continuously growing data repository includes over 190 billion lines of data derived from the analysis of patients’ tissue, blood samples and clinical outcomes. This data repository is comprised entirely of internally generated data sets at single-cell resolution. It has been optimized over years of automated high-throughput screening and virtuous learning cycles. This proprietary data repository is Notable’s digital backbone and drives its strategy of expanding its platform capabilities from disease to disease and additional predicted medical outcomes.
Clinical Validation of PPMP
To date, Notable has conducted four clinical validation trials in collaboration with leaders in the field of hematology at globally recognized university hospitals. These studies assessed PPMP’s performance across several different blood cancers and multiple standard-of-care treatment options. The study designs, patient numbers, and standard of care therapies tested are summarized in the figure below.
All of the studies share a similar design:
● Patients are enrolled into the study immediately prior to receiving treatment;
● A baseline sample of peripheral blood or bone marrow is obtained and patient responses are assessed ex vivo on the Notable PPMP platform;
● Patients then receive treatment and the outcome of that treatment (response or no response) is then compared to the predicted outcome as obtained from the platform.
The performance of a predictive diagnostic test such as PPMP can be quantified using a variety of parameters, including sensitivity, specificity, overall accuracy, negative predictive value and positive predictive value. Because the ultimate intended use of the PPMP is to select patients most likely to respond to a given treatment, Notable believes the most relevant performance parameter is PPV. PPV is calculated as the percent of patients who achieved a clinical response to their actual treatment (actual clinical responders) among all patients with a positive patient response score on PPMP (PPMP-predicted responders). For example, a PPV of 50% means that, of all patients in a cohort predicted to respond based on PPMP results, 50% did clinically respond to their actual treatment. It should be noted that clinical response to therapy does not necessarily result in long-term cure of disease.
Results of studies conducted in hematologic disorders
Myelodysplastic Syndromes (MDS)
In collaboration with Stanford University, Notable conducted a clinical validation study to evaluate the performance of its PPMP in predicting treatment response in high-risk MDS patients. The study collected samples from September 2016 to March 2019 and encompassed various drug treatments for MDS. At the time of the study, 5-azacitidine and decitabine were FDA-approved treatments for MDS, while all other therapies, including clofarabine and cytarabine, bortezomib and dexamethasone, and 5-azacitidine and venetoclax were being investigated. Clinical response was evaluated using the international Working Group 2006 response criteria in MDS, defining response as complete remission (“CR”) and partial remission (“PR”). Peripheral blood and bone marrow were collected from patients immediately prior to treatment decision, and patient responsiveness to a panel of up to 74 single therapeutic agents and up to 36 therapeutic combinations were assessed on Notable’s PPMP. Clinical outcomes after treatment were assessed by Stanford physicians and compared to predicted outcomes based on PPMP. A total of 21 patients met all study requirements and were included in the overall analysis. Overall, Notable’s PPMP demonstrated a PPV of 100%, meaning that every patient the PPMP predicted would respond to their physician-selected treatment actually demonstrated a clinical response to the treatment. To achieve a more robust estimate of the predictive precision for the PPMP, bootstrapping, a statistical resampling technique, was utilized to simulate patient data, yielding a PPV of 92% [95% CI = 0.69-1.0]. Bootstrapping is a statistical procedure that resamples a single data set to create many simulated samples. This process allows for the calculation of standard errors (how far the sample average is from the likely population average) and confidence intervals (“CI”) (the range of average performance that 95% of bootstrapped simulations fall in).
Adult AML
In collaboration with MD Anderson Cancer Center, Notable conducted a clinical validation study examining the performance of its PPMP in predicting response to the standard-of-care treatment combination of venetoclax plus decitabine in AML patients. The study collected samples between August 2018 to February 2021 from patients receiving a combination of decitabine and venetoclax. Although this combination was not FDA-approved at the study’s onset, FDA approval for AML treatment was obtained one month later. Clinical response was evaluated using 2017 European LeukemiaNet (“ELN”) AML response criteria, defining response as CR and CR with incomplete count recovery (“Cri”). Peripheral blood was collected from patients prior to treatment, and patient responsiveness to the combination treatment was assessed on PPMP. Clinical response after a patient’s actual treatment was assessed and compared to PPMP-predicted response. A total of 9 patients met all study requirements and were included in the overall analysis. Overall, based on internal studies Notable’s PPMP demonstrated PPV of 83%, meaning that 83% of patients that the PPMP predicted would respond to their treatment did achieve a clinical response to the actual treatment. Bootstrapping sampling techniques yielded a PPV of 80 % [95% CI = 0.5-1.0].
In an additional collaboration with Washington University, a clinical validation study examined the performance of PPMP in predicting response to two different standard-of-care treatment combinations: venetoclax plus decitabine or cytarabine plus idarubicin in AML patients. The study collected samples between March 2020 to June 2022 from patients receiving either cytarabine and idarubicin or decitabine and venetoclax. This ongoing study continues to recruit patients. Clinical response was evaluated using 2017 ELN AML response criteria, defining response as CR, Cri, and morphologic leukemia-free state. Peripheral blood was collected from patients prior to treatment, and patient responsiveness to the combination treatment was assessed on Notable’s PPMP. Clinical outcome after the patients’ actual treatment was evaluated and compared to the PPMP-predicted response.
For the group receiving venetoclax plus decitabine, a total of 13 patients met all study requirements and were included in the overall analysis. Overall, Notable’s PPMP demonstrated a PPV of 100%, meaning that all patients that the PPMP predicted would respond to their treatment combination did achieve a clinical response to the actual treatment. Bootstrapping sampling techniques yielded a PPV of 86% [95% CI = 0.63-1.00].
For the group receiving cytarabine plus idarubicin, a total of 18 patients met all study requirements and were included in the overall analysis. Overall, Notable’s PPMP demonstrated a PPV of 100%, meaning that all patients that the PPMP predicted would respond to this treatment combination did achieve a clinical response to their actual treatment. Bootstrapping sampling techniques yielded a PPV of 100% [95% CI = 1.0-1.0].
Pediatric AML
In collaboration with Texas Children’s Hospital, Notable conducted a clinical validation study examining the performance of PPMP in predicting response to the standard-of-care treatment, the triple combination of cytarabine, daunorubicin, and etoposide (“ADE”) in pediatric The study collected samples from September 2015 to October 2020. Patients in the study were treated with conventional chemotherapy comprised of ADE with or without atovaquone, which was under investigation through a clinical trial (NCT03568994). Clinical response was evaluated based on 1-year relapse free survival (“RFS”) or minimal residual disease (“MRD”) being less than 1%. RFS represents the duration after treatment during which a patient remains free of disease and MRD refers to the small number of residual cancer cells post-treatment. AML patients. Peripheral blood and bone marrow were collected from patients prior to treatment, and patient responsiveness to the combination treatment was assessed on PPMP and compared to minimal residual disease (MRD) negativity or 1-year relapse-free survival; these clinical outcome measures are associated with durability of treatment. MRD and 1-year relapse-free survival were compared to predicted outcome based on PPMP.
For MRD negativity as an outcome, a total of 13 patients met all study requirements and were included in the overall analysis. Overall, Notable’s PPMP yielded a PPV of 100%, meaning that all PPMP-predicted responders did achieve MRD negativity in response to their actual treatment. Bootstrapping sampling techniques yielded a PPV of 100% [95% CI = 1.0-1.0].
For 1-year relapse-free survival as an outcome, a total of 13 patients met all study requirements and were included in the overall analysis. Overall, Notable’s PPMP demonstrated a PPV of 90% [95% CI = 0.9-1.0], meaning that 90% of PPMP-predicted responders did achieve 1-year relapse-free survival in response to their actual treatment. Bootstrapping sampling techniques yielded a PPV of 99% [95% CI = 0.9-1.0].
Complementary and Companion Diagnostic Tests
By identifying and validating which patients and patient segments respond or do not respond to available standard of care treatments - disease by disease - Notable is planning to expand its platform across liquid and solid tumors, and potentially beyond cancer. The continuously increasing understanding of individual patient populations, their predicted response to available and investigational treatments, and their unmet medical needs (e.g., patients without effective treatment options) can be expected to deliver proprietary intelligence and complementary diagnostics to fuel Notable’s targeted drug in-licensing and development strategy.
For example, having identified patient populations with high unmet needs (e.g., if less than 30% of patients respond to available standard of care treatments), enables a PPMP-based pursuit and in-licensing of investigational treatments for these patients and a focus on serving patients with highest medical needs through treatments with the greatest predicted medical and commercial impact.
In such a clinical development program for a predictive precision medicine, Notable’s platform is applied as a companion diagnostic guiding patient selection for patient enrollment and treatment.
Therapeutic Product Development
Volasertib
As described above, Notable’s business strategy is focused on the in-licensing and development of - often abandoned or shelved - therapeutic assets that have already shown compelling clinical activity in approximately 10-30% of patients who PPMP can be utilized to identify. Volasertib had been developed by Boehringer Ingelheim (“BII”) and has been clinically investigated through several trials in both solid tumor indications as well as in AML.
Background and Clinical Experience with Volasertib
In 2021, Notable obtained worldwide development and commercialization rights to Volasertib from Oncoheroes Biosciences Inc. (“Oncoheroes”), a Boston-based biotechnology company focused on advancing new therapies for childhood cancers. Volasertib is a PLK-1 inhibitor with demonstrated activity in AML and other tumor types, including solid tumors, with significant unmet medical need. Building on the performance of Volasertib on PPMP, which has been and is an important and proprietary step during Notable’s in-licensing decision making, Notable will leverage its PPMP with the goal to identify and select Volasertib-responsive patients prior to their treatment and enable Notable to potentially increase response rates and fast-track Volasertib’s clinical development in this patient population.
NCT0080485, a Phase 2 study in 87 AML patients conducted in European and US hematology centers, yielded CR plus Cri rates of 31.0% by the treatment of Volasertib plus low-dose cytarabine (V+LDAC) vs 13.3% by LDAC treatment alone, indicating that the addition of Volasertib to LDAC improved the response rate compared to low-dose cytarabine (“LDAC”) monotherapy. Median event-free survival was significantly prolonged by V+LDAC compared with LDAC (5.6 vs 2.3 months; hazard ratio, 0.57; 95% confidence interval, 0.35-0.92; P=.021); median overall survival was 8.0 vs 5.2 months, respectively (hazard ratio, 0.63; 95% confidence interval, 0.40-1.00; P=.047). With respect to toxicity, serious adverse events (CTCAE grade 3-5) were noted as follows: febrile neutropenia (fever and /or illness due to depressed white blood cell count) occurred in 23 patients (54.8%) for V+LDAC and 7 patients (15.6%) for LDAC. Infections (bacterial or viral in nature) and infestations (parasitic in nature) occurred in 20 patients (47.6%) for V+LDAC and 10 patients (22.2%) for LDAC (2,3).
In NCT01721876, a follow-up Phase 3 study in 666 AML patients with centers conducted across the world, however, the proportion of patients who achieved an overall response was 27.7% (V+LDAC) compared to 17.1% Placebo + LDAC (“P+LDAC”), suggesting that there was a Volasertib-mediated benefit in a subset of patients even if this difference did not achieve statistical significance. With respect to toxicity, AEs leading to death (grade 5) were reported with a higher frequency in the V+LDAC arm (31.2%) compared to the P+LDAC arm (18.0%), potentially driven by a higher incidence of infections and infestations in the V+LDAC arm (17.1% versus 6.3%). With respect to toxicity, Serious adverse events (CTCAE grade 3-5) were noted as follows: febrile neutropenia occurred in 258 patients (58.8%) for V+LDAC and 63 patients (28.4%) for P+LDAC. Infections and infestations occurred in 255 patients (58.1%) for V+LDAC and 85 patients (38.3%) for P+LDAC.
An additional seven early-stage trials were conducted, primarily in solid tumors including urothelial, ovarian and non-small cell lung cancers. The results of these trials demonstrated that Volasertib was generally well-tolerated. With respect to toxicity, serious adverse events in Volasertib-treated patients were noted as follows: neutropenia occurred in 55 patients (29.2%), anemia (decreased red blood cell production) occurred in 16 patients (8.5%), thrombocytopenia (decrease platelet production) occurred in 19 patients (10.1%), and leukopenia (decreased leukocyte production) occurred in 9 patients (4.8%).
In addition, BI initiated a Compassionate Use Program in 2015 for patients treated with Volasertib. In this program, as of November, 2021, seven patients are still treated with and respond to long-term treatment with Volasertib.
While leveraging BI’s Volasertib dataset and years of pre-clinical and clinical development, Notable will redesign Volasertib’s late-stage re-development program with the goal of increasing the clinical response rate and outcomes (by using Notable’s PPMP) and improving Volasertib’s tolerability (by enhanced patient management in line with BI’s conclusions from its post hoc phase 3 analysis):
To maximize clinical tolerability (reduce myelosuppression and infections) and thus Volasertib’s therapeutic index and trial success, Notable plans to enhance the design of Volasertib clinical trials beyond using PPMP to select patients likely to respond. Notable’s planned enhancements are:
- Tailored dosing: a 350 mg intravenous Volasertib dose was applied in the AML Phase 2 and 3 clinical trials irrespective of the patients’ body weight/body surface. BI’s post-hoc analysis showed that lighter patients were overdosed with this 350 mg dose, resulting in higher toxicity. Notable plans on using a tailored dose, adjusted for the patients’ weight/body surface.
- Infection control: It can be concluded that a substantial proportion of the lethal infections could have been prevented with appropriate precautions and protocol-mandated infectious prophylaxis. This might not have been in place in some of the study-participating centers especially in the global phase 3 trial.
- Combination partner. Volasertib was combined with LDAC in the AML Phase 2 and 3 clinical trials. In alignment with recognized medical experts, Notable may choose a different Volasertib combination partner.
To increase trial efficacy outcomes, Notable will use its PPMP to selectively enroll patients into its trials who are predicted to clinically respond to Volasertib. In order to assess the performance of PPMP in selecting for Volasertib sensitive patients, Notable conducted an ex vivo avatar trial in a prospective patient cohort using its PPMP. An ex vivo avatar trial involves testing drug responsiveness solely ex vivo; with no patients actually receiving the drug. An ex vivo avatar trial can be informative in assessing overall predictive assay performance; any results generated in such a study need to be further validated during actual patient trials before the assay can be defined as predictive. In this study, Notable collected patient samples from 65 AML patients and tested them on PPMP using a locked assay optimized to stratify predicted responders. PPMP predicted that 20 of 65 or approximately 30% of patients in this population would respond to treatment with Volasertib, which reflects the response rate that BI found in its Phase 2 study in AML, consistent with Notable’s belief that its PPMP platform can reliably identify AML patients who will respond to their actual Volasertib treatment in the planned clinical trials. Based on the PPMP results from these 65 patients, Notable predicts that between 50 and 100% of the participants in this trial have the potential to achieve a clinical response to their actual Volasertib treatment. It should be noted that clinical response alone does not necessarily guarantee that volasertib will demonstrate clinical efficacy or that it will prove to be safe as required to receive FDA or similar regulatory approval. The figure below is illustrative and does not reflect results from actual patient testing.
Notable’s development strategy for Volasertib leverages the experience from the four PPMP clinical validation trials and the recent 100% accurate PPMP prediction of a fosciclopirox’s trial outcome as reported in December 2023.
Notable plans to initiate a single-arm, open label Volasertib Phase 2 study in relapse/refractory AML (r/r AML) in the Coming months of 2024. Upon a successful Phase 2 study focused on PPMP-predicted responders to volasertib, Notable plans to initiate a registrational Phase 3 study. From a regulatory perspective, Notable’s use of PPMP as a patient selection tool qualifies PPMP as a companion diagnostic by FDA criteria and will require a Pre-Marketing Approval (“PMA”) submission in concert with any NDA submission for volasertib. Marketing of Volasertib will require approval of both the companion diagnostic PMA submission as well as the Volasertib NDA submission.
Notable anticipates filing an IND in the first quarter of 2024, initiating the Phase 2 program in the second quarter of 2024, delivering the data of a Phase 2 dose optimization prelude targeting six patients in the fourth quarter of 2024, and enrolling the first PPMP-selected patient in the fourth quarter of 2024.
Oncoheroes License Agreement
On October 8, 2021, Notable entered into an Exclusive License Agreement (the “Oncoheroes Agreement,”) with Oncoheroes Biosciences Inc. (“Oncoheroes”), pursuant to which Notable acquired worldwide exclusive development and commercialization rights in the small molecule Volasertib for uses relating to certain types of blood cancers and all other cancers outside the indications retained by Oncoheroes under the Oncoheroes Agreement, which generally comprise indications focused on pediatric solid tumors (the “Licensed Field”). The Licensed Field includes: Acute Lymphoblastic Leukemia; Acute Megakaryocytic Leukemia; Acute Myeloblastic Leukemia; Acute Myelogenous Leukemia; Acute Myeloid Leukemia; Acute Myelomonocytic Leukemia; Acute Promyelocytic Leukemia; Chronic lymphoblastic leukemia; Chronic myelocytic leukemia; Chronic myelogenous leukemia; Chronic myeloid leukemia; Juvenile myelomonocytic leukemia; Hodgkin’s disease; Leukemia; Lymphoma (Anaplastic large cell and Large B cell); and Non-Hodgkin’s Lymphoma. In connection with the Oncoheroes Agreement, as of October 8, 2021, Notable and Oncoheroes entered into a Simple Agreement for Future Equity (“Oncoheroes SAFE”) in the amount of $1,500,000, pursuant to whereby Notable obtained the rights to acquire certain shares of Oncoheroes’ capital stock.
Pursuant to the terms of an Assignment and Licensing Agreement dated August 1, 2019, as amended on April 5, 2020 and October 2021 (the “BII Agreement”), by and between Oncoheroes and Boehringer Ingelheim International GmbH (“BII”), Oncoheroes acquired the certain assigned patents (“Assigned Patents”) and rights to develop and commercialize certain licensed products (“Licensed Products”). Pursuant to the Oncoheroes Agreement, Notable obtained from Oncoheroes the rights and licenses to develop and commercialize the Licensed Products, on the terms and conditions set forth in the Oncoheroes Agreement. The Company has a right of first refusal and right of first negotiation if Oncoheroes decides to license, sell, assign or transfer its rights or terminate the underlying licenses granted in the BII Agreement.
Under the Oncoheroes Agreement, Notable is required to pay Oncoheroes a royalty on the gross amount invoiced by Notable, its affiliates or sublicensees for the sale of Licensed Products in an arm’s length transaction to third parties (but not including sales relating to transactions between Notable, its affiliates or their respective sublicensees), less the total of certain charges or expenses as listed in the Oncoheroes Agreement (“Net Sales”) in the Licensed Field in a worldwide territory. Additionally, Notable is required to pay Oncoheroes up to an aggregate of $8 million in milestone payments upon the occurrence of certain development milestone events.
Under the Oncoheroes Agreement, Notable is required to pay Oncoheroes a royalty on Net Sales of the Licensed Products in the Licensed Field based on a sliding scale range of Net Sales, with such royalty percentage ranging from the mid-single digits to the mid-teens. Notable’s obligation to pay royalties will commence upon the commercial launch of a licensed product on a country-by-country basis in the licensed field, and will terminate, on a country-by-country basis, upon the later of (a) expiration of the last valid claim of a licensed patent in such country, (b) expiration of applicable data or other regulatory exclusivity rights, and (c) ten years from Commercial Launch of such licensed product in such country.
Pursuant to the Oncoheroes Agreement, Notable’s rights to the Assigned Patents shall continue on a country-by-country basis in each country until the expiration of Notable’s obligation to pay royalties, unless otherwise terminated as follows: (a) termination by Oncoheroes upon a material breach of the Oncoheroes Agreement by Notable, or upon Notable’s insolvency, or (b) termination by Notable (i) upon a material breach of the Oncoheroes Agreement by Oncoheroes, (ii) upon Oncoheroes’s insolvency, (iii) in the event of a termination of the underlying BII Agreement, or, (iv) at any time, either in whole or with respect to a specific Licensed Product in a specific country, with ninety (90) days written notice to Oncoheroes. Notable has the option to assume rights and obligations of Oncoheroes as licensee of BII in case of termination of the Oncoheroes Agreement.
Manufacturing
Notable relies on third parties to manufacture Volasertib. Notable has entered into agreements with contract manufacturing organizations, or CMOs, to produce drug substance for Volasertib. Notable requires all of its CMOs to conduct manufacturing activities in compliance with current good manufacturing practice, or cGMP, requirements. Notable anticipates that these CMOs will have the capacity to support both clinical supply and commercial-scale production, but Notable does not have any formal agreements at this time to cover commercial production. Notable may also elect to enter into agreements with other CMOs to manufacture supplies of drug substance and finished drug product.
Sales and Marketing
If any of Notable’s product candidates are approved, Notable intends to market and commercialize them in the U.S. and select international markets, either alone or in partnership with others. Cancer patients are managed by oncologists, medical geneticists and neurologists, and therefore Notable believes can be reached with a targeted sales force.
Competition for Volasertib
The pharmaceutical industry is characterized by rapid evolution of technologies and intense competition. While Notable believes that its product candidates, technology, knowledge, experience and scientific resources provide superior competitive advantages, it faces competition from major pharmaceutical and biotechnology companies, academic institutions, governmental agencies and public and private research institutions, among others. Any product candidates that Notable successfully develops and commercializes will compete with approved treatment options, including off-label therapies, and new therapies that may become available in the future. Key considerations that would impact Notable’s ability to effectively compete with other therapies include the efficacy, safety, method of administration, cost, level of promotional activity and intellectual property protection of Notable’s products. Many of the companies against which Notable may compete have significantly greater resources and capital than Notable in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals and marketing approved products.
While there are no current FDA-approved PLK1 inhibitors, there are several at various stages of clinical development. Onvansertib (Cardiff Oncology, Inc.), GSK461364 (GSK, plc), rigosertib (Onconova Therapeutics, Inc.) and CY140 (Cyclacel Pharmaceuticals, Inc.) all demonstrate PLK1 inhibition and are being developed in a number of solid and hematologic malignancies. There may be additional companies with PLK1 inhibitor programs suitable for addressing these patient populations that could be competitive with Notable’s efforts but that have not yet disclosed specific clinical development plans. Smaller or early-stage companies, including oncology-focused therapeutics companies, may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies. These companies may also compete with Notable in recruiting and retaining qualified scientific and management personnel, establishing clinical trial sites, enrolling patients in clinical trials and acquiring technologies complementary to, or necessary for, Notable programs. The availability of reimbursement from government and private payors will also significantly impact the pricing and competitiveness of Notable products if approved. Notable’s competitors may obtain FDA or other regulatory approvals for their products more rapidly than Notable may obtain approvals for its product candidates, which could result in its competitors establishing a strong market position before Notable will be able to commercialize its products if approved.
Fosciclopirox (CPX-POM)
On July 20, 2021, Notable entered into a Co-Development and Profit-Sharing Agreement (the “CicloMed Agreement”) with CicloMed LLC (“CicloMed”) regarding use of Notable’s precision oncology diagnostic test in the research and development of CicloMed’s CicloProx Prodrug (“CPX-POM”) product for the treatment of AML. Under the terms of the CicloMed Agreement the parties will share equally in the co-development costs, subject to a budget controlled by a joint steering committee appointed by the parties. In the event of a profit generating event, the net proceeds will be shared between the parties in accordance with the agreement’s defined compensation share which is generally on a 50/50 basis, provided that Notable’s maximum compensation share shall not exceed a mid-single digit multiple of its total incurred co-development costs. The compensation share is a percentage corresponding to the ratio of (i) a party’s total co-development costs incurred pursuant to the co-development plan to (ii) the sum of the total co-development costs incurred by both parties pursuant to such plan. As between the parties, CicloMed will own all co-development intellectual property that relates solely to CPX-POM and CPX-POM results, and Notable will own all co-development intellectual property that relates solely to the Notable test and the test results, and each party retains its own background and prior intellectual property.
Background and Clinical Experience with Fosciclopirox
Fosciclopirox (CPX-POM), a pro-drug of ciclopirox invented by scientists at The University of Kansas Cancer Center and the Institute for Advancing Medical Innovation, selectively delivers the active metabolite, CPX, to the entire urinary tract following parenteral administration. CPX inhibited cell proliferation, clonogenicity and spheroid formation, and increased cell cycle arrest at S and G0/G1 phases. Mechanistically, CPX suppressed activation of Notch signaling. Molecular modeling and cellular thermal shift assays demonstrated CPX binding to γ-secretase complex proteins Presenilin 1 and Nicastrin, which are essential for Notch activation.
To establish in vivo preclinical proof of principle, Fosciclopirox was tested in the validated N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) mouse bladder cancer model. Once-daily intraperitoneal administration of CPX-POM for four weeks at doses of 235 mg/kg and 470 mg/kg significantly decreased bladder weight, a surrogate for tumor volume, and resulted in a migration to lower stage tumors in CPX-POM treated animals. This was coupled with a reduction in the proliferation index. Additionally, there was a reduction in Presenilin 1 and Hes-1 expression in the bladder tissues of CPX-POM treated animals.
Following the completion of the first-in-human Phase 1 trial (NCT03348514), the pharmacologic activity of Fosciclopirox is currently being characterized in a Phase 1 expansion cohort study of muscle-invasive bladder cancer patients scheduled for cystectomy (NCT04608045) as well as a Phase 2 trial of newly diagnosed and recurrent urothelial cancer patients scheduled for transurethral resection of bladder tumors (NCT04525131).
In July 2021, under the terms of the CicloMed Agreement, CicloMed initiated a Phase 1b/2a clinical trial of Fosciclopirox in adult patients with relapsed or refractory AML (NCT04956042). As part of the trial, patients enrolled into the study assessed sensitivity to Fosciclopirox on Notable’s PPMP. Patients were not selected for enrollment based on PPMP results and, to avoid potential bias, PPMP analysis was blinded to the actual patient outcomes during the trial. Clinical efficacy in this heavily pretreated group of patients was defined by standard criteria in AML medical research and practice.
In December 2023, Notable reported on topline results from this trial. Eighteen heavily pre-treated patients were enrolled in the trial with nine patients evaluable for response assessment per-protocol. Fosciclopirox, administered at the Recommended Phase 2 Dose, was well-tolerated. However, none of the nine evaluable patients achieved a complete response. Stable disease, over four months, was observed in two evaluable patients.
Importantly, PPMP predicted that all patients enrolled into this trial would be non-responsive to Fosciclopirox. The accuracy of this prediction was confirmed by the actual patient responses to treatment. These PPMP results indicate that the enrolled patient population was biased towards non-responsiveness to Fosciclopirox and suggest that the negative clinical outcome of this Phase 2a trial may have been avoided if PPMP had initially been used to selectively enroll only predicted responders. Further analyses are ongoing.
Intellectual Property
Notable’s success depends in part on its ability to obtain and maintain proprietary protection for its product candidates, manufacturing and process discoveries and other know-how, to operate without infringing the proprietary rights of others, and to prevent others from infringing Notable’s proprietary rights. Notable plans to protect its proprietary positions using a variety of methods, which include protecting current U.S. and foreign patents related to proprietary technology, inventions and improvements and prosecuting additional U.S. and foreign patents that Notable determines are important to the development and implementation of its business. For example, Notable, its licensors, or Notable’s collaborators currently have, or are pursuing, patents covering the composition of matter for its drug product candidates and Notable plans to generally pursue patent protection covering methods-of-use for one or more clinical programs. Notable also relies on trade secrets, trademarks, know-how, continuing technological innovation and potential in-licensing opportunities to develop and maintain Notable’s proprietary position.
Volasertib Patents
Notable entered into the Oncoheroes License Agreement in October 2021, pursuant to which Notable acquired exclusive worldwide rights under sixty-two (62) patents and patent applications to develop, manufacture and commercialize Volasertib. Notable has exclusive licenses under the Oncoheroes License Agreement to patent rights in the U.S. and numerous foreign jurisdictions relating to Volasertib. The patent rights in-licensed under the Oncoheroes License Agreement include nineteen (19) granted patents and one (1) patent application in the U.S., and forty (40) granted patents and two (2) patent applications in foreign jurisdictions including the European Patent Office, Germany, France, United Kingdom, and Japan. All three (3) U.S. patents in the patent family covering Volasertib as a composition of matter generally in genus form expired on February 26, 2023. The two (2) U.S. patents in the patent family covering Volasertib as a composition of matter along with its various crystalline forms expire on January 30, 2027. The U.S. composition of matter patent that covers the formulation of Volasertib that is currently in clinical development expires on June 29, 2026, in each case, not including patent term adjustment or any patent term extension, and relevant foreign counterparts.
Trade Secrets
In addition to patents, Notable relies on trade secrets and know-how to develop and maintain its competitive position. Notable typically relies on trade secrets to protect aspects of its business that are not amenable to, or that it does not consider appropriate for, patent protection. The PPMP includes Notable’s trade secrets. However, the PPMP is not currently covered by a patent and no patents are pending. Notable protects trade secrets and know-how by establishing confidentiality agreements and invention assignment agreements with its employees, consultants, scientific advisors, contractors and partners. These agreements generally provide that all confidential information developed or made known during the course of an individual or entity’s relationship with Notable must be kept confidential during and after the relationship. These agreements also generally provide that all inventions resulting from work performed for Notable or relating to its business and conceived or completed during the period of employment or assignment, as applicable, shall be Notable’s exclusive property. In addition, Notable takes other appropriate precautions, such as physical and technological security measures, to guard against misappropriation of our proprietary information by third parties.
Government Regulation
Approval of Volasertib and Other Drug Products in the United States
Government authorities in the United States (“U.S.”) at the federal, state and local level and in other countries and jurisdictions, including the European Union (“EU”), extensively regulate, among other things, the research, development, testing, manufacture, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, post-approval monitoring and reporting, marketing and export and import of drug products, such as Volasertib. Generally, before a new drug can be marketed, considerable data demonstrating its quality, safety and efficacy must be obtained, organized into a format specific for each regulatory authority and submitted for review and approved by the regulatory authority.
Overview of FDA Approval Process
In the U.S., pharmaceutical products are subject to extensive regulation by the FDA. The Federal Food, Drug, and Cosmetic Act (“FDCA”), and other federal and state statutes and regulations, govern, among other things, the research, development, testing, manufacture, storage, recordkeeping, approval, labeling, promotion and marketing, distribution, post-approval monitoring and reporting, sampling, and import and export of pharmaceutical products. Failure to comply with applicable U.S. requirements may subject a company to a variety of administrative or judicial sanctions, such as FDA refusal to approve pending NDAs, warning or untitled letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, civil penalties and criminal prosecution.
Pharmaceutical product development for a new product or certain changes to an approved product in the U.S. typically involves preclinical laboratory and animal tests, the submission to the FDA of an IND, which must become effective before clinical testing may commence, and adequate and well-controlled clinical trials to establish the safety and effectiveness of the drug for each indication for which FDA approval is sought. Satisfaction of FDA pre-market approval requirements typically takes many years and the actual time required may vary substantially based upon the type, complexity and novelty of the product or disease.
Preclinical tests include laboratory evaluation of product chemistry, formulation and toxicity, as well as animal trials to assess the characteristics and potential safety and efficacy of the product. The conduct of the preclinical tests must comply with federal regulations and requirements, including good laboratory practices. The results of preclinical testing are submitted to the FDA as part of an IND along with other information, including information about product chemistry, manufacturing and controls and a proposed clinical trial protocol. Long term preclinical tests, such as animal tests of reproductive toxicity and carcinogenicity, may continue after the IND is submitted. A 30-day waiting period after the submission of each IND is required prior to the commencement of clinical testing in humans. If the FDA has neither commented on nor questioned the IND within this 30-day period, the clinical trial proposed in the IND may begin.
The clinical stage of development involves the administration of the investigational product to healthy volunteers or disease-affected patients under the supervision of qualified investigators, generally physicians not employed by, or under control of, the trial sponsor, in accordance with Good Clinical Practices (“GCPs”), which include the requirement that all research subjects provide their informed consent for their participation in any clinical trial. Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria and the parameters to be used to monitor subject safety and assess efficacy. Each protocol, and any subsequent amendments to the protocol, must be submitted to the FDA as part of an IND. Furthermore, each clinical trial must be reviewed and approved by an IRB for each institution at which the clinical trial will be conducted to ensure that the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits. The IRB also approves the informed consent form that must be provided to each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed. There also are requirements governing the reporting of ongoing clinical trials and completed clinical trial results to public registries. Information about most clinical trials must be submitted within specific timeframes for publication on the www.clinicaltrials.gov website. Information related to the product, patient population, phase of investigation, trial sites and investigators and other aspects of the clinical trial is made public as part of the registration of the clinical trial. Sponsors are also obligated to discuss the results of their clinical trials after completion. Disclosure of the results of these trials can be delayed in some cases for up to two years after the date of completion of the trial. Competitors may use this publicly available information to gain knowledge regarding the progress of development programs. Human clinical trials are typically conducted in three sequential phases, which may overlap or be combined:
● Phase 1 clinical trials generally involve a small number of healthy volunteers or disease-affected patients who are initially exposed to a single dose and then multiple doses of the product candidate. The primary purpose of these clinical trials is to assess the metabolism, pharmacologic action, side effect tolerability and safety of the drug.
● Phase 2 clinical trials involve studies in disease-affected patients to determine the dose required to produce the desired benefits. At the same time, safety and further pharmacokinetic and pharmacodynamic information is collected, possible adverse effects and safety risks are identified, and a preliminary evaluation of efficacy is conducted.
● Phase 3 clinical trials generally involve a larger number of patients at multiple sites and are designed to provide the data necessary to demonstrate the effectiveness of the product for its intended use, its safety in use and to establish the overall benefit/risk relationship of the product and provide an adequate basis for product approval. These trials may include comparisons with placebo and/or other comparator treatments. The duration of treatment is often extended to mimic the actual use of a product during marketing.
A registrational trial is a clinical trial that adequately meets regulatory agency requirements for the evaluation of a drug candidate’s efficacy and safety such that it can be used to justify the approval of the drug. Generally, registrational trials are Phase 3 trials but may be Phase 2 trials if the trial design provides a reliable assessment of clinical benefit, particularly in situations where there is an unmet medical need.
Post-approval trials, sometimes referred to as Phase 4 clinical trials, may be conducted after initial marketing approval. These trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication, particularly for long-term safety follow up. In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of an NDA.
Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and more frequently if serious adverse events occur. The FDA or the sponsor may suspend or terminate a clinical trial at any time, or the FDA may impose other sanctions on various grounds, including a finding that the research patients are being exposed to an unacceptable health risk. Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the requirements of the IRB or if the drug has been associated with unexpected serious harm to patients.
After completion of the required clinical testing, an NDA is prepared and submitted to the FDA. FDA approval of the NDA is required before marketing of the product may begin in the U.S. The NDA must include the results of all preclinical, clinical and other testing and a compilation of data relating to the product’s pharmacology, chemistry, manufacture and controls. The cost of preparing and submitting an NDA is substantial. The submission of most NDAs is additionally subject to a substantial application user fee and the manufacturer and/or sponsor under an approved NDA are also subject to annual program fees for eligible products.
The FDA has 60 days from its receipt of an NDA to determine whether the application will be accepted for filing based on the agency’s threshold determination that it is sufficiently complete to permit substantive review. Once the submission is accepted for filing, the FDA begins an in-depth review. The FDA has agreed to certain performance goals in the review of NDAs. FDA aims to complete its standard review of drug products within ten months and its priority review within six months. Priority review can be applied to drugs that the FDA determines offer major advances in treatment or provide a treatment where no adequate therapy exists. The review process for both standard and priority review may be extended by FDA for three additional months to consider certain late-submitted information, or information intended to clarify information already provided in the submission.
The FDA may also refer applications for novel drug products, or drug products that present difficult questions of safety or efficacy, to an advisory committee-typically a panel that includes clinicians and other experts-for review, evaluation and a recommendation as to whether the application should be approved. The FDA is not bound by the recommendation of an advisory committee, but it generally follows such recommendations. Before approving an NDA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP. Additionally, the FDA will inspect the facility or the facilities at which the drug is manufactured. FDA will not approve the product unless compliance with cGMP is satisfactory and the NDA contains data that provide substantial evidence that the drug is safe and effective in the indication studied.
After the FDA evaluates the NDA and the manufacturing facilities, it issues either an approval letter or a complete response letter. A complete response letter generally outlines the deficiencies in the submission and may require substantial additional testing, or information, in order for the FDA to reconsider the application. If, or when, those deficiencies have been addressed to the FDA’s satisfaction in a resubmission of the NDA, the FDA will issue an approval letter. FDA has committed to reviewing such resubmissions in two or six months depending on the type of information included.
An approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications. As a condition of NDA approval, the FDA may require a risk evaluation and mitigation strategy, or REMS, to help ensure that the benefits of the drug outweigh the potential risks. REMS can include medication guides, communication plans for healthcare professionals and elements to assure safe use, or ETASU. ETASU can include, but are not limited to, special training or certification for prescribing or dispensing, dispensing only under certain circumstances, special monitoring and the use of patient registries. The requirement for a REMS can materially affect the potential market and profitability of the drug. Moreover, product approval may require substantial post-approval testing and surveillance to monitor the drug’s safety or efficacy. Once granted, product approvals may be withdrawn if compliance with regulatory standards is not maintained or problems are identified following initial marketing.
Changes to some of the conditions established in an approved application, including changes in indications, labeling or manufacturing processes or facilities, require submission and FDA approval of a new NDA or NDA supplement before the change can be implemented. An NDA supplement for a new indication typically requires clinical data similar to that in the original application, and the FDA uses the same procedures and actions in reviewing NDA supplements as it does in reviewing NDAs.
U.S. Exclusivity
Upon NDA approval of a new chemical entity(“NCE”), which is a drug that contains no active moiety that has been approved by FDA in any other NDA, that drug receives five years of marketing exclusivity during which FDA cannot receive any Abbreviated New Drug Application (“ANDA”), seeking approval of a generic version of that drug. Certain changes to a drug, such as the addition of a new indication to the package insert, are associated with a three-year period of exclusivity during which FDA cannot approve an ANDA for a generic drug that includes the change. An ANDA may be submitted one year before NCE exclusivity expires if a Paragraph IV certification is filed. If there is no listed patent in the Orange Book, there may not be a Paragraph IV certification, and, thus, no ANDA may be filed before the expiration of the exclusivity period.
Patent Term Extension
After NDA approval, owners of relevant drug patents may apply for up to a five-year patent extension for one patent. The allowable patent term extension is calculated as half of the drug’s testing phase-the time between IND and NDA submission-and all of the review phase-the time between NDA submission and approval up to a maximum of five years. The time can be shortened if FDA determines that the applicant did not pursue approval with due diligence. The total patent term after the extension may not exceed 14 years from approval.
For patents that might expire during the application phase, the patent owner may request an interim patent extension. An interim patent extension increases the patent term by one year and may be renewed up to four times. For each interim patent extension granted, the post-approval patent extension is reduced by one year. The director of the U.S. Patent and Trademark Office must determine that approval of the drug covered by the patent for which a patent extension is being sought is likely. Interim patent extensions are not available for a drug for which an NDA has not been submitted.
Fast Track Designation and Accelerated Approval
The FDA is required to facilitate the development, and expedite the review, of drugs that are intended for the treatment of a serious or life-threatening disease or condition for which there is no effective treatment, and which demonstrate the potential to address unmet medical needs for the condition. Under the Fast Track program, the sponsor of a new drug candidate may request that the FDA designate the drug candidate for a specific indication as a Fast Track drug concurrent with, or after, the filing of the IND for the drug candidate. The FDA must determine if the drug candidate qualifies for Fast Track Designation within 60 days of receipt of the sponsor’s request.
In addition to other benefits such as the ability engage in more frequent interactions with the FDA, the FDA may initiate review of sections of a Fast Track drug’s NDA before the application is complete. This rolling review is available if the applicant provides, and the FDA approves, a schedule for the submission of the remaining information and the applicant pays applicable user fees. However, the FDA’s time period goal for reviewing an application does not begin until the last section of the NDA is submitted. Additionally, the Fast Track Designation may be withdrawn by the FDA if the FDA believes that the designation is no longer supported by data emerging in the clinical trial process.
Under the FDA’s accelerated approval regulations, the FDA may approve a drug for a serious or life-threatening illness that provides meaningful therapeutic benefit to patients over existing treatments based upon a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity or prevalence of the condition and the availability or lack of alternative treatments.
In clinical trials, a surrogate endpoint is a measurement of laboratory or clinical signs of a disease or condition that substitutes for a direct measurement of how a patient feels, functions or survives. Surrogate endpoints can often be measured more easily or more rapidly than clinical endpoints. A drug candidate approved on this basis is subject to rigorous post-marketing compliance requirements, including the completion of Phase 4 or post-approval clinical trials to confirm the effect on the clinical endpoint. Under the Food and Drug Omnibus Reform Act of 2022 (“FDORA”), the FDA may require, as appropriate, that such trials be underway prior to approval or within a specific time period after the date of approval for a product granted accelerated approval. Failure to conduct required post-approval studies, or confirm a clinical benefit during post-marketing studies, will allow the FDA to withdraw the drug from the market on an expedited basis. The FDA generally requires, unless otherwise informed by the agency, that all promotional materials for product candidates approved under accelerated regulations be subject to prior review by the FDA.
Breakthrough Therapy Designation
Breakthrough therapy designation by the FDA provides more extensive development consultation opportunities with FDA senior staff, allows for the rolling review of the drug’s application for approval and indicates that the product could be eligible for priority review if supported by clinical data at the time of application submission for drugs that are intended to treat a serious or life-threatening disease or condition where preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. Under the breakthrough therapy program, the sponsor of a new drug candidate may request that the FDA designate the drug candidate for a specific indication as a breakthrough therapy concurrent with, or after, the filing of the IND for the drug candidate. The FDA must determine if the drug candidate qualifies for breakthrough therapy designation within 60 days of receipt of the sponsor’s request.
Approval of Volasertib and Other Drug Products in the European Union
Overview
In the EU, Notable’s product candidates also may be subject to extensive regulatory requirements. As in the U.S., medicinal products can be marketed only if a marketing authorization from the competent regulatory agencies has been obtained. Similar to the U.S., the various phases of preclinical and clinical research in the EU are subject to significant regulatory controls.
The Clinical Trials Directive 2001/20/EC, the Directive 2005/28/EC on GCP, and the related national implementing provisions of the individual EU Member States govern the system for the approval of clinical trials in the EU. Under this system, an applicant must obtain prior approval from the competent national authority of the EU Member States in which the clinical trial is to be conducted. Furthermore, the applicant may only start a clinical trial at a specific trial site after the competent ethics committee has issued a favorable opinion. The clinical trial application must be accompanied by, among other documents, an IMPD, or the Common Technical Document, with supporting information prescribed by Directive 2001/20/EC, Directive 2005/28/EC, where relevant the implementing national provisions of the individual EU Member States and further detailed in applicable guidance documents. All suspected unexpected serious adverse reactions to the investigated drug that occur during the clinical trial have to be reported to the competent national authority and the Ethics Committee of the Member State where they occurred.
In April 2014, the new Clinical Trials Regulation, (EU) No 536/2014 was adopted. The Clinical Trials Regulation will be directly applicable in all the EU Member States, repealing the current Clinical Trials Directive 2001/20/EC. Conduct of all clinical trials performed in the EU will continue to be bound by currently applicable provisions until the new Clinical Trials Regulation becomes applicable. The extent to which ongoing clinical trials will be governed by the Clinical Trials Regulation will depend on when the Clinical Trials Regulation becomes applicable and on the duration of the individual clinical trial. If a clinical trial continues for more than three years from the day on which the Clinical Trials Regulation becomes applicable the Clinical Trials Regulation will at that time begin to apply to the clinical trial.
The new Clinical Trials Regulation aims to simplify and streamline the approval of clinical trials in the EU. The main characteristics of the regulation include: a streamlined application procedure via a single-entry point, the “EU portal”; a single set of documents to be prepared and submitted for the application as well as simplified reporting procedures for clinical trial sponsors; and a harmonized procedure for the assessment of applications for clinical trials, which is divided in two parts. Part I is assessed by the competent authorities of all EU Member States in which an application for authorization of a clinical trial has been submitted (Member States concerned). Part II is assessed separately by each Member State concerned. Strict deadlines have been established for the assessment of clinical trial applications. The role of the relevant ethics committees in the assessment procedure will continue to be governed by the national law of the concerned EU Member State. However, overall related timelines will be defined by the Clinical Trials Regulation.
To obtain a marketing authorization of a drug in the EU, Notable may submit Marketing Authorization Applications (“MAA”), either under the so-called centralized or national authorization procedures.
Centralized Procedure
The centralized procedure provides for the grant of a single marketing authorization following a favorable opinion by the European Medicines Agency (“EMA”), that is valid in all EU Member States, as well as Iceland, Liechtenstein and Norway. The centralized procedure is compulsory for medicines produced by specified biotechnological processes, products designated as orphan medicinal products, advanced therapy medicines (such as gene-therapy, somatic cell-therapy or tissue-engineered medicines) and products with a new active substance indicated for the treatment of specified diseases, such as HIV/AIDS, cancer, diabetes, neurodegenerative disorders or autoimmune diseases and other immune dysfunctions and viral diseases. The centralized procedure is optional for products that represent a significant therapeutic, scientific or technical innovation, or whose authorization would be in the interest of public health. Under the centralized procedure the maximum timeframe for the evaluation of an MAA by the EMA is 210 days, excluding clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the Committee of Medicinal Products for Human Use (“CHMP”). Accelerated assessment might be granted by the CHMP in exceptional cases, when a medicinal product is expected to be of a major public health interest, particularly from the point of view of therapeutic innovation. The timeframe for the evaluation of an MAA under the accelerated assessment procedure is of 150 days, excluding stop-clocks.
National Authorization Procedures
There are also two other possible routes to authorize medicinal products in several EU countries, which are available for investigational medicinal products that fall outside the scope of the centralized procedure:
● Decentralized procedure. Using the decentralized procedure, an applicant may apply for simultaneous authorization in more than one EU country of medicinal products that have not yet been authorized in any EU country and that do not fall within the mandatory scope of the centralized procedure.
● Mutual recognition procedure. In the mutual recognition procedure, a medicine is first authorized in one EU Member State, in accordance with the national procedures of that country. Following this, further marketing authorizations can be sought from other EU countries in a procedure whereby the countries concerned agree to recognize the validity of the original, national marketing authorization.
Under the above described procedures, before granting an MAA, the EMA or the competent authorities of the Member States of the European Economic Area (“EEA”), make an assessment of the risk-benefit balance of the product on the basis of scientific criteria concerning its quality, safety and efficacy.
EU Regulatory Exclusivity
In the EU, new products authorized for marketing (i.e., reference products) qualify for eight years of data exclusivity and an additional two years of market exclusivity upon marketing authorization. The data exclusivity period prevents generic applicants from relying on the preclinical and clinical trial data contained in the dossier of the reference product when applying for a generic marketing authorization in the EU during a period of eight years from the date on which the reference product was first authorized in the EU. The market exclusivity period prevents a successful generic applicant from commercializing its product in the EU until ten years have elapsed from the initial authorization of the reference product in the EU. The ten-year market exclusivity period can be extended to a maximum of eleven years if, during the first eight years of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies.
Drug Approval-Related Regulations - Rest of the World
For other countries outside of the EU and the U.S., such as countries in Eastern Europe, Latin America or Asia, the requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement vary from jurisdiction to jurisdiction. However, many countries refer to and/or reference the US FDA or EMA review and approval information package which may facilitate and expedite the process in those countries. Nevertheless, the clinical trials must be conducted in accordance with cGCP requirements and the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki. If a sponsor fails to comply with applicable foreign regulatory requirements, Notable may be subject to, among other things, fines, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution.
Regulation of Notable’s Predictive Precision Medicine Platform Tests (PPMP Tests)
CLIA and CMS for Diagnostics
The Centers for Medicare & Medicaid Services (“CMS”), an agency within the U.S. Department of Health and Human Services, regulates all clinical laboratory testing (except research) performed on humans in the United States through the Clinical Laboratory Improvements Amendments of 1988 (“CLIA”). All clinical laboratories that perform clinical lab services on human specimens for the purpose of providing information on the diagnosis, prevention or treatment of disease must receive CLIA certification. Laboratories must obtain CLIA certification and demonstrate compliance with CLIA requirements as confirmed by an inspection by CMS. Notable received its initial CLIA certification in 2018. Notable’s laboratory was additionally certified by CAP, in 2021, an organization recognized by CMS as a third-party reviewer of clinical laboratories. Several states, including, among others, New York and California, require licensure of out-of-state labs that receive specimens from the state and compliance with the state’s individual laboratory regulations.
If a testing laboratory is out of compliance with CLIA requirements, it may be subject to sanctions such as suspension, limitation or revocation of our CLIA certificate, as well as directed plan of correction, state on-site monitoring, civil money penalties, civil injunctive suit or criminal penalties. Therefore, Notable plans to maintain CLIA compliance and certification to be eligible to bill for services provided to Medicare and Medicaid beneficiaries. If a diagnostic testing company like Notable was to be found out of compliance with CLIA program requirements and subjected to sanction, its business could be harmed. Failure to comply with state licensure laws, if applicable, could lead to additional sanctions imposed by state licensing authorities.
FDA Regulation of Diagnostics
FDA approval or clearance is not currently required for predictive diagnostic tests, such as PPMP, offered as a stand-alone laboratory developed test, or LDT. If Notable is developing a drug or partnering with a drug company to launch a predictive diagnostic test as a companion diagnostic for a new drug or new drug indication, Notable would be required to obtain premarket approval, or PMA, or a 510(k) clearance in conjunction with seeking a new drug approval for the matching therapy. Historically, the FDA has exercised enforcement discretion with respect to tests performed solely in a central laboratory, like the predictive diagnostic tests or LDTs. The FDA has not required laboratories that furnish only LDTs to comply with the agency’s requirements for medical devices (e.g., establishment registration, device listing, quality system regulation, premarket clearance or premarket approval, and post-market controls).
Although the FDA proposed regulations that would apply to LDTs, the FDA decided that, at present, those regulations are not moving forward towards approval and implementation. In mid-2014, the FDA published a draft Guidance Document describing a proposed approach for a regulatory framework for LDTs that would have resulted in most of the high-value LDT tests marketed today eventually being required to obtain 510(k) clearances or PMAs. If implemented, this regulatory framework would require most hospital clinical labs to abandon a number of tests they perform or to pursue regulatory clearances or approvals to perform them. These proposals met significant resistance from Congress, the hospital industry, and independent clinical laboratories. The FDA indicated in late 2016 that it does not intend to finalize the draft Guidance Document at this time. However, the FDA continues to discuss potential regulatory approaches to LDTs.
Pricing and Reimbursement of Notable’s Therapeutic Product Candidates and PPMP-Diagnostic Testing
Pricing and reimbursement of a therapeutic product depend on multiple factors, including the clinical profile created through the research and development program or the breadth of its regulatory approval as described in the prescribing information. Uncertainty about the clinical profile or any of these factors translate into uncertainly about the coverage and reimbursement status of any future Notable products that may be sold. Sales of any Notable products (or revenues through selling the product itself) will depend, in part, on the extent to which the costs of the products will be covered by third-party payors, including government health programs such as Medicare and Medicaid, commercial health insurers, managed care organizations or pharmaceutical companies. The process for determining whether a third-party payor will provide coverage for a test sometimes is separate from the process for setting the price of a drug product or for establishing the reimbursement rate that a payor will pay for the drug product. Third-party payors may limit coverage to specific testing products on an approved list, which might not include all of the tests available for a particular indication.
In order to obtain coverage and reimbursement for any product, Notable may need to conduct robust pharmacoeconomic studies in order to demonstrate the medical necessity and cost-effectiveness of the therapeutic product or diagnostic test. Even with successful studies, Notable’s products may not be considered medically necessary or cost-effective by payers. A third-party payor’s decision to provide coverage for a test does not imply that an adequate reimbursement rate will be approved. Further, one payor’s determination to provide coverage for a product does not assure that other payors will also provide coverage, and adequate reimbursement, for the product. Third-party reimbursement may not be sufficient to enable Notable to maintain price levels high enough to realize an appropriate return on our investment in product development.
The containment of healthcare costs has become a priority of federal, state and foreign governments, and the prices of tests and drugs have been a focus in this effort. Third-party payors are increasingly challenging the prices charged for medical products and services, examining the medical necessity and reviewing the cost-effectiveness of testing products, drug products and medical services and questioning safety and efficacy. If these third-party payors do not consider our products to be cost-effective compared to other available products or treatments, they may not cover our products or, if they do, the level of payment may not be sufficient to allow Notable to sell its products at a profit. The U.S. government, state legislatures and foreign governments have shown significant interest in implementing cost-containment programs to limit the growth of government-paid healthcare costs, including price controls and restrictions on reimbursement. Adoption of such controls and measures, and tightening of restrictive policies in jurisdictions with existing controls and measures, could limit payments for Notable’s diagnostic products or treatments that require use of Notable’s testing products and could adversely affect Notable’s net revenue and results.
Pricing and reimbursement schemes vary widely from country to country. Some countries may require the completion of additional studies that compare the cost-effectiveness of a particular test to currently available tests. The downward pressure on healthcare costs in general, particularly prescription drugs and testing products, has become intense. As a result, increasingly high barriers are being erected to the entry of new products. In addition, in some countries, cross-border imports from low-priced markets exert competitive pressure that may reduce pricing within a country. Any country that has price controls or reimbursement limitations for testing products may not allow favorable reimbursement and pricing arrangements for any of our products.
Coverage policies, third-party reimbursement rates and pricing regulation may change at any time.
Other Healthcare Laws
Manufacturing, sales, promotion and other activities following product approval are also subject to regulation by numerous regulatory authorities in the U.S. in addition to the FDA, including CMS, the HHS Office of Inspector General and HHS Office for Civil Rights, other divisions of the HHS and the Department of Justice.
Healthcare providers, physicians, and third-party payors will play a primary role in the recommendation and prescription of any products for which Notable obtains marketing approval. Notable’s current and future arrangements with third-party payors, healthcare providers and physicians may expose Notable to broadly applicable fraud and abuse and other healthcare laws and regulations that may constrain the business or financial arrangements and relationships through which Notable markets, sells and distributes therapeutic and diagnostic products. In the U.S., these laws include, without limitation, state and federal anti-kickback, false claims, physician transparency, and patient data privacy and security laws and regulations, including but not limited to those described below.
The U.S. federal Anti-Kickback Statute (“AKS”), prohibits, among other things, any person or entity from knowingly and willfully offering, paying, soliciting, receiving or providing any remuneration, directly or indirectly, overtly or covertly, to induce or in return for purchasing, leasing, ordering or arranging for or recommending the purchase, lease or order of any good, facility, item or service reimbursable, in whole or in part, under Medicare, Medicaid or other federal healthcare programs. The term “remuneration” has been broadly interpreted to include anything of value. The AKS has been interpreted to apply to arrangements between pharmaceutical and medical device manufacturers on the one hand and prescribers, purchasers, formulary managers and beneficiaries on the other hand. Although there are a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution, the exceptions and safe harbors are drawn narrowly. Failure to meet all of the requirements of a particular applicable statutory exception or regulatory safe harbor does not make the conduct per se illegal under the AKS. Instead, the legality of the arrangement will be evaluated on a case-by-case basis based on a cumulative review of all its facts and circumstances. Several courts have interpreted the statute’s intent requirement to mean that if any one purpose of an arrangement involving remuneration is to induce referrals of federal healthcare covered business, the statute has been violated. In addition, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation. Moreover, a claim including items or services resulting from a violation of the AKS constitutes a false or fraudulent claim for purposes of the federal civil False Claims Act. On November 20, 2020, the Office of Inspector General (“OIG”) finalized further modifications to the AKS. Under the final rule, OIG added safe harbor protections under the AKS for certain coordinated care and value-based arrangements among clinicians, providers, and others. The final rule (with some exceptions) became effective January 19, 2021. The industry continues to evaluate what effect, if any, this rule will have.
In addition, under a federal law directed at “self-referral,” commonly known as the “Stark Law,” there are prohibitions, with certain exceptions, on referrals for certain designated health services, including laboratory services, that are covered by the Medicare and Medicaid programs by physicians who personally, or through a family member, have an investment or ownership interest in, or a compensation arrangement with, an entity performing the tests. The prohibition also extends to payment for any testing referred in violation of the Stark Law. A person who engages in a scheme to circumvent the Stark Law’s referral prohibition may be fined up to $100,000 for each such arrangement or scheme. In addition, any person who presents or causes to be presented a claim to the Medicare or Medicaid programs in violation of the Stark Law is subject to civil monetary penalties of up to $15,000 per bill submission, an assessment of up to three times the amount claimed and possible exclusion from participation in federal governmental payor programs. Bills submitted in violation of the Stark Law may not be paid by Medicare or Medicaid, and any person collecting any amounts with respect to any such prohibited bill is obligated to refund such amounts. Many states have comparable laws that are not limited to Medicare and Medicaid referrals.
Furthermore, Notable could be held liable under the federal False Claims Act, which imposes civil penalties, including through civil whistleblower or qui tam actions, against individuals or entities (including manufacturers) for, among other things, knowingly presenting, or causing to be presented to federal programs (including Medicare and Medicaid) claims for items or services that are false or fraudulent, claims for items or services not provided as claimed, or claims for medically unnecessary items or services. This could apply even if Notable is not submitting claims directly to payors as would be the case with drug products. The government may deem manufacturers of such products to have “caused” the submission of false or fraudulent claims by, for example, providing inaccurate billing or coding information to customers or promoting a product off-label. Several biopharmaceutical, medical device and other healthcare companies have been prosecuted under federal false claims and civil monetary penalty laws for, among other things, allegedly providing free product to customers with the expectation that the customers would bill federal programs for the product. Other companies have been prosecuted for causing false claims to be submitted because of the companies’ marketing of products for unapproved (e.g., or off-label), and thus non-covered, uses. In addition, the civil monetary penalties statute imposes penalties against any person who is determined to have presented or caused to be presented a claim to a federal health program that the person knows or should know is for an item or service that was not provided as claimed or is false or fraudulent.
Notable’s future marketing and activities relating to the reporting of wholesaler or estimated retail prices for our products, if approved, the reporting of prices used to calculate Medicaid rebate information and other information affecting federal, state and third-party reimbursement for our products, and the sale and marketing of our product candidates, are subject to scrutiny under these laws.
The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, created additional federal criminal statutes that prohibit, among other actions, knowingly and willfully executing, or attempting to execute, a scheme to defraud or to obtain, by means of false or fraudulent pretenses, representations or promises, any money or property owned by, or under the control or custody of, any healthcare benefit program, including private third-party payors, knowingly and willfully embezzling or stealing from a healthcare benefit program, willfully obstructing a criminal investigation of a healthcare offense and knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services. Similar to the AKS, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.
In addition, there has been a recent trend of increased federal and state regulation of payments made to physicians and certain other healthcare providers. The ACA imposed, among other things, new annual reporting requirements through the Physician Payments Sunshine Act for covered manufacturers for certain payments and “transfers of value” provided to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors) and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members. Effective January 1, 2022, these reporting obligations will extend to include transfers of value made to certain non-physician providers such as physician assistants and nurse practitioners. Failure to submit timely, accurately and completely the required information for all payments, transfers of value and ownership or investment interests may result in civil monetary penalties. Covered manufacturers must submit reports by the 90th day of each subsequent calendar year and the reported information is publicly made available on a searchable website.
Notable may also be subject to data privacy and security regulation by both the federal government and the states in which Notable conduct its business. HIPAA, as amended by HITECH, and their respective implementing regulations, including the Final HIPAA Omnibus Rule published on January 25, 2013, impose specified requirements relating to the privacy, security and transmission of individually identifiable health information held by covered entities and their business associates. Among other things, HITECH made HIPAA’s security standards directly applicable to “business associates,” defined as independent contractors or agents of covered entities that create, receive, maintain or transmit protected health information in connection with providing a service for or on behalf of a covered entity, although it is unclear that Notable would be considered a “business associate” in the normal course of our business. HITECH also increased the civil and criminal penalties that may be imposed against covered entities, business associates and possibly other persons, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorney’s fees and costs associated with pursuing federal civil actions. In addition, state laws govern the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and may not have the same requirements, thus complicating compliance efforts. See “European Data Collection” below for a discussion of data privacy and security enactments of the EU.
For example, California’s Consumer Privacy Act (“CCPA”), went into effect in January 2020, and the California Attorney General has since promulgated final regulations. The law provides broad rights to California consumers with respect to the collection and use of their personal information and imposes data protection obligations on certain businesses. While the CCPA does not apply to protected health information that is subject to HIPAA or personal information collected, used or disclosed in research, as defined by federal law, the CCPA may still affect our business activities. Moreover, on November 3, 2020, California voters passed the California Privacy Rights Act (“CPRA”), under a ballot initiative. The CPRA amends the existing CCPA to include new consumer rights and additional data protection obligations. The new data protection requirements under the CPRA apply to information collected on or after January 1, 2022. With the promulgation of final regulations, the California State Attorney General has commenced enforcement actions against CCPA violators. The uncertainty surrounding the implementation of CCPA and the amendments under the CPRA exemplifies the vulnerability of our business to the evolving regulatory environment related to personal data and protected health information. The California law further expands the need for privacy and process enhancements and commitment of resources in support of compliance. Moreover, more than ten states have proposed bills in the last year with provisions similar to the CCPA and CPRA. It is likely that other states will pass laws similar to the CCPA and the CPRA in the near future and a federal data protection law may also be on the horizon.
Similar state and foreign fraud and abuse laws and regulations, such as state anti-kickback and false claims laws, may apply to sales or marketing arrangements and claims involving healthcare items or services. Such laws are generally broad and are enforced by various state agencies and private actions. Also, many states have similar fraud and abuse statutes or regulations that may be broader in scope and may apply regardless of payor, in addition to items and services reimbursed under Medicaid and other state programs. Some state laws require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant federal government compliance guidance, and require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers, marketing expenditures or drug pricing.
In order to sell products, Notable must also comply with state laws, including those that require the registration of manufacturers and wholesale distributors of drug and biological products. These include, in certain states, manufacturers and distributors who ship products into the state even if such manufacturers or distributors have no place of business within the state. Some states also impose requirements on manufacturers and distributors to establish the pedigree of product in the chain of distribution, including some states that require manufacturers and others to adopt new technology capable of tracking and tracing product as it moves through the distribution chain. Several states have enacted legislation requiring pharmaceutical and biotechnology companies to establish marketing compliance programs, file periodic reports with the state, make periodic public disclosures on sales, marketing, pricing, clinical trials and other activities, and/or register their sales representatives, as well as to prohibit pharmacies and other healthcare entities from providing certain physician prescribing data to pharmaceutical and biotechnology companies for use in sales and marketing, and to prohibit certain other sales and marketing practices. All of Notable’s activities are potentially subject to federal and state consumer protection and unfair competition laws.
The scope and enforcement of each of these laws is uncertain and subject to rapid change in the current environment of healthcare reform, especially in light of the lack of applicable precedent and regulations. Federal and state enforcement bodies have recently increased their scrutiny of interactions between healthcare companies and healthcare providers, which has led to a number of investigations, prosecutions, convictions and settlements in the healthcare industry. It is possible that governmental authorities will conclude that Notable’s business practices may not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws and regulations. If Notable’s operations are found to be in violation of any of these laws or any other governmental regulations that may apply to Notable, the company may be subject to significant civil, criminal and administrative penalties, damages, fines, disgorgement, contractual damages, reputational harm, diminished profits and future earnings, imprisonment, exclusion of drugs from government funded healthcare programs, such as Medicare and Medicaid, and the curtailment or restructuring of our operations, as well as additional reporting obligations and oversight if Notable becomes subject to a corporate integrity agreement or other agreement to resolve allegations of non-compliance with these laws, any of which could adversely affect Notable’s ability to operate its business and financial results. If any of the physicians or other healthcare providers or entities with whom Notable expects to do business is found to be not in compliance with applicable laws, they may be subject to significant criminal, civil or administrative sanctions, including exclusions from government funded healthcare programs. Ensuring business arrangements comply with applicable healthcare laws, as well as responding to possible investigations by government authorities, can be time- and resource consuming and can divert a company’s attention from the business.
European Data Collection
The collection and use of personal health data in or arising from the EU are governed by the provisions of the Data Protection Directive, and the General Data Protection Regulation (“GDPR”). This directive imposes several requirements relating to the consent of the individuals to whom the personal data relates, the information provided to the individuals, notification of data processing obligations to the competent national data protection authorities and the security and confidentiality of the personal data. The Data Protection Directive and GDPR also impose strict rules on the transfer of personal data out of the EU, to the U.S. Failure to comply with the requirements of the Data Protection Directive, the GDPR and the related national data protection laws of the EU Member States may result in fines and other administrative penalties. The GDPR introduces new data protection requirements in the EU and substantial fines for breaches of the data protection rules. The GDPR regulations may impose additional responsibility and liability in relation to personal data that Notable processes, including in respect of clinical trials, and Notable may be required to put in place additional mechanisms ensuring compliance with the new data protection rules. This may be onerous and adversely affect our business, financial condition, results of operations and prospects.
Other Regulatory Requirements
Notable’s operations use small amounts of hazardous materials in research and development and generate regulated medical waste in the normal course of performing its predictive diagnostic tests. This subjects Notable to a variety of federal, state and local environmental and safety laws and regulations. Some of the regulations under the current regulatory structure provide for strict liability, holding a party potentially liable without regard to fault or negligence. Notable could be held liable for damages and fines as a result of Notable’s, or others’, business operations should contamination of the environment or individual exposure to hazardous substances occur. Notable cannot predict how changes in laws or development of new regulations will affect its business operations or the cost of compliance.
Current and Future Legislation
In the U.S. and other jurisdictions, there have been a number of legislative and regulatory changes and proposed changes regarding the healthcare system that could prevent or delay marketing approval of Notable’s product candidates, restrict or regulate post-approval activities and affect its ability to profitably sell any product candidates. Notable expects that current laws, as well as other healthcare reform measures that may be adopted in the future, may result in more rigorous coverage criteria and additional downward pressure on the price that Notable, or any collaborators, may receive.
Notable Background and Corporate History
Notable was incorporated as a Delaware corporation in 2014. Initially, Notable developed its PPMP as a diagnostic tool for physicians for identifying which cancer treatment would be the most effective for an individual patient. Notable then broadened its mission and applied its PPMP to streamline and accelerate the identification and validation of investigational compounds, working with multiple biotechnology and pharmaceutical companies under service-based agreements. In 2021, by entering into the Oncoheroes Agreement and the CicloMed Agreement, Notable advanced from a purely diagnostic company to an integrated - diagnostic and therapeutic - platform therapeutics company designing and developing or co-developing predictive precision medicines.
As of December 31, 2023, the Company had 34,285,714 authorized ordinary shares, of which 9,018,261 shares were outstanding and approximately 284,437 shares were reserved for issuance of ordinary shares upon the exercise of outstanding ordinary share options, ordinary share warrants, and RSUs.
Merger
On October 16, 2023, pursuant to the Merger Agreement, by and among the Company, Merger Sub and Notable Labs, Inc., Merger Sub was merged with and into Notable Labs, Inc., with Notable Labs, Inc. continuing after the merger as the surviving entity and a wholly owned subsidiary of the Company. At the effective time of the Merger, without any action on the part of any stockholder, each issued and outstanding share of pre-Merger Notable Labs, Inc.’s common stock, par value $0.001 per share (the “Notable Labs, Inc. Common Stock”), including shares underlying pre-Merger Notable Labs, Inc.’s outstanding equity awards, was converted into the right to receive 0.0629 shares (the “Exchange Ratio”) of the Company’s common stock, 0.35 NIS par value per share (the “Company Ordinary Shares”), Immediately following the effective time of the Merger, the Company effected a 1-for-35 reverse stock split of the issued and outstanding Company Ordinary Shares (the “Reverse Stock Split”). Upon completion of the Merger and the transactions contemplated in the Merger Agreement, (i) the former Notable, Inc. equity holders owned approximately 71.9% of the outstanding equity of the Company on a fully diluted basis, assuming the exercise in full of warrants to purchase 94,988 Company Ordinary Shares and including 160,635 Company Ordinary Shares underlying options to purchase shares of Notable Labs, Inc.’s Common Stock assumed by the company at closing and after adjustments based on the Company’s net cash at closing; and (ii) former Vascular Biogenics, Ltd. shareholders owned approximately 28.1% of the outstanding equity of the Company.
The Merger was treated as a reverse recapitalization effected by a share exchange for financial accounting and reporting purposes. Notable Labs, Inc. was being treated as the accounting acquirer, as its stockholders control the Company after the Merger, even though Vascular Biogenics, Ltd. was the legal acquirer. As a result, the assets and liabilities and the historical operations that are reflected in our consolidated financial statements are those of Notable Labs, Inc. as if Notable Labs, Inc. had always been the reporting company. All references to ordinary shares, warrants and options have been presented on a post-merger, post-reverse split basis.
Employees and Human Capital Resources
As of April 1, 2024, Notable has 16 full-time employees, most of whom are engaged in research and development activities. None of Notable’s employees are currently represented by a labor union or covered by a collective bargaining agreement and Notable believes that its relations with its employees are good.
The human capital objectives Notable focuses on managing its business include attracting, developing, and retaining key personnel. Notable’s team is critical to the success of its mission and organization and Notable is committed to supporting its employees’ professional advancement. Notable believes its management team has the experience necessary to effectively implement its growth strategy and continue to drive stockholder value. When making compensation decisions, Notable includes industry benchmarks and Notable believes it provides competitive compensation and benefits to attract and retain key personnel, as well as a mission- and patient-focused, safe, inclusive and respectful workplace.

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ITEM 1A. RISK FACTORS
Item 1A. RISK FACTORS
An investment in our common stock involves a high degree of risk. You should carefully consider the following risk factors in addition to other information in this Annual Report on Form 10-K before purchasing our ordinary shares. The risks and uncertainties described below are those that we currently deem to be material and that we believe are specific to our company and our industry. In addition to these risks, our business may be subject to risks currently unknown to us. If any of these or other risks actually occurs, our business may be adversely affected, the trading price of our ordinary shares may decline, and you may lose all or part of your investment.
Risks Related to Notable’s Business, Financial Position and Capital Requirements
Notable has a limited operating history that you can use to evaluate it, and the likelihood of Notable’s success must be considered in light of the problems, expenses, difficulties, complications and delays frequently encountered by a small developing company.
Notable is clinical-stage precision therapeutics company that was incorporated in June 2014 and has a limited operating history. Since inception, Notable’s operations have been primarily limited to acquiring and licensing intellectual property rights, undertaking research and conducting preclinical studies and clinical trials for Notable’s PPMP, and its current drug candidates Volasertib and Fosciclopirox. Notable has not yet obtained regulatory approval for any product candidates. Consequently, any predictions about Notable’s future success or viability, or any evaluation of Notable’s business and prospects, may not be accurate. The likelihood of Notable’s success must be considered in light of the problems, expenses, difficulties, complications and delays frequently encountered by a small developing company starting a new business enterprise and the highly competitive environment in which Notable will operate.
Notable expects its financial condition and operating results to continue to fluctuate from quarter to quarter and year to year due to a variety of factors, many of which are beyond its control. Notable will need to eventually transition from a company with a research and development focus to a company capable of undertaking commercial activities. Notable may encounter unforeseen expenses, difficulties, complications and delays, and may not be successful in such a transition. Since Notable has a limited operating history, Notable cannot assure you that its business will be profitable or that it will ever generate sufficient revenues to meet its expenses and support Notable’s anticipated activities. In addition, there is no guarantee that any of Notable’s product candidates will ever receive FDA approval.
Notable has incurred significant losses since its inception and anticipates that it will continue to incur significant losses for the foreseeable future and Notable’s management’s conclusions based on the required assessment by management per GAAP have raised substantial doubt about Notable’s ability to continue as a going concern.
Notable has devoted most of its financial resources to research and development, including Notable’s preclinical and clinical development activities. To date, Notable has funded its operations primarily through research funding, and through the sale of equity and convertible securities. Notable expects to continue to incur substantial and increased expenses, losses and negative cash flows as it expands its development activities and advances its preclinical programs. If Notable’s product candidates are not successfully developed or commercialized, including because of a lack of capital, or if Notable does not generate enough revenue following marketing approval, it will not achieve profitability and its business may fail. Even if Notable successfully obtains regulatory approval to market a product candidate, its revenues will also depend upon the size of any markets in which its product candidates receive market approval and its ability to achieve sufficient market acceptance and adequate market share for its products.
Notable expects to continue to incur significant expenses and increasing operating losses for the foreseeable future. The net losses Notable incurs may fluctuate significantly from quarter to quarter. Notable anticipates that its expenses will increase substantially if and as it:
● continues its research and preclinical and clinical development of its product candidates, both independently and under its strategic alliance agreements;
● initiates preclinical studies and clinical trials for any additional indications for its current drug candidates and any future drug candidates that it may pursue;
● continues to build its portfolio of drug candidates through the acquisition or in-license of additional drug candidates or technologies;
● continues to develop, maintain, expand and protect its intellectual property portfolio;
● continues to develop, maintain, and expand the PPMP;
● seeks to identify additional product candidates;
● pursues regulatory approvals for its current and future drug candidates that successfully complete clinical trials;
● ultimately establishes a sales, marketing, distribution and other commercial infrastructure to commercialize any drug candidate for which it may obtain marketing approval;
● seeks marketing approvals for its product candidates that successfully complete clinical trials;
● hires additional clinical, regulatory, research, scientific, executive, accounting and administrative personnel;
● incurs additional legal, accounting and other expenses in operating as a public company; and
● creates additional infrastructure to support Notable’s operations and its product development and planned future commercialization efforts.
To become and remain profitable, Notable must develop and eventually commercialize one or more drug candidates with significant market potential or license one or more of its drug candidates to an industry partner. This will require Notable to be successful in a range of challenging activities, including completing clinical trials of its drug candidates, publishing its data and findings on its drug candidates with peer reviewed publications, developing commercial scale manufacturing processes, obtaining marketing approval, manufacturing, marketing and selling any current and future drug candidates for which Notable may obtain marketing approval, and satisfying any post-marketing requirements. Notable is only in the preliminary stages of most of these activities and, in some cases, has not yet commenced certain of these activities. Notable may never succeed in any or all of these activities and, even if it does, it may never generate sufficient revenue to achieve profitability.
Because of the numerous risks and uncertainties associated with drug development, Notable is unable to accurately predict the timing or amount of expenses or when, or if, Notable will obtain marketing approval to commercialize any of its drug candidates. If Notable is required by the FDA, or other regulatory authorities such as the EMA, to perform studies and trials in addition to those currently expected, or if there are any delays in the development, or in the completion of any planned or future preclinical studies or clinical trials of its current or future drug candidates, its expenses could increase and profitability could be further delayed.
Even if Notable does achieve profitability, it may not be able to sustain or increase profitability on a quarterly or annual basis. Notable’s failure to become and remain profitable would decrease its value and could impair its ability to raise capital, maintain its research and development efforts, expand its business or continue its operations. A decline in the value of Notable also could cause investors to lose all or part of their investment in the company.
As a result, management has included disclosures in Note 1 of the financial statements and Notable’s independent auditor included an explanatory paragraph in its report on its financial statements for the year ended December 31, 2023 with respect to this uncertainty. Notable’s 2023 financial statements do not include any adjustments to reflect the possible future effects on the recoverability and classification of assets or the amounts and classification of liabilities that may result from the outcome of this uncertainty.
Notable has generated only limited revenue since inception, and may never be profitable.
Notable’s ability to generate revenue and achieve profitability depends on its ability, alone or with strategic alliance partners, to successfully complete the development of, obtain the necessary regulatory approvals for and commercialize the PPMP and Notable’s product candidates. Notable does not anticipate generating significant revenues from sales of its products for the foreseeable future, if ever. Notable’s ability to generate future revenues from product sales depends heavily on its success in:
● completing its research and preclinical development of product candidates;
● initiating and completing clinical trials for product candidates with favorable results;
● seeking, obtaining, and maintaining marketing approvals for product candidates that successfully complete clinical trials;
● establishing and maintaining supply and manufacturing relationships with third parties;
● launching and commercializing product candidates for which Notable may obtain marketing approval, with an alliance partner or, if launched independently, successfully establishing a sales force, marketing and distribution;
● maintaining, protecting and expanding its intellectual property portfolio; and
● attracting, hiring and retaining qualified personnel.
Because of the numerous risks and uncertainties associated with predictive medicine and pharmaceutical product development, Notable is unable to predict the timing or amount of increased expenses and when it will be able to achieve or maintain profitability, if ever. In addition, Notable’s expenses could increase beyond expectations if it is required by the FDA or foreign regulatory agencies to perform studies and trials in addition to those that it currently anticipates.
Even if one or more of the product candidates that Notable licenses or develops is approved for commercial sale, it anticipates incurring significant costs associated with commercializing any approved product. Even if Notable is able to generate revenues from the sale of any approved products, it may not become profitable and may need to obtain additional funding to continue operations.
Notable expects that it will need to raise additional capital, which may not be available on acceptable terms, or at all.
Developing pharmaceutical products, including conducting preclinical studies and clinical trials, is expensive. Notable anticipates that its expenses will increase substantially as it continues to develop and begin and continues clinical trials with respect to Volasertib and Fosciclopirox and any additional drug candidates; seek to identify and develop additional drug candidates; acquire or in-license other drug candidates or technologies; seek regulatory and marketing approvals for its drug candidates that successfully complete clinical trials, if any; establish sales, marketing, distribution and other commercial infrastructure in the future to commercialize various drugs for which Notable may obtain marketing approval, if any; require the manufacture of larger quantities of drug candidates for clinical development and, potentially, commercialization; maintain, expand and protect its intellectual property portfolio; develop, maintain, and expand the PPMP; hire and retain additional personnel, such as clinical, quality control and scientific personnel; add operational, financial and management information systems and personnel, including personnel to support its drug development and help it comply with its obligations as a public company; and add equipment and physical infrastructure to support its research and development programs.
Notable will be required to expend significant funds in order to advance the development of the PPMP, Volasertib, Fosciclopirox and any other drug candidate(s). In addition, while Notable may seek one or more collaborators for future development of its current drug candidates or any future drug candidates that it may develop for one or more indications, Notable may not be able to enter into a partnership or out-license for any of its drug candidates for such indications on suitable terms, on a timely basis or at all. In any event, Notable’s existing cash, cash equivalents and other capital resources will not be sufficient to fund all of the efforts that it plans to undertake or to fund the completion of development of its drug candidates or its other preclinical studies. Accordingly, Notable will be required to obtain further funding through public or private equity offerings, debt financings, collaborations and licensing arrangements or other sources. Notable does not have any committed external source of funds. Further financing may not be available to Notable on acceptable terms, or at all. Notable’s failure to raise capital as and when needed would have a negative impact on its financial condition and its ability to pursue its business strategy.
Notable expects its research and development expenses to substantially increase in connection with its ongoing activities, particularly as it advances its product candidates, Volasertib and Fosciclopirox, through clinical trials. Notable may need to raise additional capital to support its operations and such funding may not be available to it on acceptable terms, or at all. Notable cannot provide assurances that its plans will not change or that any change in circumstances will not result in the depletion of its capital resources more rapidly than it currently anticipates. For example, Notable’s preclinical or clinical trials may encounter technical or other difficulties. Any of these events may increase Notable’s development costs more than it expects. In order to support Notable’s long-term plans, it may need to raise additional capital or otherwise obtain funding through additional strategic alliances if it chooses to initiate preclinical or clinical trials for new product candidates. In any event, Notable will require additional capital to obtain regulatory approval for, and to commercialize, its current and future product candidates.
Any additional fundraising efforts may divert Notable’s management from its day-to-day activities, which may adversely affect Notable’s ability to develop and commercialize current and future product candidates. In addition, Notable cannot guarantee that future financing will be available in sufficient amounts or on terms acceptable to it, if at all. If Notable is unable to raise additional capital when required or on acceptable terms, it may be required to:
● significantly delay, scale back or discontinue the development or commercialization of all current and future product candidates;
● seek strategic alliances for research and development programs at an earlier stage than otherwise would be desirable or on terms that are less favorable than might otherwise be available; or
● relinquish or license on unfavorable terms, its rights to technologies or any current and future product candidates that it otherwise would seek to develop or commercialize ourselves. If Notable is unable to raise additional capital in sufficient amounts or on acceptable terms, it will be prevented from pursuing development and commercialization efforts, which will have a material adverse effect on its business, operating results and prospects.
Notable’s future funding requirements, both short-term and long-term, will depend on many factors, including:
● the scope, progress, timing, costs and results of preclinical studies and clinical trials of Volasertib and Fosciclopirox and its other drug candidates;
● the costs associated with maintaining, expanding and updating the PPMP;
● the costs, timing and outcome of seeking regulatory approvals;
● its headcount growth and associated costs as it expands its research and development as well as potentially establish a commercial infrastructure;
● the costs of its licensing or commercialization activities for any of its drug candidates that receive marketing approval to the extent such costs are not the responsibility of any future collaborators, including the costs and timing of establishing drug sales, marketing, distribution and manufacturing capabilities;
● its ability to enter into and the terms and timing of any collaborations, licensing agreements or other arrangements;
● revenue received from commercial sales, if any, of its current and future drug candidates;
● the costs of preparing, filing and prosecuting patent applications, maintaining and protecting its intellectual property rights and defending against intellectual property related claims;
● the number of future drug candidates that it pursues and their development requirements;
● changes in regulatory policies or laws that may affect its operations;
● changes in physician acceptance or medical society recommendations that may affect commercial efforts;
● the costs of acquiring potential new drug candidates or technology;
● the costs associated with purchasing data for the PPMP;
● the costs associated with maintaining and expanding its cybersecurity systems; and
● the costs of operating as a public company.
Future sales and issuances of Notable Ordinary Shares or rights to purchase Notable Ordinary Shares, including pursuant to Notable’s equity incentive plans, could result in additional dilution of the percentage ownership of Notable’s shareholders and could cause its share price to fall.
Additional capital will be needed in the future to continue Notable’s planned operations. To the extent Notable raises additional capital by issuing equity securities, its shareholders may experience substantial dilution. Notable may sell ordinary shares, convertible securities or other equity securities in one or more transactions at prices and in a manner Notable determines from time to time. If Notable sells ordinary shares, convertible securities or other equity securities in one or more transactions, investors may be materially diluted by subsequent sales. These sales may also result in material dilution to Notable’s existing shareholders, and new investors could gain rights superior to Notable’s existing shareholders.
Notable also has equity plans that provide for the grant of share options and other equity-based awards to Notable’s employees, directors and consultants, and has issued warrants. The exercise of any of these RSUs, options and warrants would result in additional share issuances and may be dilutive. As these securities are registered, many are available for resale into the public market. Sales of a substantial number of shares of Notable Ordinary Shares by its existing shareholders in the public market, or the perception that these sales might occur, could depress the market price of Notable Ordinary Shares and could impair its ability to raise capital through the sale of additional equity securities. Notable is unable to predict the effect that such sales may have on the prevailing market price of Notable Ordinary Shares.
Notable faces significant competition from other biopharmaceutical companies, and Notable’s operating results will suffer if it fails to compete effectively.
The biopharmaceutical industry is characterized by intense competition and rapid innovation. Notable’s competitors may be able to develop other compounds or drugs that are able to achieve similar or better results. Notable’s potential competitors include major multinational pharmaceutical companies, established biotechnology companies, specialty pharmaceutical companies and universities and other research institutions. Many of Notable’s competitors have substantially greater financial, technical and other resources, such as larger research and development staff and experienced marketing and manufacturing organizations and well-established sales forces. Smaller or early-stage companies may also prove to be significant competitors, particularly as they develop novel approaches to treating disease indications that Notable’s product candidates are also focused on treating. Established pharmaceutical companies may also invest heavily to accelerate discovery and development of novel therapeutics or to in-license novel therapeutics that could make the product candidates that Notable develops obsolete. Competition may increase further as a result of advances in the commercial applicability of technologies and greater availability of capital for investment in these industries. Notable’s competitors, either alone or with collaboration partners, may succeed in developing, acquiring or licensing on an exclusive basis drug or biologic products that are more effective, safer, more easily commercialized or less costly than its product candidates or may develop proprietary technologies or secure patent protection that it may need for the development of its technologies and products. Notable believes the key competitive factors that will affect the development and commercial success of its product candidates are efficacy, safety, tolerability, reliability, convenience of use, price and reimbursement.
Even if Notable obtains regulatory approval of drug products, the availability and price of its competitors’ products could limit the demand and the price it is able to charge for its product candidates. Notable may not be able to implement its business plan if the acceptance of its product candidates is inhibited by price competition or the reluctance of physicians to switch from existing methods of treatment to Notable’s product candidates, or if physicians switch to other new drug or biologic products or choose to reserve its product candidates for use in limited circumstances.
Notable’s product candidates, Volasertib and Fosciclopirox, are in the early stages of clinical development and their commercial viability remains subject to current and future clinical trials, regulatory approvals and the risks generally inherent in the development of a drug candidate. If Notable is unable to successfully advance or develop its product candidates, its business will be materially harmed.
In the near-term, failure to successfully advance the development of Notable’s product candidates, Volasertib and Fosciclopirox, may have a material adverse effect on the company. To date, Notable has not successfully or commercially marketed, distributed or sold any product candidate. The success of Notable’s business depends primarily upon its ability to successfully advance the development of its product candidate clinical trials, have the product candidate approved for sale by the FDA or regulatory authorities in other countries, and ultimately have the product candidates successfully commercialized by Notable or a strategic partner. Notable cannot assure you that the results of its ongoing clinical trials will support or justify the continued development of its product candidates, or that it will receive approval from the FDA, or similar regulatory authorities in other countries, to advance the development of its product candidates.
Notable’s product candidates must satisfy rigorous regulatory standards of safety and efficacy before it can advance or complete its clinical developments or it can be approved for sale. To satisfy these standards, Notable must engage in expensive and lengthy clinical trials, develop acceptable manufacturing processes, and obtain regulatory approval of its product candidates. Despite these efforts, Notable’s product candidates may not:
● offer therapeutic or other medical benefits over existing drugs or other product candidates in development to treat the same patient population;
● be proven to be safe and effective in current and future clinical trials;
● have the desired effects;
● be free from undesirable or unexpected effects meet applicable regulatory standards be capable of being formulated and manufactured in commercially suitable quantities and at an acceptable cost; or
● be successfully commercialized by it or by collaborators.
A number of companies in the pharmaceutical and biopharmaceutical industries have experienced significant delays, setbacks and failures in all stages of development, even after achieving promising results in clinical trials. Furthermore, even if the data collected from preclinical studies and clinical trials involving Notable’s product candidates demonstrate a favorable safety and efficacy profile, such results may not be sufficient to support the submission of an NDA or a BLA to obtain regulatory approval from the FDA in the United States, or other similar regulatory agencies in other jurisdictions, which is required to market and sell the product.
Notable’s product candidates will require significant additional research and development efforts, the commitment of substantial financial resources, and regulatory approvals prior to advancing into further clinical development or being commercialized by Notable or collaborators. Notable cannot assure you that its product candidates will successfully progress through the drug development process or will result in commercially viable products. Notable does not expect its product candidates to be commercialized by Notable or collaborators for at least several years.
Risks Related to the Discovery and Development of Notable’s Drug Candidates
Notable has limited experience in drug discovery and drug development and may not receive regulatory approval to market its drug candidates.
Prior to the acquisition of its drug candidates, Notable was not involved in and had no control over their preclinical and clinical development. In addition, Notable relies upon the parties from whom it has acquired its drug candidates to have conducted such research and development in accordance with the applicable protocol, legal, regulatory and scientific standards, have accurately reported the results of all clinical trials conducted prior to its acquisition of the applicable drug candidate, and have correctly collected the data from these studies and trials. To the extent any of these has not occurred, Notable’s expected development time and costs may be increased, which could adversely affect its prospects for marketing approval of, and receiving any future revenue from, these drug candidates.
In the near term, Notable is dependent on its ability to advance the development of Volasertib and Fosciclopirox. If Notable is unable to initiate or complete the clinical development of, obtain marketing approval for or successfully commercialize Volasertib and Fosciclopirox and its other drug candidates, either alone or with a collaborator, or if it experiences significant delays in doing so, Notable’s business could be substantially harmed. In addition, Notable may not continue the development of Volasertib in the United States until it completes the transfer of the Volasertib IND from Oncoheroes Biosciences, Inc. (“Oncoheroes”). Any delay of such IND transfer may delay Notable’s planned clinical trials of Volasertib.
Notable currently does not have any drugs that have received regulatory approval and may never be able to develop marketable drug candidates. Notable is investing a significant portion of its efforts and financial resources in the advancement of its drug candidates and in the development of the PPMP. Notable’s prospects are substantially dependent on its ability, or those of any future collaborator, to develop, obtain marketing approval for and successfully commercialize drug candidates in one or more disease indications.
The success of Volasertib and Fosciclopirox and Notable’s other drug candidates will depend on several factors, including the following:
● following submission of an IND, with the FDA or any comparable foreign regulatory authority, receiving clearance for the conduct of clinical trials of drug candidates and proposed design of future clinical trials;
● initiation, progress, timing, costs and results of clinical trials of its drug candidates and potential drug candidates;
● establishment of a safety, tolerability and efficacy profile that is satisfactory to the FDA or any comparable foreign regulatory authority for marketing approval;
● adequate ongoing availability of quality data sources for the PPMP and raw materials and drug product for clinical development and any commercial sales;
● obtaining and maintaining patent, trade secret protection and regulatory exclusivity, both in the United States and relevant global markets;
● the performance of its future collaborators, if any;
● the extent of any required post-marketing approval commitments to applicable regulatory authorities;
● establishment of supply arrangements with third-party raw materials suppliers and manufacturers;
● establishment of arrangements with third-party manufacturers to obtain finished drug product that is appropriately packaged for sale;
● protection of its rights in its intellectual property;
● successful launch of commercial sales following any marketing approval;
● continued acceptable safety profile following any marketing approval;
● commercial acceptance by patients, the medical community and third-party payors; and
● its ability to compete with other therapies.
Many of these factors are beyond Notable’s control, including the results of clinical trials, the time required for the FDA or any comparable foreign regulatory authorities to review any regulatory submissions it may make, potential threats to its intellectual property rights and the manufacturing, marketing and sales efforts of any future collaborator. If Notable is unable to develop, receive marketing approval for and successfully commercialize its drug candidates, on its own or with any future collaborator or experience delays as a result of any of these factors or otherwise, Notable’s business could be substantially harmed. The regulatory approval processes of the FDA and comparable foreign authorities are lengthy, time consuming, expensive and inherently unpredictable, and if Notable is ultimately unable to obtain regulatory approval for its drug candidates, its business will be substantially harmed.
The time required to obtain approval by the FDA and comparable foreign authorities is unpredictable but can take many years following the commencement of clinical trials and depends upon numerous factors, including the substantial discretion of the regulatory authorities. The results of preclinical studies and early clinical trials of Notable’s drug candidates may not be predictive of the results of later-stage clinical trials. Drug candidates in later stages of clinical trials may fail to show the desired safety and efficacy traits despite having progressed through preclinical studies and initial clinical trials. It is not uncommon for companies in the biotechnology and pharmaceutical industries to suffer significant setbacks in advanced clinical trials due to nonclinical findings made while clinical studies were underway and safety or efficacy observations made in clinical studies, including previously unreported adverse events. Notable’s future clinical trial results may not be successful, and notwithstanding any potential promising results in earlier studies, it cannot be certain that Notable will not face similar setbacks. The historical failure rate for drug candidates in Notable’s industry is high. In addition, approval policies, regulations, or the type and amount of clinical data necessary to gain approval may change during the course of a drug candidate’s clinical development and may vary among jurisdictions. Notable has not obtained final regulatory approval for any drug candidate and it is possible that none of its existing drug candidates or any drug candidates Notable may seek to develop in the future will ever obtain regulatory approval.
Notable’s drug candidates could fail to receive marketing approval for many reasons, including the following:
● the FDA or comparable foreign regulatory authorities may disagree with the design or implementation of its clinical trials, including, but not limited to, the use of genomic or biomarker signatures to identify patients that may respond to drug efficacy;
● it may be unable to demonstrate to the satisfaction of the FDA or comparable foreign regulatory authorities that a drug candidate is safe and effective for its proposed indication;
● it may be unable to identify and recruit a sufficient number of patients with relevant genomic or biomarker signatures or other specified enrollment criteria in order to conduct clinical trials on its drug candidates;
● the results of clinical trials may not meet the level of statistical significance required by the FDA or comparable foreign regulatory authorities for approval;
● the FDA or comparable foreign regulatory authorities may disagree with Notable’s interpretation of data from preclinical studies or clinical trials;
● the data collected from clinical trials of its drug candidates may not be sufficient to support the submission of an NDA or other submission or to obtain regulatory approval in the United States or elsewhere;
● the FDA or comparable foreign regulatory authorities may find deficiencies with or fail to approve the manufacturing processes or facilities of third-party manufacturers with which it contracts for clinical and commercial supplies; and
● the approval policies or regulations of the FDA or comparable foreign regulatory authorities may significantly change in a manner rendering its clinical data insufficient for approval.
Notable has not previously completed all clinical trials for any of its drug candidates. Consequently, Notable may not have the necessary capabilities, including adequate staffing, to successfully manage the execution and completion of any clinical trials it initiates in a way that leads to Notable obtaining marketing approval for its drug candidates in a timely manner, or at all. This lengthy approval process as well as the unpredictability of future clinical trial results may result in Notable’s failing to obtain regulatory approval to market its drug candidates, which would significantly harm its business, results of operations and prospects.
In addition, even if Notable was to obtain approval, regulatory authorities may approve any of its drug candidates for fewer or more limited indications than Notable requests, may not approve the price it intends to charge for its drugs, may grant approval contingent on the performance of costly post-marketing clinical trials, may approve a drug candidate with a label that does not include the labeling claims necessary or desirable for the successful commercialization of that drug candidate or may restrict its distribution. Any of the foregoing restrictions or requirements could materially harm the commercial prospects for Notable’s drug candidates.
Notable has not previously submitted an NDA to the FDA or similar drug approval applications to comparable foreign authorities, for any drug candidate, and it cannot be certain that any of its drug candidates will be successful in clinical trials or receive regulatory approval. Further, Notable’s drug candidates may not receive regulatory approval even if they are successful in clinical trials. If Notable does not receive regulatory approvals for its drug candidates, it may not be able to continue its operations. Even if Notable successfully obtains regulatory approvals to market one or more of its drug candidates, its revenues will be dependent, in part, upon the size of the markets in the territories for which it gains regulatory approval and have commercial rights. If the markets for patients that Notable is targeting for its drug candidates are not as significant as it estimates, or if the price it charges for its drug candidate is too high, Notable may not generate significant revenues from sales of such drugs, if approved.
Notable plans to seek regulatory approval to commercialize Notable’s drug candidates both in the United States and the European Union and in additional foreign countries. While the scope of regulatory approval is similar in other countries, to obtain separate regulatory approval in many other countries Notable must comply with numerous and varying regulatory requirements of such countries regarding safety and efficacy and governing, among other things, clinical trials and possible limitations placed upon commercial sales, pricing and distribution of Notable’s drug candidates, and Notable cannot predict success in these jurisdictions.
Notable may depend on enrollment of patients with specific genomic or biomarker signatures in Notable’s clinical trials in order for Notable to continue development of Notable’s drug candidates. If Notable is unable to enroll patients with specific genomic or biomarker signatures in Notable’s clinical trials, Notable’s research, development and commercialization efforts could be adversely affected.
The timely completion of clinical trials in accordance with their protocols depends, among other things, on Notable’s ability to enroll a sufficient number of patients with genomic or biomarker signatures Notable has identified and who remain in the study until its conclusion. Notable may experience difficulties in patient enrollment in its clinical trials for a variety of reasons. Patient enrollment is affected by many factors including the size and nature of the patient population with the specific genomic or biomarker signature Notable has identified, the proximity of patients to clinical sites, the eligibility criteria for the trial, the design of the clinical trial, the size of the patient population required for analysis of the trial’s primary endpoints, the proximity of patients to study sites, Notable’s ability to recruit clinical trial investigators with the appropriate competencies and experience, Notable’s ability to obtain and maintain patient consents, the risk that patients enrolled in clinical trials will drop out of the trials before completion, and competing clinical trials and clinicians’ and patients’ perceptions as to the potential advantages of the drug candidate being studied in relation to other available therapies, including any new drugs that may be approved for the indications Notable is investigating. Notable will compete with other pharmaceutical companies for clinical sites, physicians and the limited number of patients who fulfill the stringent requirements for participation in oncology clinical trials. Also, due to the confidential nature of clinical trials, Notable does not know how many of the eligible patients may be enrolled in competing studies and who are consequently not available to Notable for its clinical trials. Notable’s clinical trials may be delayed or terminated due to the inability to enroll enough patients. The delay or inability to meet planned patient enrollment may result in increased costs and delay or termination of Notable’s trials, which could have a harmful effect on Notable’s ability to develop drugs.
Delays in clinical testing could result in increased costs to Notable and delay its ability to generate revenue.
There can be no assurance that the FDA or other regulatory authorities will accept Notable’s planned or future trial designs for its drug candidates. Notable may experience delays in its clinical trials and it does not know whether planned clinical trials will begin on time, need to be redesigned, enroll patients on time or be completed on schedule, if at all. Clinical trials can be delayed for a variety of reasons, including delays related to:
● obtaining regulatory clearance to commence a trial;
● reaching agreement on acceptable terms with prospective Contract Research Organizations (“CROs”) and clinical trial sites, the terms of which can be subject to extensive negotiation and may vary significantly among different CROs and trial sites;
● obtaining Institutional Review Board (“IRB”) approval at each site;
● recruiting suitable patients to participate in a trial;
● identifying clinical sites with adequate infrastructure (including data collection) to conduct the trial;
● clinical sites deviating from trial protocol or dropping out of a trial;
● addressing patient safety concerns that arise during the course of a trial;
● having patients complete a trial or return for post-treatment follow-up;
● adding a sufficient number of clinical trial sites; or
● manufacturing sufficient quantities and quality of a drug candidate for use in clinical trials.
Notable may also experience numerous unforeseen events during, or as a result of, clinical trials that could delay or prevent its ability to receive marketing approval or commercialize its drug candidates, including:
● it may receive feedback from regulatory authorities that requires it to modify the design of its clinical trials;
● it may not have the ability to test patients for its clinical trials that require a specific genomic or biomarker signature in order to qualify for enrollment;
● clinical trials of its drug candidates may produce negative or inconclusive results, and it may decide, or regulators may require Notable, to conduct additional clinical trials or abandon drug development programs;
● the number of patients required for clinical trials of its drug candidates may be larger than it anticipates, enrollment in these clinical trials may be slower than it anticipates or participants may drop out of these clinical trials at a higher rate than it anticipates;
● its third-party contractors may fail to comply with regulatory requirements or meet their contractual obligations to it in a timely manner, or at all;
● the cost of clinical trials of its drug candidates may be greater than it anticipates;
● the supply or quality of its drug candidates or other materials necessary to conduct clinical trials of its drug candidates may be insufficient or inadequate;
● regulators may revise the requirements for approving its drug candidates, or such requirements may not be as it anticipates; and
● any future collaborators that conduct clinical trials may face any of the above issues, and may conduct clinical trials in ways they view as advantageous to themselves but that are suboptimal for Notable.
If Notable is required to conduct additional clinical trials or other testing of its drug candidates beyond those that it currently contemplates, if Notable is unable to successfully complete clinical trials of its drug candidates or other testing, if the results of these trials or tests are not positive or are only modestly positive or if there are safety concerns, Notable may:
● incur unplanned costs;
● be delayed in obtaining marketing approval for Notable’s drug candidates or not obtain marketing approval at all;
● obtain marketing approval in some countries and not in others; obtain marketing approval for indications or patient populations that are not as broad as intended or desired;
● obtain marketing approval with labeling that includes significant use or distribution restrictions or safety warnings, including boxed warnings;
● be subject to additional post-marketing testing requirements; or
● have the drug removed from the market after obtaining marketing approval.
Furthermore, Notable relies and intend to rely in the future on CROs, cancer research centers and clinical trial sites to ensure the proper and timely conduct of its clinical trials and Notable intends to have agreements governing their committed activities. They may not perform as required or Notable may face competition from other clinical trials being conducted by other pharmaceutical companies.
Notable could encounter delays if a clinical trial is suspended or terminated by it, including upon the recommendation of the Data Safety Monitoring Board (“DSMB”) for such trial; by the IRB of the institutions in which such trials are being conducted; or by the FDA or other regulatory authorities. Such authorities may impose such a suspension or termination due to a number of factors, including failure to conduct the clinical trial in accordance with regulatory requirements or Notable’s clinical protocols, inspection of the clinical trial operations or trial site by the FDA or other regulatory authorities resulting in the imposition of a clinical hold, unforeseen safety issues or adverse side effects, failure to demonstrate a benefit from using a drug, changes in governmental regulations or administrative actions or lack of adequate funding to continue the clinical trial.
Further, conducting clinical trials in foreign countries, as Notable may do for Notable’s current and future drug candidates, presents additional risks that may delay completion of its clinical trials. These risks include the failure of enrolled patients in foreign countries to adhere to clinical protocol as a result of differences in healthcare services or cultural customs, managing additional administrative burdens associated with foreign regulatory schemes, as well as political and economic risks relevant to such foreign countries.
If Notable experiences delays in the completion of, or termination of, any clinical trial of its drug candidates, the commercial prospects of Notable’s drug candidates will be harmed, and Notable’s ability to generate revenues from any of these drug candidates will be delayed. In addition, any delays in completing Notable’s clinical trials will increase Notable’s costs, slow down its drug candidate development and approval process and jeopardize Notable’s ability to commence drug sales and generate revenues. Any of these occurrences may harm Notable’s business, financial condition and prospects significantly. In addition, many of the factors that cause, or lead to, a delay in the commencement or completion of clinical trials may also ultimately lead to the denial of regulatory approval of Notable’s drug candidates.
Results of early and prior clinical trials may not be indicative of results obtained in later trials.
The results of nonclinical and preclinical studies and clinical trials of Notable’s drug candidates may not be predictive of the results of later-stage clinical trials of Notable’s drug candidates, and interim results of a clinical trial do not necessarily predict final results. In some instances, there can be significant variability in safety or efficacy results between different clinical trials of the same product candidate due to numerous factors, including changes in trial procedures and timing of such procedures as set forth in protocols, differences in the size and type of the patient populations, changes in and adherence to the dosing regimen and the rate of dropout among clinical trial participants, among other factors. For example, Volasertib was evaluated by Boehringer Ingelheim in combination with low-dose cytarabine in patients with acute myeloid leukemia (“AML”) in Phase 2 and 3 clinical trials and Notable’s planned clinical trials of Volasertib in patients with AML may lead to different results. While the Phase 3 study commissioned by Boehringer Ingelheim did not meet the primary endpoint trial efficacy outcomes, Notable, while leveraging BII’s Volasertib dataset and years of pre-clinical and clinical development, plans to redesign Volasertib’s late-stage re-development program with the goal of increasing the clinical response rate and outcomes (by using Notable’s PPMP) and improving Volasertib’s tolerability (by enhanced patient management in line with BII’s conclusions from its post hoc Phase 3 analysis), however there is no assurance that the result will be different. Product candidates in later stages of clinical trials may fail to show the desired safety and efficacy profile despite having progressed through nonclinical studies and initial clinical trials. Data obtained from preclinical and clinical activities are subject to varying interpretations, which may delay, limit or prevent regulatory approval of Notable’s product candidates.
Notable’s drug candidates may cause undesirable side effects or have other properties that could delay or prevent their regulatory approval, limit the commercial profile of an approved label, or result in significant negative consequences following marketing approval, if any.
Undesirable side effects caused by Notable’s drug candidates could cause Notable or regulatory authorities to interrupt, delay or halt clinical trials and could result in a more restrictive label or the delay or denial of regulatory approval by the FDA or other comparable foreign authorities. It is possible that there may be side effects associated with any of Notable’s drug candidates. In such an event, Notable including upon the recommendation of the DSMB, the FDA or the IRBs at the institutions in which Notable’s studies are conducted could suspend or terminate Notable’s clinical trials or the FDA or comparable foreign regulatory authorities could order Notable to cease clinical trials or deny approval of Notable’s drug candidates for any or all targeted indications. Treatment-related side effects could also affect patient recruitment or the ability of enrolled patients to complete the clinical trial or result in potential product liability claims. In addition, these side effects may not be appropriately recognized or managed by the treating medical staff. Notable expects to have to train medical personnel using Notable’s drug candidates to understand the side effect profiles for Notable’s clinical trials and upon any commercialization of any of Notable’s drug candidates. Inadequate training in recognizing or managing the potential side effects of Notable’s drug candidates could result in patient injury or death. Any of these occurrences may harm Notable’s business, financial condition and prospects significantly.
Additionally, if one or more of Notable’s drug candidates receives marketing approval, and Notable or others later identify undesirable side effects caused by such drugs, a number of potentially significant negative consequences could result, including:
● regulatory authorities may withdraw approvals of such drugs;
● Notable may be required to recall a drug or change the way such a drug is administered to patients;
● additional restrictions may be imposed on the marketing or distribution of the particular drug or the manufacturing processes for the drug or any component thereof;
● regulatory authorities may require additional warnings on the label, such as a “black box” warning or contraindication;
● Notable may be required to implement Risk Evaluation and Mitigation Strategies, or REMS, or create a medication guide outlining the risks of such side effects for distribution to patients;
● Notable could be sued and held liable for harm caused to patients;
● Notable’s drug may become less competitive; and
● Notable’s reputation may suffer.
Any of these events could prevent Notable from achieving or maintaining market acceptance of the particular drug candidate or for particular indications of a drug candidate, if approved, and could significantly harm Notable’s business, results of operations and prospects. Notable’s approach to the discovery and development of drug candidates based on the PPMP is innovative and in the early stages of development; and Notable does not know whether it will be able to develop any drugs of commercial value.
Notable is leveraging the PPMP in an attempt to create a pipeline of drug candidates using biomarker identification and patient stratification for the development of oncology drugs. While Notable believes that applying the PPMP to drugs that have failed, been abandoned or otherwise failed to meet clinical endpoints and then developing a precision oncology approach that identifies the mechanism of action, potential combination drug usage and potentially responsive patient population is a powerful strategy, Notable’s approach is both innovative and in the early stages of development. Because Notable’s approach is both innovative and in the early stages of development, the cost and time needed to develop Notable’s drug candidates is difficult to predict, and Notable’s efforts may not result in the successful discovery and development of commercially viable medicines. Notable may also be incorrect about the effects of its drug candidates on the diseases of Notable’s defined patient populations, which may limit the utility of Notable’s approach or the perception of the utility of Notable’s approach. Furthermore, Notable’s estimates of Notable’s defined patient populations available for study and treatment may be lower than expected, which could adversely affect Notable’s ability to conduct clinical trials and may also adversely affect the size of any market for medicines Notable may successfully commercialize. Notable’s approach may not result in time savings, higher success rates or reduced costs as Notable expects it to, and if not, Notable may not attract collaborators or develop new drugs as quickly or cost effectively as expected and therefore Notable may not be able to commercialize Notable’s approach as originally expected.
The PPMP may fail to help Notable discover and develop additional potential drug candidates.
Any drug discovery or drug development that Notable is conducting through the PPMP may not be successful in identifying compounds that have commercial value or therapeutic utility. The PPMP may initially show promise in identifying potential drug candidates, yet fail to yield viable drug candidates for clinical development or commercialization for a number of reasons, including:
● research programs to identify new drug candidates will require substantial technical, financial and human resources, and Notable may be unsuccessful in its efforts to identify new drug candidates. If Notable is unable to identify suitable additional compounds for preclinical and clinical development, Notable’s ability to develop drug candidates and obtain product revenues in future periods could be compromised, which could result in significant harm to Notable’s financial position and adversely impact Notable’s stock price;
● compounds identified through the PPMP may not demonstrate efficacy, safety or tolerability;
● the data available for the PPMP that seeks to correlate genomic or biomarker signatures with certain cancers may be influenced by the race of the patient which may limit the efficacy of Notable’s drug candidates;
● potential drug candidates may, on further study, be shown to have harmful side effects or other characteristics that indicate that they are unlikely to receive marketing approval and achieve market acceptance;
● competitors may develop alternative therapies that render Notable’s potential drug candidates non-competitive or less attractive; or
● a potential drug candidate may not be capable of being produced at an acceptable cost.
Any failure by Notable to comply with existing regulations could harm Notable’s reputation and operating results.
Notable will be subject to extensive regulation by U.S. federal and state and foreign governments in each of the markets where Notable intends to sell Volasertib and Fosciclopirox if and after they are approved. For example, Notable will have to adhere to all regulatory requirements including the FDA’s GCPs, Good Laboratory Practice, or GLP, and current GMP requirements, or that of applicable foreign regulatory authorities. If Notable fails to comply with applicable regulations, including FDA pre-or post- approval cGMP requirements, then the FDA or other foreign regulatory authorities could sanction Notable. Even if a drug is FDA-approved, regulatory authorities may impose significant restrictions on a drug’s indicated uses or marketing or impose ongoing requirements for potentially costly post-marketing studies.
Any action against Notable for violation of these laws, even if Notable successfully defends against it, could cause Notable to incur significant legal expenses, divert Notable’s management’s attention from the operation of Notable’s business and damage Notable’s reputation. Notable will need to expend significant resources on compliance efforts and such expenses are unpredictable and might adversely affect Notable’s results.
The FDA’s and other regulatory authorities’ policies may change and additional government regulations may be enacted that could prevent, limit or delay regulatory approval of Notable’s drug candidates. For example, in December 2016, the 21st Century Cures Act, or Cures Act, was signed into law. The Cures Act, among other things, is intended to modernize the regulation of drugs and spur innovation, but its ultimate implementation is unclear. If Notable is slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies, or if Notable is not able to maintain regulatory compliance, Notable may lose any marketing approval that Notable may have obtained and Notable may not achieve or sustain profitability, which would adversely affect its business, prospects, financial condition and results of operations.
In addition, Notable cannot predict the likelihood, nature or extent of government regulation that may arise from future legislation or administrative or executive action, either in the United States or abroad. If future legislation or administrative or executive actions impose restrictions on FDA’s ability to engage in oversight and implementation activities in the normal course, Notable’s business may be negatively impacted. In addition, if Notable is slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies, or if Notable is not able to maintain regulatory compliance, Notable may lose any marketing approval that Notable may have obtained and Notable may not achieve or sustain profitability.
If Notable pursues marketing approvals outside of the United States, Notable may be subject to extensive regulations and may not obtain marketing approvals for drugs in Europe and other jurisdictions.
In addition to regulations in the United States, should Notable or its collaborators pursue marketing approvals for Volasertib and Fosciclopirox and Notable’s other drug candidates internationally, Notable and its collaborators will be subject to a variety of regulations in other jurisdictions governing, among other things, clinical trials and any commercial sales and distribution of Notable’s drugs. Whether or not Notable, or its collaborators, obtain applicable FDA regulatory clearance and marketing approval for a drug, Notable must obtain the requisite approvals from regulatory authorities in foreign countries prior to the commencement of clinical trials or marketing of the drug in those countries. The requirements and process governing the conduct of clinical trials, drug licensing, pricing and reimbursement vary from country to country.
Subject to obtaining necessary clinical data, Notable intends to pursue marketing approvals for Volasertib and Fosciclopirox and Notable’s other drug candidates in Europe and other jurisdictions outside the United States with collaborative partners. In order to market and sell Notable’s drugs in the European Union and many other foreign jurisdictions, Notable or its potential third-party collaborators must obtain separate marketing approvals and comply with numerous and varying regulatory requirements. The approval procedure varies among countries and can involve additional testing. The time required to obtain approval may differ substantially from that required to obtain FDA marketing approval. The regulatory approval process outside of the United States generally includes all of the risks associated with obtaining FDA approval. In addition, in many countries outside of the United States, it is required that the drug be approved for reimbursement before the drug can be approved for sale in that country. Notable or its potential third-party collaborators may not obtain approvals from regulatory authorities outside of the United States on a timely basis, if at all. Approval by the FDA does not ensure approval by regulatory authorities in other countries or jurisdictions, and approval by one regulatory authority outside of the United States does not ensure approval by regulatory authorities in other countries or jurisdictions or by the FDA. However, a failure or delay in obtaining regulatory approval in one country may have a negative effect on the regulatory process in other countries. Notable may not be able to file for marketing approvals and may not receive necessary approvals to commercialize Notable’s drugs in any market.
Additionally, June 23, 2024, will mark eight years since the people of the United Kingdom voted in a referendum to leave the European Union, commonly referred to as Brexit. Today, the United Kingdom is outside the European Union and mostly no longer subject to its rules. Significant portions of the regulatory framework in the United Kingdom have been derived from European Union directives and regulations and the impacts from Brexit could materially impact the regulatory regime with respect to the approval of Notable’s drug candidates in the United Kingdom or the European Union. Any delay in obtaining, or an inability to obtain, any marketing approvals, as a result of Brexit or otherwise, would prevent Notable from commercializing its drug candidates in the United Kingdom and/or the European Union and restrict Notable’s ability to generate revenue and achieve and sustain profitability. If any of these outcomes occur, Notable may be forced to restrict or delay efforts to seek regulatory approval in the United Kingdom and/or European Union for Notable’s drug candidates, which could materially and adversely affect Notable’s business.
The FDA and other regulatory agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses.
If Notable is found to have improperly promoted off-label uses of its drug candidates, if approved, Notable may become subject to significant liability. Such enforcement has become more common in the industry. The FDA and other regulatory agencies strictly regulate the promotional claims that may be made about prescription drug products, such as Notable’s drug candidates, if approved. In particular, a drug may not be promoted for uses that are not approved by the FDA or such other regulatory agencies as reflected in the drug’s approved labeling. If Notable receives marketing approval for Notable’s drug candidates for Notable’s proposed indications, physicians may nevertheless use Notable’s drugs for their patients in a manner that is inconsistent with the approved label, if the physicians personally believe in their professional medical judgment it could be used in such a manner. However, if Notable is found to have promoted Notable’s drugs for any off-label uses, the federal government could levy civil, criminal and/or administrative penalties, and seek fines against Notable. The FDA or other regulatory authorities could also request that Notable enter into a consent decree or a corporate integrity agreement, or seek a permanent injunction against Notable under which specified promotional conduct is monitored, changed or curtailed. If Notable cannot successfully manage the promotion of Notable’s drug candidates, if approved, Notable could become subject to significant liability, which would materially adversely affect its business and financial condition.
Notable may not experience a faster development or regulatory review or approval process with potential Fast Track designation.
If a drug is intended for the treatment of a serious condition and nonclinical or clinical data demonstrate the potential to address unmet medical need for this condition, a drug sponsor may apply for FDA Fast Track designation. If Notable seeks Fast Track designation for a drug candidate, Notable may not receive it from the FDA. However, even if Notable receives Fast Track designation, Fast Track designation does not ensure that Notable will receive marketing approval or that approval will be granted within any particular timeframe. Notable may not experience a faster development or regulatory review or approval process with Fast Track designation compared to conventional FDA procedures. In addition, the FDA may withdraw Fast Track designation if it believes that the designation is no longer supported by data from Notable’s clinical development program. Fast Track designation alone does not guarantee qualification for the FDA’s priority review procedures.
A breakthrough therapy designation by the FDA for Notable’s drug candidates may not lead to a faster development or regulatory review or approval process, and it does not increase the likelihood that Notable’s drug candidates will receive marketing approval.
Notable may seek a breakthrough therapy designation for some of its drug candidates. A breakthrough therapy is defined as a drug that is intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. For drugs and biologics that have been designated as breakthrough therapies, interaction and communication between the FDA and the sponsor of the trial can help to identify the most efficient path for clinical development while minimizing the number of patients placed in ineffective control regimens. Drugs designated as breakthrough therapies by the FDA are also eligible for accelerated approval.
Designation as a breakthrough therapy is within the discretion of the FDA. Accordingly, even if Notable believes one of its drug candidates meets the criteria for designation as a breakthrough therapy, the FDA may disagree and instead determine not to make such designation. Even if Notable receives breakthrough therapy designation, the receipt of such designation for a drug candidate may not result in a faster development process, review or approval compared to drugs considered for approval under conventional FDA procedures and does not assure ultimate approval by the FDA. In addition, even if one or more of Notable’s drug candidates qualify as breakthrough therapies, the FDA may later decide that the drugs no longer meet the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.
Risks Related to Commercialization of Notable’s Drug Candidates
Even if Notable is successful in completing all preclinical studies and clinical trials, Notable may not be successful in commercializing one or more of its drug candidates.
Even if Notable completes the necessary preclinical studies and clinical trials, the marketing approval process is expensive, time-consuming and uncertain and may prevent Notable from obtaining approvals for the commercialization of some or all of Notable’s drug candidates. If Notable is not able to obtain, or if there are delays in obtaining, required regulatory approvals, Notable will not be able to commercialize its drug candidates, and Notable’s ability to generate revenue will be materially impaired.
Notable’s drug candidates and the activities associated with their development and commercialization, including their design, testing, manufacture, safety, efficacy, recordkeeping, labeling, storage, approval, advertising, promotion, sale and distribution, export and import are subject to comprehensive regulation by the FDA and other regulatory agencies in the United States and by the EMA and similar regulatory authorities outside of the United States. Failure to obtain marketing approval for a drug candidate will prevent Notable from commercializing the drug candidate. Notable has not submitted an application for or received marketing approval for any of Notable’s drug candidates in the United States or in any other jurisdiction.
Notable has only limited experience in filing and supporting the applications necessary to gain marketing approvals and expects to rely on third-party CROs or other third-party consultants or vendors to assist Notable in this process. Securing marketing approval requires the submission of extensive preclinical and clinical data and supporting information to regulatory authorities for each therapeutic indication to establish the drug candidate’s safety and efficacy. Securing marketing approval also requires the submission of information about the drug manufacturing process to, and inspection of manufacturing facilities by, the regulatory authorities. Notable’s drug candidates may not be effective, may be only moderately effective or may prove to have undesirable or unintended side effects, toxicities or other characteristics that may preclude Notable’s obtaining marketing approval or prevent or limit commercial use. New cancer drugs frequently are indicated only for patient populations that have not responded to an existing therapy or have relapsed. If any of Notable’s drug candidates receives marketing approval, the accompanying label may limit the approved use of Notable’s drug in this way, which could limit sales of the drug.
The process of obtaining marketing approvals, both in the United States and abroad, is expensive, may take many years, if approval is obtained at all, and can vary substantially based upon a variety of factors, including the type, complexity and novelty of the drug candidates involved. Changes in marketing approval policies during the development period, changes in or the enactment of additional statutes or regulations, or changes in regulatory review for each submitted drug application, may cause delays in the approval or rejection of an application. Regulatory authorities have substantial discretion in the approval process and may refuse to accept any application or may decide that Notable’s data is insufficient for approval and require additional preclinical, clinical or other studies. In addition, varying interpretations of the data obtained from preclinical studies and clinical trials could delay, limit or prevent marketing approval of a drug candidate. Any marketing approval Notable ultimately obtains may be limited or subject to restrictions or post-approval commitments that render the approved drug not commercially viable.
If Notable’s drugs do not gain market acceptance, Notable’s business will suffer because Notable might not be able to fund future operations.
A number of factors may affect the market acceptance of Notable’s drugs or any other products Notable develops or acquires, including, among others:
● the price of Notable’s drugs relative to other products for the same or similar treatments;
● the perception by patients, physicians and other members of the health care community of the effectiveness and safety of Notable’s drugs for their indicated applications and treatments;
● Notable’s ability to fund its sales and marketing efforts; and
● the effectiveness of Notable’s sales and marketing efforts.
If Notable’s drugs do not gain market acceptance, Notable may not be able to fund future operations, including developing, testing and obtaining regulatory approval for new drug candidates and expanding Notable’s sales and marketing efforts for Notable’s approved drugs, which would cause Notable’s business to suffer.
Notable may rely on orphan drug designation to commercialize some of Notable’s drug candidates, and even if orphan drug designation is granted, such designation may not confer marketing exclusivity or other commercial advantages or expected commercial benefits.
Notable may rely on orphan drug designation for its drug candidates. In the United States, orphan drug designation entitles a party to financial incentives such as opportunities for grant funding towards clinical trial costs, tax advantages and user-fee waivers. In addition, if a drug that has orphan drug designation subsequently receives the first FDA marketing approval for the disease for which it has such designation, the drug is entitled to orphan drug exclusivity. Orphan drug exclusivity in the United States provides that the FDA may not approve any other applications, including a full NDA, to market the same drug for the same indication for seven years, and except in limited circumstances the applicable exclusivity period is ten years in Europe. The European exclusivity period can be reduced to six years if a drug no longer meets the criteria for orphan drug designation or if the drug is sufficiently profitable so that market exclusivity is no longer justified.
Even if Notable, or any future collaborators, obtains orphan drug designation for a drug candidate, Notable, or they, may not be able to obtain or maintain orphan drug exclusivity for that drug candidate. Notable may not be the first to obtain marketing approval of any drug candidate for which Notable has obtained orphan drug designation for the orphan-designated indication due to the uncertainties associated with developing pharmaceutical products, and it is possible that another company also holding orphan drug designation for the same drug candidate will receive marketing approval for the same indication before Notable does. If that were to happen, Notable’s application for that indication may not be approved until the competing company’s period of exclusivity expires. In addition, exclusive marketing rights in the United States may be limited if Notable seeks approval for an indication broader than the orphan-designated indication or may be lost if the FDA later determines that the request for designation was materially defective or if Notable is unable to assure sufficient quantities of the drug to meet the needs of patients with the rare disease or condition. Further, even if Notable, or any future collaborators, obtains orphan drug exclusivity for a drug, that exclusivity may not effectively protect the drug from competition because different drugs with different active moieties may be approved for the same condition. Even after an orphan drug is approved, the FDA can subsequently approve the same drug with the same active moiety for the same condition if the FDA concludes that the later drug is clinically superior in that it is shown to be safer, more effective or makes a major contribution to patient care or the manufacturer of the drug with orphan exclusivity is unable to maintain sufficient drug quantity. Orphan drug designation neither shortens the development time or regulatory review time of a drug nor gives the drug any advantage in the regulatory review or approval process, nor does it prevent competitors from obtaining approval of the same drug candidate as Notable’s for indications other than those in which Notable has been granted orphan drug designation.
On August 3, 2017, the U.S. Congress passed the FDA Reauthorization Act of 2017, or FDARA. FDARA, among other things, codified the FDA’s preexisting regulatory interpretation, to require that a drug sponsor demonstrate the clinical superiority of an orphan drug that is otherwise the same as a previously approved drug for the same rare disease in order to receive orphan drug exclusivity. The legislation reverses prior precedent holding that the Orphan Drug Act unambiguously requires that the FDA recognize the orphan exclusivity period regardless of a showing of clinical superiority. Moreover, in the Consolidated Appropriations Act of 2021, Congress did not further change this interpretation when it clarified that the interpretation codified in FDARA would apply in cases where FDA issued an orphan designation before the enactment of FDARA but where product approval came after the enactment of FDARA. Congress or the FDA may further reevaluate the Orphan Drug Act and its regulations and policies. Notable does not know if, when or how the FDA may change the orphan drug regulations and policies in the future, and it is uncertain how any changes might affect Notable’s business. Depending on what changes the FDA may make to orphan drug regulations and policies, Notable’s business could be adversely impacted.
If Notable is required by the FDA to obtain approval of a companion diagnostic in connection with approval of a therapeutic drug candidate, and Notable does not obtain or face delays in obtaining FDA approval of a diagnostic device, Notable will not be able to commercialize the drug candidate and Notable’s ability to generate revenue will be materially impaired.
According to FDA guidance, if the FDA determines that a companion diagnostic device is essential to the safe and effective use of a novel therapeutic drug or indication, the FDA generally will not approve the therapeutic drug or new therapeutic drug indication if the companion diagnostic is not also approved or cleared for that indication. Under the Federal Food, Drug, and Cosmetic Act, or FDCA, companion diagnostics are regulated as medical devices, and the FDA has generally required companion diagnostics intended to select the patients who will respond to cancer treatment to obtain Premarket Approval, or a PMA, for the diagnostic. The PMA process, including the gathering of clinical and preclinical data and the submission to and review by the FDA, involves a rigorous premarket review during which the applicant must prepare and provide the FDA with reasonable assurance of the device’s safety and effectiveness and information about the device and its components regarding, among other things, device design, manufacturing and labeling. A PMA is not guaranteed and may take considerable time, and the FDA may ultimately respond to a PMA submission with a “not approvable” determination based on deficiencies in the application and require additional clinical trial or other data that may be expensive and time-consuming to generate and that can substantially delay approval. As a result, if Notable is required by the FDA to obtain approval of a companion diagnostic for a therapeutic drug candidate, and Notable does not obtain or there are delays in obtaining FDA approval of a diagnostic device, Notable may not be able to commercialize the drug candidate on a timely basis or at all and Notable’s ability to generate revenue will be materially impaired.
Any drug candidate that Notable obtains marketing approval for could be subject to post-marketing restrictions or withdrawal from the market and Notable may be subject to substantial penalties if Notable fails to comply with regulatory requirements or if Notable experiences unanticipated problems with Notable’s drugs, when and if any of them are approved.
Any drug candidate for which Notable obtains marketing approval, along with the manufacturing processes, post-approval clinical data, labeling, advertising and promotional activities for such drug, will be subject to continual requirements of and review by the FDA and other regulatory authorities. These requirements include submissions of safety and other post-marketing information and reports, registration and listing requirements, cGMP requirements relating to manufacturing, quality control, quality assurance and corresponding maintenance of records and documents, requirements regarding the distribution of samples to physicians and recordkeeping. Even if marketing approval of a drug candidate is granted, the approval may be subject to limitations on the indicated uses for which the drug may be marketed or to the conditions of approval, including the requirement to implement a REMS. New cancer drugs frequently are indicated only for patient populations that have not responded to an existing therapy or have relapsed. If any of Notable’s drug candidates receives marketing approval, the accompanying label may limit the approved use of Notable’s drug in this way, which could limit sales of the drug.
The FDA may also impose requirements for costly post-marketing studies or clinical trials and surveillance to monitor the safety or efficacy of the drug, including the adoption and implementation of REMS. The FDA and other agencies, including the Department of Justice, or the DOJ, closely regulate and monitor the post-approval marketing and promotion of drugs to ensure they are marketed and distributed only for the approved indications and in accordance with the provisions of the approved labeling. The FDA and DOJ impose stringent restrictions on manufacturers’ communications regarding off-label use, and if Notable does not market its drugs for their approved indications, Notable may be subject to enforcement action for off-label marketing. Violations of the FDCA and other statutes, including the False Claims Act, relating to the promotion and advertising of prescription drugs may lead to investigations and enforcement actions alleging violations of federal and state healthcare fraud and abuse laws, as well as state consumer protection laws.
In addition, later discovery of previously unknown adverse events or other problems with Notable’s drugs, manufacturers or manufacturing processes, or failure to comply with regulatory requirements, may have various consequences, including:
● restrictions on such drugs, manufacturers or manufacturing processes;
● restrictions and warnings on the labeling or marketing of a drug;
● restrictions on drug distribution or use;
● requirements to conduct post-marketing studies or clinical trials;
● warning letters or untitled letters;
● withdrawal of the drugs from the market;
● refusal to approve pending applications or supplements to approved applications that Notable submits;
● recall of drugs;
● fines, restitution or disgorgement of profits or revenues;
● suspension or withdrawal of marketing approvals;
● damage to relationships with any potential collaborators;
● unfavorable press coverage and damage to Notable’s reputation;
● refusal to permit the import or export of Notable’s drugs;
● drug seizure;
● injunctions or the imposition of civil or criminal penalties; or
● litigation involving patients using Notable’s drugs.
Notable operates in a highly competitive and rapidly changing industry.
Biotechnological and pharmaceutical drug development is highly competitive and subject to rapid and significant technological advancements. Notable’s success is highly dependent upon Notable’s ability to in-license, acquire, develop and obtain regulatory approval for new and innovative drugs on a cost-effective basis and to market them successfully. In doing so, Notable faces and will continue to face intense competition from a variety of businesses, including large, fully integrated, well-established pharmaceutical companies who already possess a large share of the market, specialty pharmaceutical and biopharmaceutical companies, academic institutions, government agencies and other private and public research institutions in the United States, the European Union and other jurisdictions.
Many of the companies against which Notable is competing or against which Notable may compete in the future have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals and marketing approved drugs than Notable does. These third parties compete with Notable in recruiting and retaining qualified scientific and management personnel, establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, Notable’s programs. Mergers and acquisitions in the pharmaceutical and biotechnology industries could result in even more resources being concentrated among a small number of Notable’s competitors.
Competition may further increase as a result of advances in the commercial applicability of technologies and greater availability of capital for investment in these industries. Notable’s competitors may succeed in developing, acquiring or licensing, on an exclusive basis, drugs that are more effective or less costly than any drug candidate that Notable may develop.
Established pharmaceutical and biotechnology companies may invest heavily to accelerate discovery and development of novel compounds or to in-license novel compounds that could make Notable’s drug candidates less competitive. In addition, any new drug that competes with an approved drug must demonstrate compelling advantages in efficacy, convenience, tolerability and safety in order to overcome price competition and to be commercially successful. Accordingly, Notable’s competitors may succeed in obtaining patent protection, discovering, developing, receiving FDA approval for or commercializing drugs before Notable does, which would have an adverse impact on Notable’s business and results of operations.
The availability of Notable’s competitors’ drugs could limit the demand and the price Notable is able to charge for any drug candidate Notable commercialized, if any. The inability to compete with existing or subsequently introduced drugs would harm Notable’s business, financial condition and results of operations.
If Notable is unable to develop satisfactory sales and marketing capabilities, Notable may not succeed in commercializing Volasertib and Fosciclopirox or any other drug candidate for which it obtains marketing approval.
Notable has no experience in marketing and selling drug products. Notable has not entered into arrangements for the sale and marketing of Volasertib and Fosciclopirox or any other drug candidate, if approved. Typically, pharmaceutical companies would employ groups of sales representatives and associated sales and marketing staff numbering in the hundreds to thousands of individuals to call on a large number of physicians and hospitals. Notable may seek to collaborate with a third party to market Notable’s drugs or itself may seek to market and sell Notable’s drugs. If Notable seeks to collaborate with a third party, Notable cannot be sure that a collaborative agreement can be reached on terms acceptable to Notable. If Notable seeks to market and sell its drugs directly, Notable will need to hire additional personnel skilled in marketing and sales. Notable cannot be sure that Notable will be able to acquire, or establish third party relationships to provide, any or all of these marketing and sales capabilities. The establishment of a direct sales force or a contract sales force or a combination direct and contract sales force to market Notable’s drugs will be expensive and time-consuming and could delay any drug launch. Further, Notable can give no assurances that Notable may be able to maintain a direct and/or contract sales force for any period of time or that Notable’s sales efforts will be sufficient to generate or to grow Notable’s revenues or that Notable’s sales efforts will ever lead to profits.
Even if Notable obtains regulatory approvals to commercialize Volasertib and Fosciclopirox or Notable’s other drug candidates, Notable’s drug candidates may not be accepted by physicians or the medical community in general.
There can be no assurance that Volasertib and Fosciclopirox and Notable’s other drug candidates or any other drug candidate successfully developed by Notable, independently or with partners, will be accepted by physicians, hospitals and other health care facilities. Volasertib and Fosciclopirox and any future drug candidates Notable develops will compete with a number of drugs manufactured and marketed by major pharmaceutical and biotech companies. The degree of market acceptance of any drugs Notable develops depends on a number of factors, including:
● Notable’s demonstration of the clinical efficacy and safety of Volasertib and Fosciclopirox and Notable’s other drug candidates;
● timing of market approval and commercial launch of Volasertib and Fosciclopirox and Notable’s other drug candidates;
● the clinical indication(s) for which Volasertib and Fosciclopirox and Notable’s other drug candidates are approved;
● drug label and package insert requirements;
● advantages and disadvantages of Notable’s drug candidates compared to existing continued interest in and growth of the market for anticancer drugs;
● strength of sales, marketing, and distribution support;
● drug pricing in absolute terms and relative to alternative treatments;
● future changes in health care laws, regulations, and medical policies; and
● availability of reimbursement codes and coverage in select jurisdictions, and future changes to reimbursement policies of government and third-party payors.
Significant uncertainty exists as to the coverage and reimbursement status of any drug candidate for which Notable obtains regulatory approval. In the United States and markets in other countries, sales of any drugs for which Notable receives regulatory approval for commercial sale will depend in part on the availability of reimbursement from third-party payors. Third-party payors include government health administrative authorities, managed care providers, private health insurers and other organizations.
Healthcare reform measures could hinder or prevent Notable’s drug candidates’ commercial success.
The U.S. government and other governments have shown significant interest in pursuing healthcare reform. Any government-adopted reform measures could adversely impact the pricing of healthcare drugs and services in the United States or internationally and the amount of reimbursement available from governmental agencies or other third-party payors. The continuing efforts of the U.S. and foreign governments, insurance companies, managed care organizations and other payors of health care services to contain or reduce health care costs may adversely affect Notable’s ability to set prices for its drugs which Notable believes are fair, and Notable’s ability to generate revenues and achieve and maintain profitability.
In the United States, some states have implemented, and other states are considering, pharmaceutical price controls or patient access constraints under their Medicaid program. There have also been recent state legislative efforts that have generally focused on increasing transparency around drug costs or limiting drug prices. In addition, the growth of large managed care organizations and prescription benefit managers, as well as the prevalence of generic substitution, has hindered price increases for prescription drugs. Continued intense public scrutiny of the price of drugs, together with government and payor dynamics, may limit the ability of producers and marketers to set or adjust the price of products based on their value. Outside the United States, numerous major markets, including the EU, Japan and China, have pervasive government involvement in funding healthcare, and, in that regard, fix the pricing and reimbursement of pharmaceutical products. Consequently, Notable’s products will be subject to increasing government decision-making and budgetary actions. There can be no assurance that new or proposed products will be considered cost-effective or that adequate third-party reimbursement will be available to enable the producer or marketer of such product to maintain price levels sufficient to realize an appropriate return.
New laws, regulations and judicial decisions, or new interpretations of existing laws, regulations and decisions, that relate to healthcare availability, methods of delivery or payment for products and services, or sales, marketing or pricing, may limit Notable’s potential revenue, and Notable may need to revise its research and development programs. The pricing and reimbursement environment may change in the future and become more challenging due to several reasons, including policies advanced by the current executive administration in the United States, new healthcare legislation or fiscal challenges faced by government health administration authorities. Specifically, in both the United States and some foreign jurisdictions, there have been a number of legislative and regulatory proposals to change the health care system in ways that could affect Notable’s ability to sell its drugs profitably.
For example, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act, or the ACA, has substantially changed the way healthcare is financed by both government health plans and private insurers, and significantly impacts the pharmaceutical industry. The ACA contains a number of provisions that are expected to impact Notable’s business and operations in ways that may negatively affect Notable’s potential revenues in the future. For example, the ACA imposes a non-deductible excise tax on pharmaceutical manufacturers or importers that sell branded prescription drugs to government programs which Notable believes will increase the cost of Notable’s drugs. In addition, as part of the ACA’s provisions closing a funding gap that currently exists in the Medicare Part D prescription drug program, Notable will be required to provide a discount on branded prescription drugs equal to 50% of the government-negotiated price, for drugs provided to certain beneficiaries who fall within the donut hole (which was subsequently increased to 70%, the current discount owed as of January 1, 2019 pursuant to the Bipartisan Budget Act of 2018, or BBA). Similarly, ACA increases the level of Medicaid rebates payable by manufacturers of brand-name drugs from 15.1% to 23.1% and requires collection of rebates for drugs paid by Medicaid managed care organizations. The ACA also includes significant changes to the 340B drug discount program including expansion of the list of eligible covered entities that may purchase drugs under the program. At the same time, the expansion in eligibility for health insurance benefits created under ACA is expected to increase the number of patients with insurance coverage who may receive Notable’s drugs. While it is too early to predict all the specific effects the ACA or any future healthcare reform legislation will have on Notable’s business, they could have a material adverse effect on Notable’s business and financial condition.
Congress periodically adopts legislation like the ACA and the Medicare Prescription Drug, Improvement, and Modernization Act of 2003, or the MMA, that modifies Medicare reimbursement and coverage policies pertaining to prescription drugs. Implementation of these laws is subject to ongoing revision through regulatory and sub regulatory policies. Congress also may consider additional changes to Medicare policies, potentially including Medicare prescription drug policies, as part of ongoing budget negotiations. While the scope of any such legislation is uncertain at this time, there can be no assurances that future legislation or regulations will not decrease the coverage and price that Notable may receive for Notable’s proposed drugs. Other third-party payors are increasingly challenging the prices charged for medical products and services. It will be time consuming and expensive for Notable to go through the process of seeking coverage and reimbursement from Medicare and private payors. Notable’s proposed drugs may not be considered cost-effective, and coverage and reimbursement may not be available or sufficient to allow Notable to sell Notable’s proposed drugs on a profitable basis. Further federal and state proposals and health care reforms are likely which could limit the prices that can be charged for the drug candidates that Notable develop and may further limit Notable’s commercial opportunities. Notable’s results of operations could be materially adversely affected by proposed healthcare reforms, by the Medicare prescription drug coverage legislation, by the possible effect of such current or future legislation on amounts that private insurers will pay and by other health care reforms that may be enacted or adopted in the future.
In September 2007, the Food and Drug Administration Amendments Act of 2007 was enacted, giving the FDA enhanced post-marketing authority, including the authority to require post-marketing studies and clinical trials, labeling changes based on new safety information, and compliance with REMS approved by the FDA. The FDA’s exercise of this authority could result in delays or increased costs during drug development, clinical trials and regulatory review, increased costs to assure compliance with post-approval regulatory requirements, and potential restrictions on the sale and/or distribution of approved drugs.
Notable’s relationships with healthcare providers, physicians and third-party payors will be subject to applicable anti-kickback, fraud and abuse, false claims, transparency, health information privacy and security, and other healthcare laws and regulations, which, in the event of a violation, could expose Notable to criminal sanctions, civil penalties, contractual damages, reputational harm, administrative burdens and diminished profits and future earnings.
Healthcare providers, physicians and third-party payors will play a primary role in the recommendation and prescription of any drug candidates for which Notable obtains marketing approval. Notable’s future arrangements with healthcare providers, physicians and third-party payors may expose Notable to broadly applicable fraud and abuse and other healthcare laws and regulations that may constrain the business or financial arrangements and relationships through which Notable markets, sells and distributes any drugs for which Notable obtain marketing approval. In addition, Notable may be subject to transparency laws and patient privacy regulation by U.S. federal and state governments and by governments in foreign jurisdictions in which Notable conducts its business. Restrictions under applicable federal and state healthcare laws and regulations include the following:
● the federal Anti-Kickback Statute prohibits, among other things, persons from knowingly and willfully soliciting, offering, receiving or providing remuneration, directly or indirectly, in cash or in kind, to induce or reward, or in return for, either the referral of an individual for, or the purchase, order or recommendation or arranging of, any good or service, for which payment may be made under a federal healthcare program such as Medicare and Medicaid;
● the federal False Claims Act imposes criminal and civil penalties, including through civil whistleblower or qui tam actions, against individuals or entities for, among other things, knowingly presenting, or causing to be presented, false or fraudulent claims for payment by a federal healthcare program or making a false statement or record material to payment of a false claim or avoiding, decreasing or concealing an obligation to pay money to the federal government, with potential liability including mandatory treble damages and significant per-claim penalties;
● the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, imposes criminal and civil liability for executing a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters;
● HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009, and their respective implementing regulations, also imposes obligations, including mandatory contractual terms, with respect to safeguarding the privacy, security and transmission of individually identifiable health information;
● the federal Physician Payments Sunshine Act requires applicable manufacturers of covered drugs to report payments and other transfers of value to physicians and teaching hospitals; and
● analogous state and foreign laws and regulations, such as state anti-kickback and false claims laws and transparency statutes, may apply to sales or marketing arrangements and claims involving healthcare items or services reimbursed by non-governmental third-party payors, including private insurers.
Some state laws require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government and may require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers or marketing expenditures. Additionally, some state and local laws require the registration of pharmaceutical sales representatives in the jurisdiction. State and foreign laws also govern the privacy and security of health information in some circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts.
Efforts to ensure that Notable’s business arrangements with third parties will comply with applicable healthcare laws and regulations will involve substantial costs. It is possible that governmental authorities will conclude that Notable’s business practices may not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws and regulations. If Notable’s operations are found to be in violation of any of these laws or any other governmental regulations that may apply to Notable, it may be subject to significant civil, criminal and administrative penalties, damages, fines, imprisonment, exclusion of drugs from government funded healthcare programs, such as Medicare and Medicaid, and the curtailment or restructuring of Notable’s operations. If any of the physicians or other healthcare providers or entities with whom Notable expects to do business is found to be not in compliance with applicable laws, they may be subject to criminal, civil or administrative sanctions, including exclusions from participation in government funded healthcare programs.
Recently enacted and future legislation may increase the difficulty and cost for Notable to obtain marketing approval of and commercialize its drug candidates and affect the prices Notable may obtain for any drugs that are approved in the United States or foreign jurisdictions.
In the United States and some foreign jurisdictions, there have been a number of legislative and regulatory changes and proposed changes regarding the healthcare system that could prevent or delay marketing approval of Notable’s drug candidates, restrict or regulate post-approval activities and affect Notable’s ability to profitably sell any drug candidates for which Notable obtains marketing approval. The pharmaceutical industry has been a particular focus of these efforts and has been significantly affected by legislative initiatives. Current laws, as well as other healthcare reform measures that may be adopted in the future, may result in more rigorous coverage criteria and in additional downward pressure on the price that Notable receives for any FDA approved drug.
In the United States, the MMA changed the way Medicare covers and pays for pharmaceutical products. The legislation expanded Medicare coverage for drug purchases by the elderly and introduced a new reimbursement methodology based on average sales prices for physician-administered drugs. In addition, this legislation provided authority for limiting the number of drugs that will be covered in any therapeutic class. Cost reduction initiatives and other provisions of this legislation could decrease the coverage and price that Notable receives for any approved drugs.
While the MMA applies only to drug benefits for Medicare beneficiaries, private payors often follow Medicare coverage policy and payment limitations in setting their own reimbursement rates. Therefore, any reduction in reimbursement that results from the MMA may result in a similar reduction in payments from private payors.
In March 2010, President Obama signed into law the ACA. Among the provisions of the ACA of potential importance to Notable’s business, including, without limitation, Notable’s ability to commercialize and the prices Notable may obtain for any of its drug candidates that are approved for sale, are the following:
● an annual, non-deductible fee on any entity that manufactures or imports specified branded prescription drugs and biologic agents;
● an increase in the statutory minimum rebates a manufacturer must pay under the Medicaid Drug Rebate Program;
● expansion of healthcare fraud and abuse laws, including the civil False Claims Act and the federal Anti-Kickback Statute, new government investigative powers and enhanced penalties for noncompliance;
● a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 50% (and 70% starting January 1, 2019) point-of-sale discounts off negotiated prices;
● extension of manufacturers’ Medicaid rebates;
● expansion of eligibility criteria for Medicaid programs;
● expansion of the entities eligible for discounts under the Public Health Service pharmaceutical pricing;
● new requirements to report certain financial arrangements with physicians and teaching hospitals;
● a new requirement to annually report drug samples that manufacturers and distributors provide to physicians; and
● a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research.
In addition, other legislative changes have been proposed and adopted since the ACA was enacted. These changes include the Budget Control Act of 2011, which, among other things, led to aggregate reductions to Medicare payments to providers of up to 2% per fiscal year that started in 2013 and, due to subsequent legislative amendments to the statute, will stay in effect through 2032 unless additional congressional action is taken, and the American Taxpayer Relief Act of 2012, which, among other things, reduced Medicare payments to several types of providers and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.
In August 2022, the Inflation Reduction Act of 2022 (the “IRA”) was signed into law. The IRA includes several provisions that may impact Notable’s business to varying degrees, including provisions that create a $2,000 out-of-pocket cap for Medicare Part D beneficiaries, impose new manufacturer financial liability on all drugs in Medicare Part D, allow the U.S. government to negotiate Medicare Part B and Part D pricing for certain high-cost drugs and biologics without generic or biosimilar competition, require companies to pay rebates to Medicare for drug prices that increase faster than inflation, and delay the rebate rule that would require pass through of pharmacy benefit manager rebates to beneficiaries. The effect of IRA on Notable’s business and the healthcare industry in general is not yet known.
These new laws may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices Notable may obtain for any of its drug candidates for which Notable may obtain regulatory approval or the frequency with which any such drug candidate is prescribed or used. Further, there have been several recent U.S. congressional inquiries and proposed state and federal legislation designed to, among other things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, reduce the costs of drugs under Medicare and reform government program reimbursement methodologies for drug products.
Notable expects that these healthcare reforms, as well as other healthcare reform measures that may be adopted in the future, may result in additional reductions in Medicare and other healthcare funding, more rigorous coverage criteria, new payment methodologies and additional downward pressure on the price that Notable receives for any approved drug and/or the level of reimbursement physicians receive for administering any approved drug Notable might bring to market. Reductions in reimbursement levels may negatively impact the prices Notable receives or the frequency with which Notable’s drugs are prescribed or administered. Any reduction in reimbursement from Medicare or other government programs may result in a similar reduction in payments from private payors.
The costs of prescription pharmaceuticals have also been the subject of considerable discussion in the United States, and members of Congress have stated that they will address such costs through new legislative and administrative measures. To date, there have been several recent U.S. congressional inquiries and proposed and enacted state and federal legislation designed to, among other things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, reduce the costs of drugs under Medicare and reform government program reimbursement methodologies for drug products. While any proposed measures will require authorization through additional legislation to become effective, Congress has indicated that it will continue to seek new legislative and/or administrative measures to control drug costs. At the state level, legislatures are increasingly passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.
Legislative and regulatory proposals have been made to expand post-approval requirements and restrict sales and promotional activities for pharmaceutical products. Notable cannot be sure whether additional legislative changes will be enacted, or whether FDA regulations, guidance or interpretations will be changed, or what the impact of such changes on the marketing approvals of Notable’s drug candidates, if any, may be. Increased scrutiny by the U.S. Congress of the FDA’s approval process may significantly delay or prevent marketing approval, as well as subject Notable to more stringent product labeling and post-marketing testing and other requirements.
If Notable or any third-party manufacturers or contractors Notable engages now or in the future fail to comply with environmental, health and safety laws and regulations, Notable could become subject to fines or penalties or incur costs or liabilities that could harm Notable’s business.
Notable and third-party manufacturers it engages now are, and any third-party manufacturers Notable may engage in the future will be, subject to numerous environmental, health and safety laws and regulations, including those governing laboratory procedures and the handling, use, storage, treatment and disposal of hazardous materials and wastes. Notable’s operations, including work conducted through third-party manufacturers or contractors, involve the use of hazardous and flammable materials, including chemicals and biological materials. Notable’s operations also produce hazardous waste products. Notable generally contracts with third parties for the disposal of these materials and wastes. Notable cannot eliminate the risk of contamination or injury from these materials. In the event of contamination or injury resulting from Notable’s use of hazardous materials, Notable could be held liable for any resulting damages, and any liability could exceed Notable’s resources. Liability under certain environmental laws governing the release and cleanup of hazardous materials is joint and several and could be imposed without regard to fault. Notable also could incur significant costs associated with civil or criminal fines and penalties or become subject to injunctions limiting or prohibiting Notable’s activities for failure to comply with such laws and regulations.
Although Notable maintains general liability insurance as well as workers’ compensation insurance to cover Notable for costs and expenses Notable may incur due to injuries to Notable’s employees resulting from the use of hazardous materials, this insurance may not provide adequate coverage against potential liabilities. Notable does not maintain insurance for environmental liability or toxic tort claims that may be asserted against Notable in connection with Notable’s, or its contractors, storage or disposal of biological, hazardous or radioactive materials.
In addition, Notable may incur substantial costs in order to comply with current or future environmental, health and safety laws and regulations. These current or future laws and regulations may impair Notable’s research, development or production efforts. Notable’s failure to comply with these laws and regulations also may result in substantial fines, penalties or other sanctions.
Further, with respect to the operations of Notable’s current and any future third-party contract manufacturers or other contractors, it is possible that if they fail to operate in compliance with applicable environmental, health and safety laws and regulations or properly dispose of wastes associated with Notable’s drugs, Notable could be held liable for any resulting damages, suffer reputational harm or experience a disruption in the manufacture and supply of Notable’s drug candidates or drugs. In addition, Notable’s supply chain may be adversely impacted if any of its third-party contract manufacturers become subject to injunctions or other sanctions as a result of their non-compliance with environmental, health and safety laws and regulations.
Notable may experience challenges with the acquisition, development, enhancement or deployment of technology necessary for the PPMP.
Notable operates in businesses that require sophisticated computer systems and software for data collection, data processing, cloud-based platforms, analytics, statistical projections and forecasting, mobile computing, social media analytics and other applications and technologies. Notable seeks, in part, to address Notable’s technology risks by increasing its reliance on the use of innovations by cross-industry technology leaders and adapting these for Notable’s applicable needs and applications. Some of the technologies supporting Notable’s industry are changing rapidly and Notable must continue to adapt to these changes in a timely and effective manner at an acceptable cost. Notable also must continue to obtain and utilize data in forms that are easy to use while simultaneously providing clear answers to complex questions. There can be no guarantee that Notable will be able to develop, acquire or integrate new technologies, that these new technologies will meet Notable’s needs or achieve Notable’s expected goals, or that Notable will be able to do so as quickly or cost-effectively as its competitors. Significant technological change could render the PPMP obsolete. Notable’s continued success will depend on its ability to adapt to changing technologies, manage and process ever-increasing amounts of data and information and improve the performance, features and reliability of Notable’s platform and capabilities in response to changing internal and industry demands. Notable may experience difficulties that could delay or prevent the successful design, development, testing, and introduction of advanced versions of the PPMP, limiting Notable’s ability to identify new drug candidates. New services, or enhancements to existing services using the PPMP, may not adequately meet Notable’s requirements. Any of these failures could have a material adverse effect on Notable’s operating results and financial condition.
Risks Related to Notable’s Reliance on Third Parties
Notable relies on third parties to conduct Notable’s preclinical studies and clinical trials. If these third parties do not successfully perform their contractual legal and regulatory duties or meet expected deadlines, Notable may not be able to obtain regulatory approval for or commercialize Notable’s drug candidates and Notable’s business could be substantially harmed.
Notable has relied upon and plans to continue to rely upon third-party medical institutions, clinical investigators, contract laboratories and other third party CROs to monitor and manage data for Notable’s ongoing preclinical and clinical programs. Notable also relies on these parties for execution of Notable’s preclinical studies and clinical trials, and controls only certain aspects of their activities. Nevertheless, Notable is responsible for ensuring that each of Notable’s studies is conducted in accordance with the applicable protocol, legal, regulatory and scientific standards, and Notable’s reliance on the CROs does not relieve Notable of its regulatory responsibilities. Notable and its CROs are required to comply with GCPs, which are regulations and guidelines enforced by the FDA, the Competent Authorities of the Member States of the European Economic Area, or EEA, and comparable foreign regulatory authorities, for all of Notable’s drugs in clinical development.
Regulatory authorities enforce these GCPs through periodic inspections of trial sponsors, principal investigators and trial sites. If Notable or any of its CROs fail to comply with applicable GCPs, the clinical data generated in Notable’s clinical trials may be deemed unreliable and the FDA, the EMA or comparable foreign regulatory authorities may require Notable to perform additional clinical trials before approving Notable’s marketing applications. Notable cannot assure you that upon inspection by a given regulatory authority, such regulatory authority will determine that any of Notable’s clinical trials comply with GCP regulations. In addition, Notable’s clinical trials must be conducted with product produced under current Good Manufacturing Practices (“cGMP”) regulations. Notable’s failure to comply with these regulations may require Notable to repeat clinical trials, which would delay the regulatory approval process.
If any of Notable’s relationships with these third-party CROs terminate, Notable may not be able to enter into arrangements with alternative CROs or to do so on commercially reasonable terms. In addition, Notable’s CROs are not Notable’s employees, and except for remedies available to Notable under its agreements with such CROs, Notable cannot control whether or not they devote sufficient time and resources to Notable’s on-going clinical, nonclinical and preclinical programs. If CROs do not successfully carry out their contractual duties or obligations or meet expected deadlines, if they need to be replaced or if the quality or accuracy of the clinical data they obtain is compromised due to the failure to adhere to Notable’s clinical protocols, regulatory requirements or for other reasons, Notable’s clinical trials may be extended, delayed or terminated and Notable may not be able to obtain regulatory approval for or successfully commercialize Notable’s drug candidates. As a result, Notable’s results of operations and the commercial prospects for Notable’s drug candidates would be harmed, Notable’s costs could increase and Notable’s ability to generate revenues could be delayed.
Many of the third parties with whom Notable contracts may also have relationships with other commercial entities, including Notable’s competitors, for whom they may also be conducting clinical trials or other drug development activities that could harm Notable’s competitive position. If the third parties conducting Notable’s Good Laboratory Practices (“GLP”) preclinical studies or Notable’s clinical trials do not perform their contractual duties or obligations, experience work stoppages, do not meet expected deadlines, terminate their agreements with Notable or need to be replaced, or if the quality or accuracy of the clinical data they obtain is compromised due to their failure to adhere to Notable’s clinical trial protocols or to GCPs, or for any other reason, Notable may need to enter into new arrangements with alternative third parties. Switching or adding additional CROs involves additional cost and requires management time and focus. In addition, there is a natural transition period when a new CRO commences work. As a result, delays occur, which can materially impact Notable’s ability to meet its desired clinical development timelines. Though Notable carefully manages relationships with its CROs, there can be no assurance that Notable will not encounter similar challenges or delays in the future or that these delays or challenges will not have a material adverse impact on Notable’s business, financial condition and prospects.
Notable is substantially dependent on third parties for the manufacture of Notable’s clinical supplies of its drug candidates, and Notable intends to rely on third parties to produce commercial supplies of any approved drug candidate. Therefore, Notable’s development of its drugs could be stopped or delayed, and Notable’s commercialization of any future drug could be stopped or delayed or made less profitable if third party manufacturers fail to obtain approval of the FDA or comparable regulatory authorities or fail to provide Notable with drug products in sufficient quantities or at acceptable prices.
The manufacture of pharmaceutical products is complex and requires significant expertise, capital investment, process controls and know-how. Common difficulties in pharmaceutical manufacturing may include: sourcing and producing raw materials, transferring technology from chemistry and development activities to production activities, validating initial production designs, scaling manufacturing techniques, improving costs and yields, establishing and maintaining quality controls and stability requirements, eliminating contaminations and operator errors, and maintaining compliance with regulatory requirements. Notable does not currently have nor does Notable plan to acquire the infrastructure or capability internally in accordance with cGMP prescribed by the FDA or to produce an adequate supply of compounds to meet future requirements for clinical trials and commercialization of Notable’s drugs. Drug manufacturing facilities are subject to inspection before the FDA will issue an approval to market a new drug product, and all of the manufacturers that Notable intends to use must adhere to the cGMP regulations prescribed by the FDA.
Notable expects therefore to rely on third-party manufacturers for clinical supplies of Notable’s drug candidates that Notable may develop. These third-party manufacturers will be required to comply with cGMPs, and other applicable laws and regulations. Notable will have no control over the ability of these third parties to comply with these requirements, or to maintain adequate quality control, quality assurance and qualified personnel. If the FDA or any other applicable regulatory authorities find deficiencies with or do not approve the facilities of these third parties for the manufacture of Notable’s other drug candidates or any drugs that Notable may successfully develop, or if it withdraws any such approval, or if Notable’s suppliers or contract manufacturers decide they no longer want to supply or manufacture for Notable, Notable may need to find alternative manufacturing facilities, in which case Notable might not be able to identify manufacturers for clinical or commercial supply on acceptable terms, or at all. Any of these factors would significantly impact Notable’s ability to develop, obtain regulatory approval for or market Notable’s drug candidates and adversely affect Notable’s business.
Notable and/or its third-party manufacturers may be adversely affected by developments outside of Notable’s control, and these developments may delay or prevent further manufacturing of Notable’s drugs. Adverse developments may include labor disputes, resource constraints, shipment delays, inventory shortages, lot failures, impacts related to the COVID-19 pandemic or another epidemic or infectious disease outbreak, unexpected sources of contamination, lawsuits related to Notable’s manufacturing techniques, equipment used during manufacturing, or composition of matter, unstable political environments, acts of terrorism, war, natural disasters, and other natural and man-made disasters. If Notable or its third-party manufacturers were to encounter any of the above difficulties, or otherwise fail to comply with contractual obligations, Notable’s ability to provide any drug for clinical trial or commercial purposes would be jeopardized. This may increase the costs associated with completing Notable’s clinical trials and commercial production. Further, production disruptions may cause Notable to terminate ongoing clinical trials and/or commence new clinical trials at additional expense. Notable may also have to take inventory write-offs and incur other charges and expenses for drugs that fail to meet specifications or pass safety inspections. If production difficulties cannot be solved with acceptable costs, expenses, and timeframes, Notable may be forced to abandon its clinical development and commercialization plans, which could have a material adverse effect on Notable’s business, prospects, financial condition, and the value of Notable’s securities.
Notable, or third-party manufacturers on whom Notable relies, may be unable to successfully scale-up manufacturing of Notable’s drug candidates in sufficient quality and quantity, which would delay or prevent Notable from developing its drug candidates and commercializing approved drugs, if any.
In order to conduct clinical trials of Notable’s drug candidates and commercialize any approved drug candidates, Notable, or its manufacturers, will need to manufacture them in large quantities. Notable, or its manufacturers, may be unable to successfully increase the manufacturing capacity for any of Notable’s drug candidates in a timely or cost-effective manner, or at all. In addition, quality issues may arise during scale-up activities. If Notable, or any of its manufacturers, are unable to successfully scale up the manufacture of Notable’s drug candidates in sufficient quality and quantity, the development, testing, and clinical trials of that drug candidate may be delayed or infeasible, and regulatory approval or commercial launch of any resulting drug may be delayed or not obtained, which could significantly harm Notable’s business. If Notable is unable to obtain or maintain third-party manufacturing for commercial supply of Notable’s drug candidates, or to do so on commercially reasonable terms, Notable may not be able to develop and commercialize its drug candidates successfully.
Notable’s failure to find third party collaborators to assist or share in the costs of drug development could materially harm Notable’s business, financial condition and results of operations.
Notable’s strategy for the development and commercialization of its proprietary drug candidates may include the formation of collaborative arrangements with third parties. Existing and future collaborators have significant discretion in determining the efforts and resources they apply and may not perform their obligations as expected. Potential third-party collaborators include biopharmaceutical, pharmaceutical and biotechnology companies, academic institutions and other entities. Third-party collaborators may assist Notable in:
● funding research, preclinical development, clinical trials and manufacturing;
● seeking and obtaining regulatory approvals; and
● successfully commercializing any future drug candidates.
If Notable is not able to establish further collaboration agreements, Notable may be required to undertake drug development and commercialization at Notable’s own expense. Such an undertaking may limit the number of drug candidates that Notable will be able to develop, significantly increase Notable’s capital requirements and place additional strain on Notable’s internal resources. Notable’s failure to enter into additional collaborations could materially harm Notable’s business, financial condition and results of operations.
In addition, Notable’s dependence on licensing, collaboration and other agreements with third parties may subject Notable to a number of risks. These agreements may not be on terms that prove favorable to Notable and may require Notable to relinquish certain rights in its drug candidates. To the extent Notable agrees to work exclusively with one collaborator in a given area, Notable’s opportunities to collaborate with other entities could be curtailed. Lengthy negotiations with potential new collaborators may lead to delays in the research, development or commercialization of drug candidates. The decision by Notable’s collaborators to pursue alternative technologies or the failure of Notable’s collaborators to develop or commercialize successfully any drug candidate to which they have obtained rights from Notable could materially harm Notable’s business, financial condition and results of operations.
Cash balances held at banking institutions are in excess of FDIC coverage.
Notable maintains significant amounts of cash and cash equivalents at one or more financial institutions that are in excess of federally insured limits. Interest bearing and non-interest-bearing accounts Notable hold at banking institutions are guaranteed by the Federal Deposit Insurance Corporation (“FDIC”) up to $250,000. Substantially all of Notable’s cash balances held at banking institutions are in excess of FDIC coverage. Notable considers this to be a normal business risk.
Risks Related to The Discovery and Development of Product Candidates
Clinical studies of Notable’s product candidates may not be successful. If Notable is unable to generate successful results from clinical studies of Notable’s product candidates, or experience significant delays in doing so, Notable’s business may be materially harmed.
Notable has no products approved for commercial marketing and all of Notable’s product candidates are either about to enter into clinical testing or in clinical development. Notable’s ability to achieve and sustain profitability depends on obtaining regulatory approvals for and, if approved, successfully commercializing its product candidates, either alone or with third parties. Before obtaining regulatory approval for the commercial distribution of Notable’s product candidates, Notable or an existing or future collaborator must conduct extensive clinical trials to demonstrate the safety and efficacy of Notable’s product candidates.
The success of Notable’s product candidates will depend on several factors, including the following:
● successful enrollment in clinical trials and completion of clinical studies with favorable results;
● receipt of marketing approvals from applicable regulatory authorities;
● obtaining and maintaining patent and trade secret protection for current and future product candidates;
● establishing and maintaining manufacturing relationships with third parties or establishing Notable’s own manufacturing capability; and
● successfully commercializing Notable’s products, if approved, including successfully establishing a sales force, marketing and distribution infrastructure, whether alone or in collaboration with others.
If Notable does not achieve one or more of these factors in a timely manner or at all, it could experience significant delays or an inability to successfully complete the development or commercialization of its product candidates, which would materially harm Notable’s business.
Notable’s product candidates may exhibit undesirable side effects when used alone or in combination with other approved pharmaceutical products or investigational new drugs, which may delay or preclude further development or regulatory approval, or limit their use if approved.
Undesirable side effects caused by Notable’s product candidates could cause Notable or regulatory authorities to interrupt, delay or halt clinical trials and could result in a more restrictive label or the delay or denial of regulatory approval by the FDA or other regulatory authorities. Results of Notable’s trials could reveal a high and unacceptable severity and prevalence of side effects. In such an event, Notable’s trials could be suspended or terminated and the FDA or comparable foreign regulatory authorities could order Notable to cease further development of or deny approval of Notable’s product candidates for any or all targeted indications. Such side effects could also affect patient recruitment, the ability of enrolled patients to complete the trial or result in potential product liability claims. Any of these occurrences may materially and adversely affect Notable’s business, financial condition, results of operations and prospects.
Further, clinical trials by their nature test product candidates in only samples of the potential patient populations. With a limited number of patients and limited duration of exposure in such trials, rare and severe side effects of Notable’s product candidates may not be uncovered until a significantly larger number of patients are exposed to the product candidate.
If any of Notable’s product candidates receive marketing approval, and causes serious, unexpected, or undesired side effects, a number of potentially significant negative consequences could result, including:
● regulatory authorities may withdraw, suspend, or limit their approval of the product or impose restrictions on its distribution in the form of a modified risk evaluation and mitigation strategy;
● regulatory authorities may require the addition of labeling statements, such as warnings or contraindications;
● Notable may be required to change the way the product is administered or conduct additional clinical trials or post-marketing surveillance;
● Notable could be sued and held liable for harm caused to patients; or
● Notable’s reputation may suffer.
Any of these events could prevent Notable from achieving or maintaining market acceptance of the affected product and could substantially increase the costs of commercializing Notable’s future products and impair Notable’s ability to generate revenues from the commercialization of these products.
Even if Notable completes the necessary preclinical studies and clinical trials, Notable cannot predict whether or when Notable will obtain regulatory approval to commercialize a product candidate and Notable cannot, therefore, predict the timing of any revenue from a future product.
Notable cannot commercialize a product until the appropriate regulatory authorities, such as the FDA, have reviewed and approved the product candidate. The regulatory authorities may not complete their review processes in a timely manner, or Notable may not be able to obtain regulatory approval for many reasons including:
● regulatory authorities disagreeing with the design or implementation of Notable’s clinical trials;
● such authorities may disagree with Notable’s interpretation of data from preclinical studies or clinical trials;
● such authorities may not accept clinical data from trials which are conducted at clinical facilities or in countries where the standard of care is potentially different from that of the United States;
● unfavorable or unclear results from Notable’s clinical trials or results that may not meet the level of statistical significance required by the FDA or comparable foreign regulatory agencies for approval;
● serious and unexpected drug-related side effects experienced by participants in Notable’s clinical trials or by individuals using drugs similar to Notable’s product candidates;
● the population studied in the clinical trial may not be sufficiently broad or representative to assure safety in the full population for which Notable seeks approval;
● Notable may be unable to demonstrate that a product candidate’s clinical and other benefits outweigh its safety risks;
● such authorities may not agree that the data collected from clinical trials of Notable’s product candidates are acceptable or sufficient to support the submission of an NDA or other submission or to obtain regulatory approval in the United States or elsewhere, and such authorities may impose requirements for additional preclinical studies or clinical trials;
● such authorities may disagree regarding the formulation, labeling and/or the specifications of Notable’s product candidates;
● such authorities may find deficiencies in the manufacturing processes or facilities of Notable’s third-party manufacturers with which Notable contracts for clinical and commercial supplies; or the approval policies; or
● regulations of such authorities may significantly change in a manner rendering Notable’s or any of Notable’s potential future collaborators’ clinical data insufficient for approval.
Additional delays may result if an FDA advisory committee recommends restrictions on approval or recommends non-approval. In addition, Notable may experience delays or rejections based upon additional government regulation from future legislation or administrative action, or changes in regulatory agency policy during the period of product development, clinical trials and the review process.
Even if Notable obtains regulatory approval for Notable’s product candidates, Notable will still face extensive regulatory requirements and Notable’s products may face future development and regulatory difficulties.
Even if Notable obtains regulatory approval in the United States, the FDA may still impose significant restrictions on the indicated uses or marketing of Notable’s product candidates, or impose ongoing requirements for potentially costly post-approval studies or post-market surveillance. The FDA may also require risk evaluation and mitigation strategies as a condition of approval of Notable’s product candidates, which could include requirements for a medication guide, physician communication plans or additional elements to ensure safe use, such as restricted distribution methods, patient registries and other risk minimization tools. Additionally, the manufacturing processes, packaging, distribution, adverse event reporting, labeling, advertising, promotion, and recordkeeping for the product will be subject to extensive and ongoing FDA regulatory requirements, in addition to other potentially applicable federal and state laws. These requirements include monitoring and reporting of adverse events and other post-marketing information and reports, registration, as well as continued compliance with cGMP regulations. The holder of an approved NDA must also submit new or supplemental applications and obtain FDA approval for certain changes to the approved product, product labeling or manufacturing process. If Notable or a regulatory agency discovers previously unknown problems with a product such as AEs of unanticipated severity or frequency, or problems with the facility where the product is manufactured, a regulatory agency may impose restrictions relative to that product or the manufacturing facility, including requiring recall or withdrawal of the product from the market or suspension of manufacturing.
If Notable fails to comply with applicable regulatory requirements following approval of any of Notable’s product candidates, a regulatory agency may:
● issue a warning letter asserting that Notable is in violation of the law;
● seek an injunction or impose civil or criminal penalties or monetary fines;
● suspend or withdraw regulatory approval;
● suspend any ongoing clinical trials;
● refuse to approve a pending NDA or supplements to an NDA submitted by the combined business;
● seize product or require a product recall; or
● refuse to allow Notable to enter into supply contracts, including government contracts.
Any government investigation of alleged violations of law could require Notable to expend significant time and resources in response and could generate negative publicity. The occurrence of any event or penalty described above may inhibit Notable’s ability to commercialize Notable’s future products, if approved, and generate revenues.
Notable may use Notable’s financial and human resources to pursue a particular research program or product candidate and fail to capitalize on programs or product candidates that may be more profitable or for which there is a greater likelihood of success.
As a result of Notable’s limited financial and human resources, Notable will have to make strategic decisions as to which product candidates to pursue and may forego or delay pursuit of opportunities with other product candidates or for other indications that later prove to have greater commercial potential. Notable’s resource allocation decisions may cause Notable to fail to capitalize on viable commercial products or profitable market opportunities. Notable’s spending on research and development programs and product candidates for specific indications may not yield any commercially viable products. If Notable does not accurately evaluate the commercial potential or target market for a particular product candidate, Notable may relinquish valuable rights to that product candidate through strategic alliance, licensing or other royalty arrangements in cases in which it would have been more advantageous for Notable to retain sole development and commercialization rights to such product candidate, or Notable may allocate internal resources to a product candidate in a therapeutic area in which it would have been more advantageous to enter into a partnering arrangement.
Notable faces significant competition from other biotechnology and pharmaceutical companies and Notable’s operating results will suffer if Notable fails to compete effectively.
The biopharmaceutical industry is characterized by intense competition and rapid innovation. Notable’s competitors may be able to develop other compounds or drugs that are able to achieve similar or better results. Notable’s potential competitors include major multinational pharmaceutical companies, established biotechnology companies, specialty pharmaceutical companies and universities and other research institutions. Many of Notable’s competitors have substantially greater financial, technical and other resources, such as larger research and development staff and experienced marketing and manufacturing organizations and well-established sales forces. Smaller or early-stage companies may also prove to be significant competitors, particularly as they develop novel approaches to treating disease indications that Notable’s product candidates are also focused on treating. Established pharmaceutical companies may also invest heavily to accelerate discovery and development of novel therapeutics or to in-license novel therapeutics that could make the product candidates that Notable develops obsolete. Mergers and acquisitions in the biotechnology and pharmaceutical industries may result in even more resources being concentrated in Notable’s competitors. Competition may increase further as a result of advances in the commercial applicability of technologies and greater availability of capital for investment in these industries. Notable’s competitors, either alone or with collaboration partners, may succeed in developing, acquiring or licensing on an exclusive basis drug or biologic products that are more effective, safer, more easily commercialized or less costly than Notable’s product candidates or may develop proprietary technologies or secure patent protection that Notable may need for the development of Notable’s technologies and products. Notable believes the key competitive factors that will affect the development and commercial success of Notable’s product candidates are efficacy, safety, tolerability, reliability, convenience of use, price and reimbursement.
Even if Notable obtains regulatory approval of drug products, the availability and price of Notable’s competitors’ products could limit the demand and the price Notable is able to charge for Notable’s product candidates. Notable may not be able to implement Notable’s business plan if the acceptance of Notable’s product candidates is inhibited by price competition or the reluctance of physicians to switch from existing methods of treatment to Notable’s product candidates, or if physicians switch to other new drug or biologic products or choose to reserve Notable’s product candidates for use in limited circumstances.
The commercial success of Notable’s product candidates will depend upon the acceptance of these product candidates by the medical community, including physicians, patients and healthcare payors.
The degree of market acceptance of any product candidates will depend on a number of factors, including:
● demonstration of clinical safety and efficacy compared to other products;
● the relative convenience, ease of administration and acceptance by physicians, patients and healthcare payors;
● the prevalence and severity of any AEs;
● limitations or warnings contained in the FDA-approved label for such products;
● availability of alternative treatments;
● pricing and cost-effectiveness;
● the effectiveness of Notable’s, or any of Notable’s collaborators’, sales and marketing strategies;
● Notable’s ability to obtain hospital or payor formulary approval;
● Notable’s ability to obtain and maintain sufficient third-party coverage and adequate reimbursement; and
● the willingness of patients to pay out-of-pocket in the absence of third-party coverage.
If a product is approved but does not achieve an adequate level of acceptance by physicians, patients and healthcare payors, Notable may not generate sufficient revenues from such product and Notable may not become or remain profitable. Such increased competition may decrease any future potential revenue for current and future product candidates due to increasing pressure for lower pricing and higher discounts in the commercialization of Notable’s product.
If Notable is unable to establish sales and marketing capabilities or enter into agreements with third parties to market and sell Notable’s product candidates, Notable may be unable to generate any revenues.
Notable currently does not have an organization for the sales, marketing and distribution of pharmaceutical products and the cost of establishing and maintaining such an organization may exceed the cost-effectiveness of doing so. In order to market any products that may be approved, Notable must build Notable’s sales, marketing, managerial and other non-technical capabilities or make arrangements with third parties to perform these services. With respect to future programs, Notable may rely completely on an alliance partner for sales and marketing. In addition, Notable may enter into strategic alliances with third parties to commercialize other product candidates, if approved, including in markets outside of the United States or for other large markets that are beyond Notable’s resources. Although Notable intends to establish a sales organization if Notable is able to obtain approval to market any product candidates for niche markets in the United States, Notable will also consider the option to enter into strategic alliances for current and future product candidates in the United States if commercialization requirements exceed Notable’s available resources. This will reduce the revenue generated from the sales of these products.
Any future strategic alliance partners may not dedicate sufficient resources to the commercialization of Notable’s product candidates, if approved, or may otherwise fail in their commercialization due to factors beyond Notable’s control. If Notable is unable to establish effective alliances to enable the sale of Notable’s product candidates, if approved, to healthcare professionals and in geographical regions, including the United States, that will not be covered by Notable’s own marketing and sales force, or if Notable’s potential future strategic alliance partners do not successfully commercialize the product candidates that may be approved, Notable’s ability to generate revenues from product sales will be adversely affected.
If Notable is unable to establish adequate sales, marketing and distribution capabilities, whether independently or with third parties, Notable may not be able to generate sufficient product revenue and may not become profitable. Notable will be competing with many companies that currently have extensive and well-funded marketing and sales operations. Without an internal team or the support of a third party to perform marketing and sales functions, Notable may be unable to compete successfully against these more established companies.
If Notable obtains approval to commercialize any approved products outside of the United States, a variety of risks associated with international operations could materially adversely affect Notable’s business.
If Notable obtains approval to commercialize any approved products outside of the United States, Notable expects that Notable will be subject to additional risks related to entering into international business relationships, including:
● different regulatory requirements for drug approvals in foreign countries;
● differing payor reimbursement regimes, governmental payors or patient self-pay systems and price controls;
● reduced protection for intellectual property rights;
● unexpected changes in tariffs, trade barriers and regulatory requirements;
● economic weakness, including inflation, or political instability in particular foreign economies and markets;
● compliance with tax, employment, immigration and labor laws for employees living or traveling abroad;
● foreign taxes, including withholding of payroll taxes;
● foreign currency fluctuations, which could result in increased operating expenses and reduced revenues, and other obligations incident to doing business in another country;
● workforce uncertainty in countries where labor unrest is more common than in the United States;
● production shortages resulting from any events affecting raw material supply or manufacturing capabilities abroad; and
● business interruptions resulting from geopolitical actions, including war and terrorism, or natural disasters including earthquakes, typhoons, floods and fires.
Coverage and adequate reimbursement may not be available for Notable’s product candidates, if approved, which could make it difficult for Notable to sell products profitably.
Market acceptance and sales of any product candidates that Notable develops will depend on coverage and reimbursement policies and may be affected by future healthcare reform measures. Government authorities and third-party payors, such as private health insurers, government payors and health maintenance organizations, decide which drugs they will pay for and establish reimbursement levels. Notable cannot be sure that coverage and adequate reimbursement will be available for any current and future product candidates. In the United States, the Centers for Medicare & Medicaid Services (“CMS”), an agency within the U.S. Department of Health and Human Services (“HHS”), decides whether and to what extent a new drug will be covered and reimbursed under Medicare. Private payors tend to follow the coverage reimbursement policies established by CMS to a substantial degree. It is difficult to predict what CMS will decide with respect to reimbursement for novel product candidates. Inadequate reimbursement amounts may reduce the demand for, or the price of, Notable’s future products. Further, one payor’s determination to provide coverage for a product does not assure that other payors will also provide coverage for the product. If reimbursement is not available, or is available only at limited levels, Notable may not be able to successfully commercialize product candidates that Notable develops and that may be approved. Thus, even if Notable succeeds in bringing a product to market, it may not be considered medically necessary or cost-effective, and the amount reimbursed for any products may be insufficient to allow Notable to sell Notable’s products on a competitive basis.
There have been a number of legislative and regulatory proposals to change the healthcare system in the United States and in some foreign jurisdictions that could affect Notable’s ability to sell products profitably. These legislative and/or regulatory changes may negatively impact the reimbursement for drug products, following approval. The availability of numerous generic treatments may also substantially reduce the likelihood of reimbursement for Notable’s future products. Notable expects to experience pricing pressures in connection with the sale of any products that Notable develops, due to the trend toward managed healthcare, the increasing influence of health maintenance organizations and additional legislative changes. The downward pressure on healthcare costs in general, and prescription drugs in particular, has and is expected to continue to increase in the future. For instance, government and private payors who reimburse patients or healthcare providers are increasingly seeking greater upfront discounts, additional rebates and other concessions to reduce prices for pharmaceutical products. If Notable fails to successfully secure and maintain reimbursement coverage for Notable’s future products or are significantly delayed in doing so, Notable will have difficulty achieving market acceptance of Notable’s future products and Notable’s business will be harmed.
In addition, in some non-U.S. jurisdictions, the proposed pricing for a drug must be approved before it may be lawfully marketed. The requirements governing drug pricing vary widely from country to country. For example, the European Union provides options for its member states to restrict the range of medicinal products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use. A member state may approve a specific price for the medicinal product or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the medicinal product on the market. There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any of Notable’s products. Historically, products launched in the European Union do not follow price structures of the U.S. and generally tend to be priced significantly lower.
If Notable fails to comply with environmental, health and safety laws and regulations, Notable could become subject to fines or penalties or incur costs that could have a material adverse effect on the success of Notable’s business.
Notable is subject to numerous environmental, health and safety laws and regulations, including those governing laboratory procedures and the handling, use, storage, treatment and disposal of hazardous materials and wastes. Notable’s operations involve the use of hazardous and flammable materials, including chemicals and biological materials. Notable’s operations also produce hazardous waste products. Notable generally contracts with third parties for the disposal of these materials and wastes. Notable cannot eliminate the risk of contamination or injury from these materials. In the event of contamination or injury resulting from Notable’s use of hazardous materials, Notable could be held liable for any resulting damages, and any liability could exceed Notable’s resources. Notable also could incur significant costs associated with civil or criminal fines and penalties.
Although Notable maintains workers’ compensation insurance to cover Notable for costs and expenses, Notable may incur due to injuries to Notable’s employees resulting from the use of hazardous materials or other work-related injuries, this insurance may not provide adequate coverage against potential liabilities. In addition, Notable may incur substantial costs in order to comply with current or future environmental, health and safety laws and regulations. These current or future laws and regulations may impair Notable’s research, development or production efforts. Failure to comply with these laws and regulations also may result in substantial fines, penalties or other sanctions.
Risks Related to Notable’s Reliance on Third Parties
Notable relies on third parties to conduct some aspects of Notable’s compound formulation, research, preclinical studies and clinical trials, and those third parties may not perform satisfactorily, including failing to meet deadlines for the completion of such formulation, research or testing.
Notable does not expect to independently conduct all aspects of Notable’s drug discovery activities, compound formulation research, preclinical studies and clinical trials of product candidates. Notable currently relies and expects to continue to rely on third parties to conduct some aspects of Notable’s preclinical studies, clinical studies and formulation development.
Any of these third parties may terminate their engagements with Notable at any time. If Notable needs to enter into alternative arrangements, it will delay Notable’s product development activities. Notable’s reliance on these third parties for research and development activities will reduce Notable’s control over these activities but will not relieve Notable of Notable’s responsibilities. For example, for product candidates that Notable develops and commercializes on Notable’s own, Notable will remain responsible for ensuring that each of Notable’s IND-enabling studies and clinical trials are conducted in accordance with the study plan and protocols for the trial.
If these third parties do not successfully carry out their contractual duties, meet expected deadlines or conduct Notable’s studies in accordance with regulatory requirements or Notable’s stated study plans and protocols, Notable will not be able to complete, or may be delayed in completing, the necessary preclinical studies to enable Notable to select viable product candidates for IND submissions and will not be able to, or may be delayed in Notable’s efforts to, successfully develop and commercialize such product candidates.
Notable relies on third-party manufacturers to produce the supply of Notable’s preclinical product candidates, and Notable intends to rely on third parties to produce future clinical supplies of product candidates that Notable advances into clinical trials and commercial supplies of any approved product candidates.
Reliance on third-party manufacturers entails risks, including risks that Notable would not be subject to if Notable manufactured the product candidates ourselves, including:
● the inability to meet any product specifications and quality requirements consistently;
● a delay or inability to procure or expand sufficient manufacturing capacity;
● manufacturing and product quality issues related to scale-up of manufacturing;
● costs and validation of new equipment and facilities required for scale-up;
● a failure to comply with cGMP and similar foreign standards;
● the inability to negotiate manufacturing or supply agreements with third parties under commercially reasonable terms;
● termination or nonrenewal of manufacturing agreements with third parties in a manner or at a time that is costly or damaging to Notable;
● the reliance on a limited number of sources, and in some cases, single sources for raw materials, such that if Notable is unable to secure a sufficient supply of these product components, Notable will be unable to manufacture and sell current and future product candidates in a timely fashion, in sufficient quantities or under acceptable terms;
● the lack of qualified backup suppliers for any raw materials that are currently purchased from a single source supplier;
● operations of Notable’s third-party manufacturers or suppliers could be disrupted by conditions unrelated to Notable’s business or operations, including the bankruptcy of the manufacturer or supplier;
● carrier disruptions or increased costs that are beyond Notable’s control; and
● the failure to deliver products under specified storage conditions and in a timely manner.
Any of these events could lead to clinical study delays or failure to obtain regulatory approval, or impact Notable’s ability to successfully commercialize future products, if approved. Some of these events could be the basis for FDA action, including injunction, recall, seizure or total or partial suspension of production.
Notable relies on limited sources of supply for the drug substance of product candidates and any disruption in the chain of supply may cause a delay in developing and commercializing these product candidates.
Notable has established manufacturing relationships with a limited number of suppliers to manufacture raw materials and the drug substance used to create Notable’s product candidates. The availability of such suppliers to manufacture raw materials for Notable’s product candidates may be limited. Further, each supplier may require licenses to manufacture such components if such processes are not owned by the supplier or in the public domain. As part of any marketing approval, a manufacturer and its processes are required to be qualified by the FDA prior to commercialization. If supply from the approved vendor is interrupted, there could be a significant disruption in commercial supply. An alternative vendor would need to be qualified through an NDA supplement which could result in further delay. The FDA or other regulatory agencies outside of the United States may also require additional studies if a new supplier is relied upon for commercial production. Switching vendors may involve substantial costs and is likely to result in a delay in Notable’s desired clinical and commercial timelines.
These factors could cause the delay of clinical trials, regulatory submissions, required approvals or commercialization of Notable’s product candidates, cause Notable to incur higher costs and prevent Notable from commercializing Notable’s products successfully. Furthermore, if Notable’s suppliers fail to deliver the required commercial quantities of active pharmaceutical ingredients on a timely basis and at commercially reasonable prices, and Notable is unable to secure one or more replacement suppliers capable of production in a timely manner at a substantially equivalent cost, Notable’s clinical trials may be delayed or Notable could lose potential revenue.
Manufacturing issues may arise that could increase product and regulatory approval costs or delay commercialization.
Manufacturing of product candidates and conducting required stability testing, product, packaging, equipment and process-related issues may require refinement or resolution in order to proceed with any clinical trials and obtain regulatory approval for commercial marketing. Notable may identify significant impurities, which could result in increased scrutiny by the regulatory agencies, delays in clinical programs and regulatory approval, increases in Notable’s operating expenses, or failure to obtain or maintain approval for product candidates or any approved products.
Notable intends to rely on third parties to conduct, supervise and monitor Notable’s clinical trials, and if those third parties perform in an unsatisfactory manner, it may harm Notable’s business.
Notable intends to rely on CROs and clinical trial sites to ensure the proper and timely conduct of Notable’s clinical trials. While Notable will have agreements governing their activities, Notable has limited influence over their actual performance. Notable will control only certain aspects of Notable’s CROs’ activities. Nevertheless, Notable will be responsible for ensuring that each of Notable’s clinical trials are conducted in accordance with the applicable protocol, legal, regulatory and scientific standards and Notable’s reliance on the CROs will not relieve Notable of Notable’s regulatory responsibilities.
Notable and Notable’s CROs will be required to comply with the FDA’s or other regulatory agency’s GCPs, for conducting, recording and reporting the results of IND-enabling studies and clinical trials to assure that data and reported results are credible and accurate and that the rights, integrity and confidentiality of future clinical trial participants are protected. The FDA and non-U.S. regulatory agencies enforce these GCPs through periodic inspections of trial sponsors, principal investigators and clinical trial sites. If Notable or Notable’s future CROs fail to comply with applicable GCPs, the clinical data generated in Notable’s clinical trials may be deemed unreliable and the FDA or applicable non-U.S. regulatory agency may require Notable to perform additional clinical trials before approving any marketing applications for the relevant jurisdiction. Upon inspection, the FDA or applicable non-U.S. regulatory agency may determine that Notable’s future clinical trials do not comply with GCPs. In addition, Notable’s future clinical trials will require a sufficiently large number of test subjects to evaluate the safety and effectiveness of a potential drug product. Accordingly, if Notable’s future CROs fail to comply with these regulations or fail to recruit a sufficient number of patients, Notable may be required to repeat such clinical trials, which would delay the regulatory approval process.
Notable’s future CROs will not be Notable’s employees, and Notable will not be able to control whether or not they devote sufficient time and resources to Notable’s future clinical and nonclinical programs. These CROs may also have relationships with other commercial entities, including Notable’s competitors, for whom they may also be conducting clinical trials, or other drug development activities which could harm Notable’s competitive position. If Notable’s future CROs do not successfully carry out their contractual duties or obligations, fail to meet expected deadlines, or if the quality or accuracy of the clinical data they obtain is compromised due to the failure to adhere to Notable’s clinical protocols or regulatory requirements, or for any other reasons, Notable’s clinical trials may be extended, delayed or terminated, and Notable may not be able to obtain regulatory approval for, or successfully commercialize Notable’s product candidates. As a result, Notable’s financial results and the commercial prospects for such products and any product candidates that Notable develop would be harmed, Notable’s costs could increase, and Notable’s ability to generate revenues could be delayed.
Notable intends to rely on other third parties to store and distribute drug products for any clinical trials that Notable may conduct. Any performance failure on the part of Notable’s distributors could delay clinical development or marketing approval of Notable’s product candidates or commercialization of Notable’s products, if approved, producing additional losses and depriving Notable of potential product revenue.
Risks Related to Notable’s Intellectual Property
If Notable is unable to obtain or protect intellectual property rights related to Notable’s current and future products and product candidates, Notable may not be able to compete effectively in Notable’s markets.
Notable’s success depends in part on Notable’s ability to obtain and maintain patents and other forms of intellectual property rights, including in-licenses of intellectual property rights of others, for Notable’s product candidates, methods used to develop and manufacture Notable’s product candidates and methods for treating patients using Notable’s product candidates, as well as Notable’s ability to preserve Notable’s trade secrets, to prevent third parties from infringing upon Notable’s proprietary rights and to operate without infringing upon the proprietary rights of others. The strength of patents in the biotechnology and pharmaceutical field involves complex legal and scientific questions and can be uncertain. The patent applications that Notable own or in-license may fail to result in patents with claims that cover the products in the United States or in other countries. There is no assurance that all of the potentially relevant prior art relating to Notable’s patents and patent applications has been found; such prior art can invalidate a patent or prevent a patent from issuing based on a pending patent application. Even if patents do successfully issue, third parties may challenge their validity, enforceability or scope, which may result in such patents being narrowed or invalidated. Furthermore, even if they are unchallenged, Notable’s patents and patent applications may not adequately protect Notable’s intellectual property or prevent others from designing around Notable’s claims.
If the patent applications Notable holds or has in-licensed with respect to Notable’s programs or product candidates fail to issue or if their breadth or strength of protection is threatened, it could dissuade companies from collaborating with Notable to develop product candidates, and threaten Notable’s ability to commercialize, future products. Notable cannot offer any assurances about which, if any, patents will issue or whether any issued patents will be found invalid and unenforceable or will be threatened by third parties. A patent may be challenged through one or more of several administrative proceedings including post-grant challenges, re-examination or opposition before the United States Patent and Trademark Office (“USPTO”) or foreign patent offices. Any successful challenge of patents or any other patents owned by or licensed to Notable could deprive Notable of rights necessary for the successful commercialization of any product candidates that Notable may develop.
Since patent applications in the United States and most other countries are confidential for a period of time after filing, and some remain so until issued, Notable cannot be certain that Notable was the first to file any patent application related to a product candidate. Furthermore, in certain situations, if Notable and one or more third parties have filed patent applications in the United States and claiming the same subject matter, an administrative proceeding, known as an interference, can be initiated to determine which applicant is entitled to the patent on that subject matter. Such an interference proceeding provoked by third parties or brought by Notable may be necessary to determine the priority of inventions with respect to Notable’s patents or patent applications, or those of Notable’s licensors. An unfavorable outcome could require Notable to cease using the related technology or to require Notable to license rights to it from the prevailing party. Notable’s business could be harmed if the prevailing party does not offer Notable a license at all, or on commercially reasonable terms. Notable’s defense of a patent or patent application in such a proceeding may not be successful and, even if successful, may result in substantial costs and distract Notable’s management and other employees.
In addition, patents have a limited lifespan. In the United States, the natural expiration of a patent is generally 20 years after it is filed. Various extensions may be available however the life of a patent, and the protection it affords is limited. Once the patent life has expired for a product, Notable may be open to competition from generic medications. Further, if Notable encounters delays in regulatory approvals, the period of time during which Notable could market a product candidate under patent protection could be reduced.
In addition to the protection afforded by patents, Notable relies on trade secret protection and confidentiality agreements to protect proprietary know-how that is not patentable, including processes for which patents are difficult to enforce and any other elements of Notable’s drug discovery and development processes that involve proprietary know-how, information or technology that is not covered by patents. Although each of Notable’s employees agrees to assign their inventions to Notable through an employee inventions agreement, and all of Notable’s employees, consultants, advisors and any third parties who have access to Notable’s proprietary know-how, information or technology are required to enter into confidentiality agreements, Notable cannot provide any assurances that all such agreements have been duly executed, that Notable’s trade secrets and other confidential proprietary information will not be disclosed or that competitors will not otherwise gain access to Notable’s trade secrets or independently develop substantially equivalent information and techniques. In addition, others may independently discover Notable’s trade secrets and proprietary information. For example, the FDA, as part of its Transparency Initiative, is currently considering whether to make additional information publicly available on a routine basis, including information that Notable may consider to be trade secrets or other proprietary information, and it is not clear at the present time how the FDA’s disclosure policies may change in the future, if at all.
Further, the laws of some foreign countries do not protect proprietary rights to the same extent or in the same manner as the laws of the United States. As a result, Notable may encounter significant problems in protecting and defending Notable’s intellectual property both in the United States and abroad. If Notable is unable to prevent material disclosure of the non-patented intellectual property related to Notable’s technologies to third parties, and there is no guarantee that Notable will have any such enforceable trade secret protection, Notable may not be able to establish or maintain a competitive advantage in Notable’s market, which could materially adversely affect Notable’s business, results of operations and financial condition.
Third-party claims of intellectual property infringement may prevent or delay Notable’s development and commercialization efforts.
Notable’s commercial success depends in part on Notable’s avoiding infringement of the patents and proprietary rights of third parties. There is a substantial amount of litigation, both within and outside the United States, involving patent and other intellectual property rights in the biotechnology and pharmaceutical industries, including patent infringement lawsuits. Numerous U.S. and foreign issued patents and pending patent applications, which are owned by third parties, exist in the fields in which Notable is pursuing development candidates. As the biotechnology and pharmaceutical industries expand and more patents are issued, the risk increases that Notable’s product candidates may be subject to claims of infringement of the patent rights of third parties.
Third parties may assert that Notable is employing their proprietary technology without authorization. There may be third-party patents or patent applications with claims to materials, formulations, methods of manufacture or methods for treatment related to the use or manufacture of Notable’s product candidates. Because patent applications can take many years to issue, there may be currently pending patent applications which may later result in patents that Notable’s product candidates may infringe. In addition, third parties may obtain patents in the future and claim that use of Notable’s technologies infringes upon these patents. If any third-party patents were held by a court of competent jurisdiction to cover the manufacturing process of any of Notable’s product candidates, any molecules formed during the manufacturing process or any final product itself, the holders of any such patents may be able to block Notable’s ability to commercialize such product candidate unless Notable obtained a license under the applicable patents, or until such patents expire. Similarly, if any third-party patents were held by a court of competent jurisdiction to cover aspects of Notable’s formulations, processes for manufacture or methods of use, including combination therapy, the holders of any such patents may be able to block Notable’s ability to develop and commercialize the applicable product candidate unless Notable obtained a license or until such patent expires. In either case, such a license may not be available on commercially reasonable terms or at all.
Parties making claims against Notable may obtain injunctive or other equitable relief, which could effectively block Notable’s ability to further develop and commercialize one or more of Notable’s product candidates. Defense of these claims, regardless of their merit, would involve substantial litigation expense and would be a substantial diversion of management or employee resources from Notable’s business. In the event of a successful claim of infringement against Notable, Notable may have to pay substantial damages, including treble damages and attorneys’ fees for willful infringement, pay royalties, redesign Notable’s infringing products or obtain one or more licenses from third parties, which may be impossible or require substantial time and monetary expenditure.
If Notable fails to obtain licenses or comply with Notable’s obligations in these agreements under which Notable licenses intellectual property rights from third parties or otherwise experiences disruptions to Notable’s business relationships with Notable’s licensors, Notable could lose license rights that are important to Notable’s business.
Notable is a party to intellectual property license agreements that are important to Notable’s business and expect to enter into additional license agreements in the future. Notable’s existing license agreements impose, and Notable expects that future license agreements will impose, various obligations on Notable.
Notable may need to obtain licenses from third parties to advance Notable’s research or allow commercialization of Notable’s product candidates, and Notable has done so from time to time. Notable may fail to obtain any of these licenses at a reasonable cost or on reasonable terms, if at all. In that event, Notable would be unable to further develop and commercialize one or more of Notable’s product candidates, which could harm Notable’s business significantly. Notable cannot provide any assurances that third-party patents do not exist which might be enforced against Notable’s future products, resulting in either an injunction prohibiting Notable’s sales, or, with respect to Notable’s sales, an obligation on Notable’s part to pay royalties and/or other forms of compensation to third parties.
Notable may be involved in lawsuits to protect or enforce Notable’s patents or the patents of Notable’s licensees, which could be expensive, time consuming and unsuccessful.
Competitors may infringe on Notable’s patents or the patents of Notable’s licensees. To counter infringement or unauthorized use, Notable may be required to file infringement claims, which can be expensive and time-consuming. In addition, in an infringement proceeding, a court may decide that a patent of ours or of Notable’s licensees is not valid or is unenforceable, or may refuse to stop the other party from using the technology at issue on the grounds that Notable’s patents do not cover the technology in question. An adverse result in any litigation or defense proceedings could put one or more of Notable’s patents at risk of being invalidated or interpreted narrowly and could put Notable’s patent applications at risk of not issuing.
Notable’s defense in a lawsuit may fail and, even if successful, may result in substantial costs and distract Notable’s management and other employees. Notable may not be able to prevent, alone or with Notable’s licensees, misappropriation of Notable’s intellectual property rights, particularly in countries where the laws may not protect those rights as fully as in the United States.
Furthermore, because of the substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some of Notable’s confidential information could be compromised by disclosure during this type of litigation. There could also be public announcements of the results of hearings, motions or other interim proceedings or developments. If securities analysts or investors perceive these results to be negative, it could have a material adverse effect on the price of Notable’s ordinary shares.
Notable may be subject to claims that Notable’s employees, consultants or independent contractors have wrongfully used or disclosed confidential information of third parties.
Notable employ individuals who were previously employed at other biotechnology or pharmaceutical companies. Notable may be subject to claims that Notable or Notable’s employees, consultants or independent contractors have inadvertently or otherwise used or disclosed confidential information of Notable’s employees’ former employers or other third parties. Notable may also be subject to claims that former employers or other third parties have an ownership interest in Notable’s patents. Litigation may be necessary to defend against these claims. There is no guarantee of success in defending these claims, and if Notable is successful, litigation could result in substantial cost and be a distraction to Notable’s management and other employees.
Risks Related to Notable’s Business Operations and Industry
Notable’s future success depends on Notable’s ability to attract and retain key executives and to attract, retain and motivate qualified personnel.
Notable is highly dependent on principal members of Notable’s executive team, and any reduction or loss of their services may adversely impact the achievement of Notable’s objectives. While Notable has entered into employment agreements with Notable’s principal executive officers, any of them could leave Notable’s employment at any time, as all of Notable’s employees are “at will” employees. Recruiting and retaining other qualified employees for Notable’s business, including scientific and technical personnel, will also be critical to Notable’s success. There is currently a shortage of skilled executives in Notable’s industry, which is likely to continue. As a result, competition for skilled personnel is intense and the turnover rate can be high. Notable may not be able to attract and retain personnel on acceptable terms given the competition among numerous pharmaceutical companies for individuals with similar skill sets. In addition, failure to succeed in clinical trials may make it more challenging to recruit and retain qualified personnel. The inability to recruit any executive or key employee or the loss of the services of any executive or key employee might impede progress of Notable’s research, development and commercialization objectives.
Notable may need to expand Notable’s organization and may experience difficulties in managing this growth, which could disrupt Notable’s operations.
In the future Notable may expand Notable’s employee base to increase Notable’s managerial, scientific, operational, commercial, financial and other resources and Notable may hire more consultants and contractors. Future growth would impose significant additional responsibilities on Notable’s management, including the need to identify, recruit, maintain, motivate and integrate additional employees, consultants and contractors. Also, Notable’s management may need to divert a disproportionate amount of its attention away from Notable’s day-to-day activities and devote a substantial amount of time to managing these growth activities. Notable may not be able to effectively manage the expansion of Notable’s operations, which may result in weaknesses in Notable’s infrastructure or give rise to operational mistakes, loss of business opportunities, loss of employees or reduced productivity among remaining employees. Notable’s expected growth could require significant capital expenditures and may divert financial resources from other projects, such as the development of additional product candidates. Moreover, if Notable’s management is unable to effectively manage Notable’s growth, Notable’s expenses may increase more than expected, Notable’s ability to generate and/or grow revenues could be reduced, and Notable may not be able to implement Notable’s business strategy. Notable’s future financial performance and Notable’s ability to commercialize product candidates and compete effectively will depend, in part, on Notable’s ability to effectively manage any future growth.
Notable’s employees may engage in misconduct or other improper activities, including noncompliance with regulatory standards and requirements and insider trading.
Notable is exposed to the risk of employee fraud or other misconduct. Misconduct by employees could include intentional or nonintentional failures to comply with the regulations of the FDA and non-U.S. regulators, to provide accurate information to the FDA and non-U.S. regulators, to comply with healthcare fraud and abuse laws and regulations in the United States and abroad, to report financial information or data accurately or to disclose unauthorized activities to Notable. In particular, sales, marketing and business arrangements in the healthcare industry are subject to extensive laws and regulations intended to prevent fraud, misconduct, kickbacks, self-dealing and other abusive practices. These laws and regulations may restrict or prohibit a wide range of pricing, discounting, marketing and promotion, sales commission, customer incentive programs and other business arrangements.
Employee misconduct could also involve the improper use of information obtained in the course of clinical trials, which could result in regulatory sanctions and cause serious harm to Notable’s reputation. Notable has adopted a code of conduct, but it is not always possible to identify and deter employee misconduct, and the precautions Notable takes to detect and prevent this activity may not be effective in controlling unknown or unmanaged risks or losses or in protecting Notable from governmental investigations or other actions or lawsuits stemming from a failure to comply with these laws or regulations. If any such actions are instituted against Notable, and Notable is not successful in defending itself or asserting Notable’s rights, those actions could have a significant impact on Notable’s business, including the imposition of civil, criminal and administrative penalties, damages, fines, possible exclusion from Medicare, Medicaid and other government healthcare programs, additional reporting requirements and/or oversight, particularly if Notable becomes subject to a corporate integrity agreement or similar agreement to resolve allegations of non-compliance, disgorgement, imprisonment, and contractual damages. Even if Notable is ultimately successful in defending against any such action, Notable could be required to divert financial and managerial resources in doing so and adverse publicity could result, all of which could harm Notable’s business.
Future relationships with customers and third-party payors as well as certain of Notable’s business operations may be subject, directly or indirectly, to federal and state healthcare fraud and abuse laws, false claims laws and health information privacy and security laws. If Notable is unable to comply, or have not fully complied, with such laws, Notable could face criminal sanctions, civil penalties, contractual damages, reputational harm and diminished profits and future earnings.
If Notable obtains FDA approval for any of Notable’s product candidates and begins commercializing those products in the United States, Notable’s operations may be directly, or indirectly through Notable’s customers, further subject to various federal and state fraud and abuse laws, including, without limitation, the federal Anti-Kickback Statute and the federal False Claims Act. These laws may impact, among other things, Notable’s proposed sales, marketing and education programs. In addition, Notable may be subject to patient privacy regulation by the federal government and by the U.S. states and foreign jurisdictions in which Notable conducts Notable’s business. The healthcare laws and regulations that may affect Notable’s ability to operate include:
● The federal Anti-Kickback Statute, which prohibits, among other things, persons and entities from knowingly and willfully soliciting, receiving, offering or paying remuneration, directly or indirectly, to induce, or in return for, either the referral of an individual, or the purchase or recommendation of an item or service for which payment may be made under a federal healthcare program, such as the Medicare and Medicaid programs. Remuneration has been interpreted broadly to include anything of value. Although there are a number of statutory exemptions and regulatory safe harbors protecting certain common activities from prosecution, the exemptions and safe harbors are drawn narrowly, and those activities may be subject to scrutiny or penalty if they do not qualify for an exemption or safe harbor. A conviction for violation of the Anti-Kickback Statute requires mandatory exclusion from participation in federal healthcare programs. This statute has been applied to arrangements between pharmaceutical manufacturers and those in a position to purchase products or refer others, including prescribers, patients, purchasers and formulary managers. In addition, the ACA amended the Social Security Act to provide that the U.S. government may assert that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the federal civil False Claims Act penalties for which are described below.
● Federal civil and criminal false claims laws and civil monetary penalty laws, including the federal False Claims Act, which imposes criminal or civil penalties, including through civil whistleblower or qui tam actions, against individuals or entities for, among other things, knowingly presenting, or causing to be presented, claims for payment to the federal government, including Medicare or Medicaid, that are false or fraudulent or making a false statement to avoid, decrease or conceal an obligation to pay money to the federal government. Liability under the False Claims Act is potentially significant in the healthcare industry because the statute provides for treble damages and mandatory penalties of $5,500 to $11,000 per false claim or statement ($12,537 to $25,076 per false claim or statement for penalties assessed after May 9, 2022, for violations occurring after November 2, 2015).
● The civil monetary penalties statute, which imposes penalties against any person or entity who, among other things, is determined to have presented or caused to be presented a claim to a federal healthcare program that the person knows or should know is for an item or service that was not provided as claimed or is false or fraudulent.
● HIPAA, which imposes civil and criminal penalties for, among other things, knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program or obtain, by means of false or fraudulent pretenses, representations or promises, any money or property owned by, or under the custody or control of, any healthcare benefit program, regardless of the payor (e.g., public or private), knowingly and willfully embezzling or stealing from a health care benefit program, willfully obstructing a criminal investigation of a healthcare offense and knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false statements in connection with the delivery of, or payment for, healthcare benefits, items or services relating to healthcare.
● HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009, or HITECH, and its implementing regulations, which imposes certain requirements on certain types of individuals and entities, such as healthcare providers, health plans and healthcare clearing houses, known as “covered entities,” as well as their “business associates,” independent contractors or agents of covered entities that receive or obtain individually identifiable health information in connection with providing a service on behalf of a covered entity, relating to the privacy, security and transmission of individually identifiable health information.
● The federal Physician Payments Sunshine Act, which requires certain manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program, with specific exceptions, to report annually to CMS, information related to payments or other transfers of value made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors) and teaching hospitals, or to entities or individuals at the request of, or designated on behalf of, physicians and teaching hospitals, and further requires applicable manufacturers and applicable group purchasing organizations to report annually to CMS ownership and investment interests held by physicians and their immediate family members. These reporting obligations have extended, such that beginning January 1, 2022, companies must also report payments and transfers of value provided to non-physician providers and other types of healthcare professionals such as physician assistants and nurse practitioners. Failure to submit timely, accurately and completely the required information for all covered payments, transfers of value and ownership or investment interests may result in civil monetary penalties. In addition, many states also govern the reporting of payments or other transfers of value, many of which differ from each other in significant ways, are often not pre-empted, and may have a more prohibitive effect than the Sunshine Act, thus further complicating compliance efforts.
● Many state and foreign law equivalents of each of the above federal laws, such as: anti-kickback and false claims laws which may apply to items or services reimbursed by any third party payor, including commercial insurers; state laws that require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government; state laws that require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers or marketing expenditures; state and local laws that require the registration of pharmaceutical sales representatives; and state and foreign laws governing the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.
In addition, the European Union has established its own data security and privacy legal framework, including but not limited to Directive 95/46/EC. The European General Data Protection Regulation contains new provisions specifically directed at the processing of health information, higher sanctions and extra-territoriality measures intended to bring non-European Union companies under the regulation.
If Notable’s operations are found to be in violation of any of the laws described above or any other governmental regulations or laws that apply to Notable, Notable may be subject to penalties, including, without limitation, civil, criminal and administrative penalties, damages, fines, possible exclusion from Medicare, Medicaid and other government healthcare programs, additional reporting requirements and/or oversight, particularly if Notable becomes subject to a corporate integrity agreement or similar agreement to resolve allegations of non-compliance, disgorgement, imprisonment, contractual damages, reputational harm, diminished profits and future earnings, and curtailment or restructuring of Notable’s operations, any of which could adversely affect Notable’s ability to operate Notable’s business and Notable’s results of operations.
Recent and future healthcare legislation may further impact Notable’s business operations.
The United States and some foreign jurisdictions are considering or have enacted a number of legislative and regulatory proposals to change the healthcare system in ways that could affect Notable’s ability to sell Notable’s products profitably. Among policy makers and payors in the United States and elsewhere, there is significant interest in promoting changes in healthcare systems with the stated goals of containing healthcare costs, improving quality or expanding access. In the United States, the pharmaceutical industry has been a particular focus of these efforts and has been significantly affected by major legislative initiatives.
Notable expects that healthcare reform measures that may be adopted in the future may result in more rigorous coverage criteria and lower reimbursement, and in additional downward pressure on the price that Notable receives for any approved product. Any reduction in reimbursement from Medicare or other government-funded programs may result in a similar reduction in payments from private payors.
Notable cannot predict what healthcare reform initiatives may be adopted in the future. Further federal, state and foreign legislative and regulatory developments are likely, and Notable expects ongoing initiatives to increase pressure on drug pricing. Such reforms could have an adverse effect on anticipated revenues from product candidates that Notable may successfully develop and for which Notable may obtain regulatory approval and may affect Notable’s overall financial condition and ability to develop product candidates.
Notable face potential product liability, and, if successful claims are brought against Notable, Notable may incur substantial liability and costs.
The use of Notable’s product candidates in current and future clinical trials and the sale of any products for which Notable obtains marketing approval exposes Notable to the risk of product liability claims. Product liability claims might be brought against Notable by consumers, healthcare providers, pharmaceutical companies or others selling or otherwise coming into contact with Notable’s products. For example, unanticipated adverse effects could result from the use of Notable’s current and future products or product candidates which may result in a potential product liability claim. If Notable cannot successfully defend against product liability claims, Notable could incur substantial liability and costs. In addition, regardless of merit or eventual outcome, product liability claims may result in:
● impairment of Notable’s business reputation;
● withdrawal of clinical trial participants;
● costs due to related litigation;
● distraction of management’s attention from Notable’s primary business;
● substantial monetary awards to patients or other claimants;
● the inability to commercialize Notable’s product candidates; and
● decreased demand for Notable’s product candidates, if approved for commercial sale.
Notable has obtained product liability insurance relating to the use of Notable’s therapeutics in current and future clinical trials. However, such insurance coverage may not be sufficient to reimburse Notable for any expenses or losses Notable may suffer. Moreover, insurance coverage is becoming increasingly expensive and in the future Notable may not be able to obtain or maintain insurance coverage at a reasonable cost or in sufficient amounts to protect Notable against losses due to liability. If and when Notable obtains marketing approval for product candidates, Notable intends to expand Notable’s insurance coverage to include the sale of commercial products; however, Notable may be unable to obtain product liability insurance on commercially reasonable terms or in adequate amounts. On occasion, large judgments have been awarded in class action lawsuits based on drugs that had unanticipated adverse effects. A successful product liability claim or series of claims brought against Notable could cause Notable’s share price to decline and, if judgments exceed Notable’s insurance coverage, could adversely affect Notable’s results of operations and business.
Cyber security risks and the failure to maintain the confidentiality, integrity, and availability of Notable’s computer hardware, software, and Internet applications and related tools and functions could result in damage to Notable’s reputation and/or subject Notable to costs, fines or lawsuits.
Notable’s business requires manipulating, analyzing and storing large amounts of data. In addition, Notable relies on a global enterprise software system to operate and manage Notable’s business. Notable also maintains personally identifiable information about Notable’s employees. Notable’s business therefore depends on the continuous, effective, reliable, and secure operation of Notable’s computer hardware, software, networks, Internet servers, and related infrastructure. To the extent that Notable’s hardware or software malfunctions or access to Notable’s data by internal research personnel is interrupted, Notable’s business could suffer. The integrity and protection of Notable’s employees and company data is critical to Notable’s business and employees have a high expectation that Notable will adequately protect their personal information. The regulatory environment governing information, security and privacy laws is increasingly demanding and continues to evolve. Maintaining compliance with applicable security and privacy regulations may increase Notable’s operating costs. Although Notable’s computer and communications hardware is protected through physical and software safeguards, it is still vulnerable to fire, storm, flood, power loss, earthquakes, telecommunications failures, physical or software break-ins, software viruses, and similar events. These events could lead to the unauthorized access, disclosure and use of non-public information. The techniques used by criminal elements to attack computer systems are sophisticated, change frequently and may originate from less regulated and remote areas of the world. As a result, Notable may not be able to address these threats proactively or implement adequate preventative measures. If Notable’s computer systems are compromised, Notable could be subject to fines, damages, litigation and enforcement actions, and Notable could lose trade secrets, the occurrence of which could harm Notable’s business. In addition, any sustained disruption in internet access provided by other companies could harm Notable’s business.
Business disruptions could seriously harm future revenue and financial condition and increase Notable’s costs and expenses.
Notable’s operations, and those of CROs and other contractors and consultants, could be subject to earthquakes, power shortages, telecommunications failures, water shortages, floods, hurricanes, typhoons, fires, extreme weather conditions, medical epidemics and other natural or man-made disasters or business interruptions, for which Notable is predominantly self-insured. The occurrence of any of these business disruptions could seriously harm Notable’s operations and financial condition and increase Notable’s costs and expenses.
Notable’s corporate headquarters are located in Foster City, California, an area prone to wildfires and earthquakes. These and other natural disasters could severely disrupt Notable’s operations, and have a material adverse effect on Notable’s business, results of operations, financial condition and prospects. If a natural disaster, power outage or other event occurred that prevented Notable from using all or a significant portion of Notable’s headquarters, that damaged critical infrastructure, or that otherwise disrupted operations, it may be difficult or, in certain cases, impossible for Notable to continue Notable’s business for a substantial period of time. Any disaster recovery and business continuity plans Notable has in place may prove inadequate in the event of a serious disaster or similar event. Notable may incur substantial expenses as a result of the limited nature of Notable’s disaster recovery and business continuity plans, which, could have a material adverse effect on Notable’s business.
Notable will need to increase the size of Notable’s organization and the scope of Notable’s outside vendor relationships, and Notable may experience difficulties in managing growth.
Notable’s management and scientific personnel, systems and facilities currently in place may not be adequate to support Notable’s future growth. Notable needs to effectively manage Notable’s operations, growth and various projects and requires that Notable:
● manages Notable’s clinical trials effectively, including Notable’s existing and planned clinical trials;
● manages Notable’s internal development efforts effectively while carrying out Notable’s contractual obligations to licensors, contractors and other third parties;
● continues to improve Notable’s operational, financial and management controls and reporting systems and procedures; and
● continues to attract and retain sufficient numbers of talented employees.
Notable is utilizing and expects in the future to utilize the services of vendors and research partners or collaborators to perform tasks including preclinical studies and clinical trial management, statistics and analysis, regulatory affairs, medical advisory, market research, formulation development, chemistry, manufacturing and control activities, other drug development functions, legal, auditing, financial advisory, and investor relations. Notable’s growth strategy may also entail expanding Notable’s group of contractors or consultants to implement these and other tasks going forward. Because Notable relies on numerous consultants to outsource many key functions of Notable’s business, Notable will need to be able to effectively manage these consultants to ensure that they successfully carry out their contractual obligations and meet expected deadlines. However, if Notable is unable to effectively manage Notable’s outsourced activities or if the quality or accuracy of the services provided by consultants is compromised for any reason, Notable’s clinical trials may be extended, delayed or terminated, and Notable may not be able to obtain regulatory approval for Notable’s drug candidate or otherwise advance Notable’s business. There can be no assurance that Notable will be able to manage Notable’s existing consultants or find other competent outside contractors and consultants on economically reasonable terms, or at all. If Notable is not able to effectively expand Notable’s organization by hiring new employees and expanding Notable’s groups of consultants and contractors, Notable may be unable to successfully implement the tasks necessary to further develop and commercialize Notable’s drug candidates and, accordingly, may not achieve Notable’s research, development and commercialization goals.
Disruptions to Notable’s information technology systems, including future cyber-attacks and security breaches, and the costs of maintaining secure and effective information technology systems could negatively affect Notable’s business and results of operations.
The efficient operation of Notable’s businesses is highly dependent on computer hardware and software systems, including Notable’s customized information technology systems that form Notable’s PPMP. Information systems are vulnerable to security breaches by computer hackers and cyber terrorists. Notable relies on industry accepted security measures and technology to securely maintain confidential and proprietary information maintained on Notable’s information systems, and continue to invest in maintaining and upgrading these systems and applications to ensure risk is controlled. Regardless of Notable’s efforts to maintain and upgrade Notable’s cyber security systems, there can be no assurance that Notable will not suffer an intrusion, that unauthorized parties will not gain access to confidential or personal information, or that any such incident will be discovered promptly. The techniques used by criminals to obtain unauthorized access to sensitive data change frequently and often are not recognized until launched against a target, and Notable may be unable to anticipate these techniques or implement adequate preventative measures. The failure to promptly detect, determine the extent of and appropriately respond to a significant data security breach could have a material adverse impact on Notable’s business, financial condition and results of operations. In addition, the unavailability of the information systems or failure of these systems to perform as anticipated for any reason, including a major disaster or business interruption resulting in an inability to access data stored in these systems or sustain the data center systems necessary to support functions to meet Notable’s needs, and any inability to respond to, or recover from, such an event, could disrupt Notable’s business and could result in decreased performance and increased overhead costs, causing Notable’s business and results of operations to suffer.
Additionally, Notable’s operations involve the receipt and storage of sensitive data, including personal information about Notable’s employees and proprietary business information of ours and Notable’s vendors. Notable may also share information with vendors that assist Notable in conducting Notable’s business, as required by law, with the permission of the individual or as permitted under applicable privacy policies.
Despite the utilization of information security measures, Notable cannot be certain that all of Notable’s IT systems or the IT systems of Notable’s vendors are or will be able to prevent, contain or detect any future cyber-attacks or security breaches from known malware, malware that may be developed in the future or otherwise. Cyber-attacks are rapidly evolving and becoming increasingly sophisticated and difficult to detect, and therefore, Notable may be unable to anticipate these attacks or implement adequate preventive measures. Additionally, unauthorized parties may attempt to gain access to Notable’s or a vendor’s systems or facilities through fraud, trickery or other forms of deception involving Notable’s employees or vendors. To the extent that any attack or breach results in the loss, damage or misappropriation of information, Notable may be adversely affected by claims from persons participating in Notable’s clinical trials, shareholders and others and by costly inquiries or enforcement actions on the part of regulatory authorities. Notable’s operations could also be significantly disrupted by these claims, as well as by the need to spend significant time and expense to upgrade, fix or replace Notable’s systems. Notable could also lose credibility with persons participating in Notable’s clinical trials and suffer damage to Notable’s reputation and future sales, if any. In addition, the cost of complying with stricter privacy and information security laws and standards and developing, maintaining and upgrading technology systems to address future advances in technology, could be significant and Notable could experience problems and interruptions associated with the implementation of new or upgraded systems and technology or with maintenance or adequate support of existing systems.
Notable’s failure to successfully acquire, develop and market additional drug candidates could impair Notable’s ability to grow.
As part of Notable’s growth strategy, Notable may evaluate, acquire, license, develop and/or market additional drug candidates and technologies. Notable’s internal research capabilities are limited and Notable may be dependent upon pharmaceutical and biopharmaceutical companies, academic scientists and other researchers to sell or license drug candidates or technologies to Notable. The success of this strategy depends partly upon Notable’s ability to identify, select and acquire promising pharmaceutical drug candidates and technologies. The process of proposing, negotiating and implementing a license or acquisition of a drug candidate is lengthy and complex. Other companies, including some with substantially greater financial, marketing and sales resources, may compete with Notable for the license or acquisition of drug candidates and technologies. Notable has limited resources to identify and execute the acquisition or in-licensing of potential drug candidates and technologies and to integrate them into Notable’s current infrastructure. Moreover, Notable may devote resources to potential acquisitions or in-licensing opportunities that are never completed, or Notable may fail to realize the anticipated benefits of such efforts. Furthermore, Notable may not be able to acquire the rights to additional drug candidates on terms that Notable finds acceptable, or at all.
In addition, future acquisitions of intellectual property rights may entail numerous operational and financial risks, including:
● exposure to unknown liabilities;
● disruption of Notable’s business and diversion of Notable’s management’s and technical personnel’s time and attention to develop acquired drug candidates or technologies;
● incurrence of substantial debt or dilutive issuances of securities to pay for acquisition costs;
● higher than expected acquisition costs; and
● increased amortization expenses.
Any drug candidate that Notable acquires may require additional development efforts prior to commercial sale or out-licensing, including extensive clinical testing and approval by the FDA and applicable foreign regulatory authorities. All drug candidates are prone to risks of failure typical of pharmaceutical drug development, including the possibility that a drug candidate will not be shown to be sufficiently safe and effective for approval by regulatory authorities. In addition, Notable cannot provide assurance that any drugs that Notable may develop or approved drugs that Notable may acquire will be manufactured profitably or achieve market acceptance.
Notable has obtained statistical data, market data and other industry data and forecasts used throughout this report from market research, publicly available information and industry publications which Notable believes are reliable but have not been verified by any third party.
This report contains estimates, projections and other information concerning Notable’s industry, Notable’s business and the markets for Notable’s drug candidates, including data regarding the estimated size of such markets and the incidence of certain medical conditions. Notable obtained the industry, market and similar data set forth in this report from Notable’s internal estimates and research and from academic and industry research, publications, surveys and studies conducted by third parties, including governmental agencies. In some cases, Notable does not expressly refer to the sources from which this data is derived. Information that is based on estimates, forecasts, projections, market research or similar methodologies is inherently subject to uncertainties, and actual events or circumstances may differ materially from events and circumstances that are assumed in this information. While Notable believes Notable’s internal research is reliable, such research has not been verified by any third party.
Risks Related to Notable’s Incorporation in Israel
Your rights and responsibilities as Notable’s shareholder will be governed by Israeli law, which may differ in some respects from the rights and responsibilities of shareholders of U.S. corporations.
Because Notable is incorporated under Israeli law, the rights and responsibilities of its shareholders are governed by Notable’s articles of association and Israeli law. These rights and responsibilities differ in some material respects from the rights and responsibilities of shareholders of U.S. corporations. In particular, a shareholder of an Israeli company has a duty to act in good faith and in a customary manner in exercising its rights and performing its obligations towards the company and other shareholders and to refrain from abusing its power in the company, including, among other things, in voting at the general meeting of shareholders on certain matters, such as an amendment to the company’s articles of association, an increase of the company’s authorized share capital, a merger of the company and approval of related party transactions that require shareholder approval. A shareholder also has a general duty to refrain from discriminating against other shareholders. In addition, a controlling shareholder or a shareholder who knows that it possesses the power to determine the outcome of a shareholder vote or to appoint or prevent the appointment of an officer of the company has a duty to act in fairness towards the company with regard to such vote or appointment. However, Israeli law does not define the substance of this duty of fairness. There is limited case law available to assist Notable in understanding the nature of this duty or the implications of these provisions. These provisions may be interpreted to impose additional obligations and liabilities on Notable’s shareholders that are not typically imposed on shareholders of U.S. corporations.
Provisions of Israeli law and Notable’s amended and restated articles of association could make it more difficult for a third party to acquire Notable or increase the cost of acquiring Notable, even if doing so would benefit Notable’s shareholders.
Israeli law regulates mergers, requires tender offers for acquisitions of shares above specified thresholds, requires special approvals for transactions involving directors, officers or significant shareholders and regulates other matters that may be relevant to such types of transactions. For example, a tender offer for all of a company’s issued and outstanding shares can only be completed if the acquirer receives positive responses from the holders of at least 95% of the issued share capital. Completion of the tender offer also requires approval of a majority of the offerees that do not have a personal interest in the tender offer, unless at least 98% of the company’s outstanding shares are tendered. Furthermore, the shareholders, including those who indicated their acceptance of the tender offer (unless the acquirer stipulated in its tender offer that a shareholder that accepts the offer may not seek appraisal rights), may, at any time within six months following the completion of the tender offer, petition an Israeli court to alter the consideration for the acquisition.
Further, Israeli tax considerations may make potential transactions undesirable to Notable or to some of its shareholders whose country of residence does not have a tax treaty with Israel granting tax relief to such shareholders from Israeli tax. For example, Israeli tax law does not recognize tax-free share exchanges to the same extent as U.S. tax law. With respect to mergers, Israeli tax law allows for tax deferral in certain circumstances but makes the deferral contingent on the fulfillment of a number of conditions, including, in some cases, a holding period of two years from the date of the transaction during which sales and dispositions of shares of the participating companies are subject to certain restrictions. Moreover, with respect to certain share swap transactions, the tax deferral is limited in time, and when such time expires, the tax becomes payable even if no disposition of the shares has occurred.
Certain U.S. shareholders may be subject to adverse tax consequences if Notable is characterized as “Controlled Foreign Corporation.”
Each “Ten Percent Shareholder” in a non-U.S. corporation that is classified as a “controlled foreign corporation” (“CFC”) for U.S. federal income tax purposes generally is required to include in income for U.S. federal tax purposes such Ten Percent Shareholder’s pro rata share of the CFC’s “Subpart F income” and investment of earnings in U.S. property, even if the CFC has made no distributions to its shareholders. A non-U.S. corporation generally will be classified as a CFC for U.S. federal income tax purposes if Ten Percent Shareholders own, directly or indirectly, more than 50% of either the total combined voting power of all classes of stock of such corporation entitled to vote or of the total value of the stock of such corporation. A “Ten Percent Shareholder” is a U.S. person (as defined by the Code), who owns or is considered to own 10% or more of the total combined voting power of all classes of stock entitled to vote of such corporation. The determination of CFC status is complex and includes attribution rules, the application of which is not entirely certain.
Notable does not believe that it was a CFC for the taxable year ended December 31, 2022, or that Notable is currently a CFC. It is possible, however, that a shareholder treated as a U.S. person for U.S. federal income tax purposes will acquire, directly or indirectly, enough shares to be treated as a Ten Percent Shareholder after application of the constructive ownership rules and, together with any other Ten Percent Shareholders of the company, cause Notable to be treated as a CFC for U.S. federal income tax purposes. Notable believes that certain of its shareholders are Ten Percent Shareholders for U.S. federal income tax purposes. Holders should consult their own tax advisors with respect to the potential adverse U.S. federal income tax consequences of becoming a Ten Percent Shareholder in a CFC.
Notable is expected to be classified as a PFIC in the 2023 taxable year, and its U.S. shareholders may suffer adverse tax consequences as a result.
Generally, if, for any taxable year, at least 75% of Notable’s gross income is passive income, or at least 50% of the value of Notable’s assets is attributable to assets that produce passive income or are held for the production of passive income, including cash, Notable would be characterized as a PFIC for U.S. federal income tax purposes. For purposes of these tests, passive income includes dividends, interest, and gains from the sale or exchange of investment property and rents and royalties other than rents and royalties which are received from unrelated parties in connection with the active conduct of a trade or business. If Notable is characterized as a PFIC, Notable’s U.S. shareholders may suffer adverse tax consequences, including having gains realized on the sale of Notable Ordinary Shares treated as ordinary income, rather than capital gain, the loss of the preferential rate applicable to dividends received on Notable Ordinary Shares by individuals who are U.S. Holders, and having interest charges apply to distributions by Notable and the proceeds of share sales.
Because PFIC status depends on the composition of Notable’s income and the composition and value of its assets (which may be determined in part by reference to the market value of Notable Ordinary Shares, which may be volatile) from time to time, there can be no assurance that Notable will not be considered a PFIC for any taxable year. Notable is not expected to be a PFIC for its 2021 or 2022 taxable year and Notable is expected to be a PFIC for the current taxable year. However, the determination of whether Notable is a PFIC is a fact-intensive determination made on an annual basis applying principles and methodologies that in some circumstances are unclear and subject to varying interpretation. As Notable’s PFIC status depends on the composition of its income and the composition and value of its assets (which may be determined in part by reference to the market value of Notable Ordinary Shares, which may be volatile) between the start and end of Notable’s current taxable year, Notable cannot conclusively determine its current PFIC status at this time and there can be no assurance that Notable’s determination of its PFIC status set forth above will not be challenged by the IRS.
Potential political, economic and military instability in the State of Israel, where some of Notable’s consultants are located, may adversely affect Notable’s results of operations.
Notable is incorporated under Israeli law and some of Notable’s consultants who are involved with its financial and accounting operations are located in the State of Israel. Accordingly, political, economic and military conditions in Israel directly affect Notable’s business. Since the State of Israel was established in 1948, a number of armed conflicts have occurred between Israel and its neighboring countries.
Any hostilities involving Israel, or a significant downturn in the economic or financial condition of Israel, could affect adversely Notable’s operations. Since October 2000, there have been increasing occurrences of terrorist violence. Ongoing and revived hostilities, including the hostilities that began in October 2023, or other Israeli political or economic factors could harm Notable’s operations.
The tax benefits that are available to Notable if and when it generates taxable income require it to meet various conditions and may be prevented or reduced in the future, which could increase Notable’s costs and taxes.
If and when Notable generates taxable income, it would be eligible for certain tax benefits provided to “Benefited Enterprises” under the Israeli Law for the Encouragement of Capital Investments, 1959, as amended (the “Investment Law”). In order to remain eligible for the tax benefits for “Benefited Enterprises” Notable must continue to meet certain conditions stipulated in the Investment Law and its regulations, as amended. In addition, Notable informed the Israeli Tax Authority of its choice of 2012 as a “Benefited Enterprise” election year, all under the Investment Law. The benefits available to Notable under this tax regulation are subject to the fulfillment of conditions stipulated in the regulation. Further, in the future these tax benefits may be reduced or discontinued. If these tax benefits are reduced, cancelled or discontinued, Notable’s Israeli taxable income would be subject to regular Israeli corporate tax rates. The standard corporate tax rate for Israeli companies is 23% for 2018 and thereafter. Additionally, if Notable increases its activities outside of Israel through acquisitions, for example, its expanded activities might not be eligible for inclusion in future Israeli tax benefit programs.
Risks Related to Ownership of Ordinary Shares of Notable
The market price of Notable Ordinary Shares may be highly volatile, and you may not be able to resell your shares at the purchase price.
An active trading market for Notable Ordinary Shares may not be available. You may not be able to sell your shares quickly or at the market price if trading in Notable Ordinary Shares is not active.
The market price of Notable Ordinary Shares has been and is likely to remain volatile. Notable’s share price could be subject to wide fluctuations in response to a variety of factors, including the following:
● a slowdown in the healthcare industry or the general economy;
● inability to obtain adequate supply of the components for any of Notable’s products, or inability to do so at acceptable prices;
● failure to successfully develop and commercialize Notable’s product candidates;
● failure to obtain additional funding;
● performance of third parties on whom Notable may rely, including for the manufacture of the components for its product, including their ability to comply with regulatory requirements;
● the results of Notable’s current and any future clinical trials of its product candidates;
● unanticipated or serious safety concerns related to the use of any of Notable’s products;
● adverse regulatory decisions;
● the entry into, or termination of, key agreements, including key commercial partner agreements;
● the initiation of, material developments in or conclusion of litigation to enforce or defend any of Notable’s intellectual property rights or defend against the intellectual property rights of others;
● announcements by Notable, commercial partners or competitors of new products or product enhancements, clinical progress or the lack thereof, significant contracts, commercial relationships or capital commitments;
● competition from existing technologies and products or new technologies and products that may emerge;
● the loss of key employees;
● disputes or other developments relating to proprietary rights, including patents, litigation matters and Notable’s ability to obtain patent protection for Notable’s licensed and owned technologies;
● changes in estimates or recommendations by securities analysts, if any, who cover Notable’s ordinary shares;
● the perception of the biopharmaceutical industry by the public, legislatures, regulators and the investment community;
● sales of Notable’s ordinary shares by Notable or its stockholders in the future;
● general and industry-specific economic conditions that may affect Notable’s research and development expenditures;
● the low trading volume and the high proportion of shares held by affiliates;
● changes in the listing status of Notable’s securities on Nasdaq;
● changes in the structure of health care payment systems; and
● period-to-period fluctuations in Notable’s financial results.
Moreover, the stock markets in general have experienced substantial volatility that has often been unrelated to the operating performance of individual companies. These broad market fluctuations may also adversely affect the trading price of Notable’s ordinary shares.
In the past, following periods of volatility in the market price of a company’s securities, stockholders have often instituted class action securities litigation against those companies. Such litigation, if instituted, could result in substantial costs and diversion of management attention and resources, which could significantly harm Notable’s profitability and reputation.
There has been limited trading volume for Notable Ordinary Shares.
Even though Notable Ordinary Shares have been listed on Nasdaq, there has been limited liquidity in the market for the Notable Ordinary Shares, which could make it more difficult for holders to sell their Notable Ordinary Shares. There can be no assurance that an active trading market for Notable Ordinary Shares will be sustained. In addition, the stock market generally has experienced extreme price and volume fluctuations that have often been unrelated or disproportionate to the operating performance of listed companies. Broad market and industry factors may negatively affect the market price of Notable Ordinary Shares, regardless of its actual operating performance. The market price and liquidity of the market for Notable Ordinary Shares that will prevail in the market may be higher or lower than the price you pay and may be significantly affected by numerous factors, some of which are beyond Notable’s control.
Notable’s principal shareholders own a significant percentage of its shares and will be able to exert significant control over matters subject to shareholder approval.
As of February 16, 2024, to the best of Notable’s information, its directors, officers, 5% shareholders and their respective affiliates beneficially owned approximately 38% of Notable’s outstanding voting shares. Therefore, these shareholders have the ability to influence Notable through their ownership positions. These shareholders may be able to determine all matters requiring shareholder approval. For example, these shareholders, if they were to act together, may be able to control elections of directors, amendments of Notable’s organizational documents, or approval of any merger, sale of assets, or other major corporate transaction. This may prevent or discourage unsolicited acquisition proposals or offers for Notable Ordinary Shares that you may believe are in your best interest as one of Notable’s shareholders.
Notable does not intend to pay dividends on Notable Ordinary Shares in the foreseeable future, so any returns will be limited to the value of its shares.
Notable has never declared or paid any cash dividends on its share capital. Notable currently anticipates that it will retain future earnings for the development, operation and expansion of its business and does not anticipate declaring or paying any cash dividends for the foreseeable future. Any return to shareholders will therefore be limited to the appreciation of their shares. In addition, Israeli law limits Notable’s ability to declare and pay dividends and may subject Notable’s dividends to Israeli withholding taxes. Furthermore, Notable’s payment of dividends (out of tax-exempt income) may retroactively subject it to certain Israeli corporate income taxes, to which Notable would not otherwise be subject.
If equity research analysts do not publish research reports about Notable’s business or if they issue unfavorable commentary or downgrade Notable Ordinary Shares, the price of Notable Ordinary Shares could decline.
The trading market for Notable Ordinary Shares relies in part on the research and reports that equity research analysts publish about Notable and its business. The price of Notable Ordinary Shares could decline if it does not obtain research analyst coverage, or one or more securities analysts downgrade the Notable Ordinary Shares, or if those analysts issue other unfavorable commentary or expectations that Notable is unable to meet or cease publishing reports about Notable or its business.
Notable will incur costs and demands upon management as a result of complying with the laws and regulations affecting public companies.
Notable will incur significant legal, accounting, and other expenses that Notable did not incur as a private company, including costs associated with public company reporting requirements. Notable will also incur costs associated with corporate governance requirements, including requirements under the Sarbanes-Oxley Act, as well as new rules implemented by the SEC and Nasdaq. These rules and regulations are expected to increase Notable’s legal and financial compliance costs and to make some activities more time-consuming and costly. For example, Notable’s management team will consist of the executive officers of Notable prior to completion of the merger, some of whom may not have previously managed and operated a public company. These executive officers and other personnel will need to devote substantial time to gaining expertise regarding operations as a public company and compliance with applicable laws and regulations. These rules and regulations may also make it difficult and expensive for Notable to obtain directors and officers liability insurance. As a result, it may be more difficult for Notable to attract and retain qualified individuals to serve on Notable’s board of directors or as executive officers of Notable, which may adversely affect investor confidence in Notable and could cause Notable’s business or stock price to suffer. Further, Notable may need to add additional experience and personnel to support its public company operations. The loss of any existing personnel in these areas or Notable’s inability to achieve or manage such expansion effectively may result in weaknesses in its infrastructure and Notable’s business, financial condition and results of operations may be materially adversely affected.
Anti-takeover provisions in Notable’s charter documents could make an acquisition of Notable more difficult.
Provisions in Notable’s articles of association and memorandum of association may delay or prevent an acquisition. The Companies Law allows Notable to create and issue shares having rights different from the ordinary shares, including shares providing certain preferred rights with respect to voting, distributions or other matters and shares having preemptive rights. No preferred shares are currently authorized under Notable’s amended and restated articles of association. In the future, if Notable were to authorize, create and issue a specific class of preferred shares, such class of shares, depending on the specific rights that may be attached to it, may have the ability to frustrate or prevent a takeover or otherwise prevent Notable’s shareholders from realizing a potential premium over the market value of their ordinary shares. The authorization and designation of a class of preferred shares will require an amendment to Notable’s amended and restated articles of association, which requires the prior approval of the holders of a majority of the voting power attaching to Notable’s issued and outstanding shares at a general meeting.
Notable is expected to take advantage of reduced disclosure and governance requirements applicable to smaller reporting companies, which could result in its ordinary shares being less attractive to investors.
Notable has annual revenues below $100 million and a public float of less than $700 million and therefore will continue to qualify as a smaller reporting company under the rules of the SEC. As a smaller reporting company, Notable will be able to take advantage of reduced disclosure requirements, such as simplified executive compensation disclosures and reduced financial statement disclosure requirements in its SEC filings. Decreased disclosures in Notable’s SEC filings due to its status as a smaller reporting company may make it harder for investors to analyze its results of operations and financial prospects. d Notable cannot predict if investors will find Notable’s ordinary shares less attractive if it relies on these exemptions. If some investors find its ordinary shares less attractive as a result, there may be a less active trading market for its ordinary shares and its stock price may be more volatile. Notable may take advantage of the reporting exemptions applicable to a smaller reporting company until it is no longer a smaller reporting company. Notable would continue to be a smaller reporting company if Notable has (i) less than $250 million in market value of its shares held by non-affiliates as of the last business day of its second fiscal quarter or (ii) less than $100 million of annual revenues in its most recent fiscal year completed before the last business day of its second fiscal quarter and a market value of its shares held by non-affiliates of less than $700 million as of the last business day of its second fiscal quarter.
Notable’s failure to meet the continued listing requirements of the Nasdaq could result in a delisting of Notable’s ordinary shares.
If Notable fails to satisfy the continued listing requirements of the Nasdaq, such as the corporate governance requirements or the minimum closing bid price requirement, Nasdaq may take steps to delist Notable’s ordinary shares. Such a delisting would likely have a negative effect on the price of Notable’s ordinary shares and would impair your ability to sell or purchase Notable’s ordinary shares when you wish to do so. In the event of a delisting, Notable can provide no assurance that any action taken by Notable to restore compliance with listing requirements would allow Notable’s ordinary shares to become listed again, stabilize the market price or improve the liquidity of Notable’s ordinary shares, prevent Notable’s ordinary shares from dropping below the Nasdaq minimum bid price requirement or prevent future non-compliance with Nasdaq’s listing requirements.
Notable’s management has limited public company experience. As a result of being a public company, Notable will be subject to additional regulatory compliance requirements which must be managed efficiently for Notable to operate effectively.
Notable has never operated as a public company and will incur significant legal, accounting and other expenses that are not incurred by private company. The individuals who will constitute Notable’s management team have limited experience managing a publicly-traded company, and limited experience complying with the increasingly complex and changing laws pertaining to public companies. Notable’s management team and other personnel will need to devote a substantial amount of time to compliance, and Notable may not effectively or efficiently manage its transition into a public company.
Notable could be subject to securities class action litigation.
In the past, securities class action litigation has often been brought against a company following a decline in the market price of its securities. This risk is especially relevant for Notable, because biotechnology and pharmaceutical companies have experienced significant stock price volatility in recent years. If Notable faces such litigation, it could result in substantial costs and a diversion of management’s attention and resources, which could harm Notable’s business.

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ITEM 1B. UNRESOLVED STAFF COMMENTS
Item 1B. UNRESOLVED STAFF COMMENTS
Not applicable.

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ITEM 2. PROPERTIES
Item 2. PROPERTIES
Our corporate headquarters is currently located in Foster City, CA and is leased pursuant to a four-year lease with 3 years and one month remaining. The current lease payment is $43,894 per month with a 3.0% escalation each year.

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ITEM 3. LEGAL PROCEEDINGS
Item 3. LEGAL PROCEEDINGS
From time to time, we may become involved in litigation or other legal proceedings relating to claims arising in the ordinary course of business. We are not currently party to any legal proceedings that are likely to have a material adverse effect on our results of operations, financial condition or cash flows.

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ITEM 4. MINE SAFETY DISCLOSURE
Item 4. MINE SAFETY DISCLOSURES
Not applicable.
PART II

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ITEM 5. MARKET FOR REGISTRANT'S COMMON EQUITY
Item 5. MARKET FOR REGISTRANT’S COMMON EQUITY, RELATED STOCKHOLDER MATTERS AND ISSUER PURCHASES OF EQUITY SECURITIES
Market Information
Our ordinary shares are listed on the Nasdaq Capital Market under the symbol “NTBL.”
Holders of Record
According to our transfer agent, as of March 29, 2024, there were 138 record holders of our ordinary shares. None of our shareholders have different voting rights from other shareholders. Certain shares are held in “street” name and accordingly, the number of beneficial owners of such shares is not known or included in the foregoing number. This number of holders of record also does not include shareholders whose shares may be held in trust by other entities.
Dividends
We have never declared or paid any cash dividends to our shareholders. We currently anticipate that we will retain all of our future earnings, if any, for use in the operation of our business. Additionally, our ability to pay dividends on our ordinary shares may be limited by restrictions under Israeli law.
Transfer Agent
Our Transfer Agent is Equiniti Trust Company, LLC. The telephone number of Equiniti Trust Company, LLC is (718) 921-8124.
Recent Sales of Unregistered Securities
None.

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ITEM 6. SELECTED FINANCIAL DATA
Item 6. [RESERVED]

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ITEM 7. MANAGEMENT'S DISCUSSION AND ANALYSIS
Item 7. MANAGEMENT’S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS
The following discussion of our financial condition and results of operations should be read in conjunction with our financial statements and the related notes to those statements included elsewhere in this Annual Report. In addition to historical financial information, the following discussion and analysis contains forward-looking statements that involve risks, uncertainties and assumptions. See “Cautionary Note Regarding Forward-Looking Statements.” Our actual results and timing of selected events may differ materially from those anticipated in these forward-looking statements as a result of many factors, including those discussed under “Item 1A. Risk Factors” and elsewhere in this Annual Report.
Overview
Notable is a clinical-stage platform therapeutics company developing predictive precision medicines for patients with cancer. Through its proprietary Predictive Precision Medicines Platform or PPMP, Notable bio-simulates a patient’s cancer treatment ex vivo (outside of the body) and seeks to precisely predict whether or not an individual patient will clinically respond to their actual treatment. In four independent clinical validation trials with recognized medical centers, PPMP predicted responders with 83-100% precision. To pursue improved medical outcomes compared to traditional precision medicines, PPMP does not depend on genetic or other biomarkers. Instead, PPMP generates multi-dimensional measures of biological response of cells to drugs and then integrates and translates these data by computational algorithms into a patient response predictor.
PPMP is designed to enable Notable to identify and select patients expected to be clinically responsive prior to the initiation of their treatment and potentially enable fast-track therapeutic development in this patient population. Notable utilizes its PPMP to evaluate investigational compounds for in-licensing and development or co-development that have shown clinical activity, with the goal of improving patient response and the success, speed and value of developing these compounds, compared with traditional drug development.
Using PPMP, Notable targets in-licensing assets that have already demonstrated compelling clinical activity but have been abandoned because the activity was limited to a subset of 10% to 30% of treated patients, a likely hurdle to successful development, regulatory approval, and commercialization. Notable has screened and evaluated hundreds of assets on its PPMP platform, and for many of these assets, believes it can predict with relatively high precision which patients will clinically respond. This provides Notable with the opportunity to selectively enroll predicted responders into clinical trials, and thus to fast-track development of these assets selectively in clinical responders delivering higher response rates.
Notable is seeking to create a growing portfolio of predictive precision medicines using its PPMP. PPMP has already guided Notable in the selection of its first two candidate predictive precision medicines, two clinical-stage candidates for development in platform-predicted responders with acute myeloid leukemia (“AML”). Notable’s lead asset derived from PPMP is Volasertib, a polo like kinase 1 (“PLK1”) inhibitor proven to induce cell cycle arrest and apoptosis in various cancer cells. Notable expects to initiate a Phase 2 trial evaluating Volasertib in adult AML in the second quarter of 2024, which includes a dose optimization prelude targeting 6 patients. The results of these first 6 patients are expected in the fourth quarter of 2024, and the enrollment of the first PPMP-predicted responder is expected in the same quarter. In addition, Notable is co-developing, with CicloMed LLC (“CicloMed”), Fosciclopirox for patients with AML. This co-development partnership resulted from a successful pre-clinical application of PPMP for Fosciclopirox. Notable is also using PPMP to identify additional compelling assets for in-licensing and fast-tracking additional assets as it builds out its development pipeline.
By continually advancing and expanding the reach of the PPMP across patient segments, diseases and predicted medical outcomes, Notable aims to be the leader in predictive precision medicine and revolutionize the way in which patients seek and receive treatments that are most likely to work best for them - with major impact for patients and the healthcare community.
Merger Transaction
On October 16, 2023, pursuant to the Merger Agreement, by and among the Company, Merger Sub and Notable Labs, Inc., Merger Sub was merged with and into Notable Labs, Inc., with Notable Labs, Inc. continuing after the merger as the surviving entity and a wholly owned subsidiary of the Company. At the effective time of the Merger, without any action on the part of any stockholder, each issued and outstanding share of pre-Merger Notable Labs, Inc.’s common stock, par value $0.001 per share (the “Notable Labs, Inc. Common Stock”), including shares underlying pre-Merger Notable Labs, Inc.’s outstanding equity awards, was converted into the right to receive 0.0629 shares (the “Exchange Ratio”) of the Company’s common stock, 0.35 NIS par value per share (the “Company Ordinary Shares”), Immediately following the effective time of the Merger, the Company effected a 1-for-35 reverse stock split of the issued and outstanding Company Ordinary Shares (the “Reverse Stock Split”). Upon completion of the Merger and the transactions contemplated in the Merger Agreement, (i) the former Notable, Inc. equity holders owned approximately 71.9% of the outstanding equity of the Company on a fully diluted basis, assuming the exercise in full of warrants to purchase 94,988 Company Ordinary Shares and including 160,635 Company Ordinary Shares underlying options to purchase shares of Notable Labs, Inc.’s Common Stock assumed by the company at closing and after adjustments based on the Company’s net cash at closing; and (ii) former Vascular Biogenics, Ltd. shareholders owned approximately 28.1% of the outstanding equity of the Company.
The Merger was treated as a reverse recapitalization effected by a share exchange for financial accounting and reporting purposes. Notable Labs, Inc. was being treated as the accounting acquirer, as its stockholders control the Company after the Merger, even though Vascular Biogenics, Ltd. was the legal acquirer. As a result, the assets and liabilities and the historical operations that are reflected in our consolidated financial statements are those of Notable Labs, Inc. as if Notable Labs, Inc. had always been the reporting company. All references to ordinary shares, warrants and options have been presented on a post-merger, post-reverse split basis.
Financial Overview
Revenues and Cost of Revenues
Notable does not expect to generate any material revenue from the sale of any products unless or until Notable obtains regulatory approval of and commercializes any of its therapeutic products.
Notable continued to perform certain diagnostics services on a limited basis as an outsourced provider through the year ended December 31, 2023 and 2022, but such activities do not represent its major and ongoing central operations and Notable does not expect to derive any material revenue as a result.
Notable recognizes revenue from diagnostic services in the amount that reflects the consideration that it expects to be entitled as Notable performs its obligation under a contract with a customer by processing diagnostic tests on laboratory samples and making the test results available to its customers. Revenue is recorded considering a five-step revenue recognition model that includes identifying the contract with a customer, identifying the performance obligations in the contract, determining the transaction price, allocating the transaction price to the performance obligations, and recognizing revenue when, or as, an entity satisfies a performance obligation. Notable generally has a contract or a purchase order from a customer with the specified required terms, including the number of diagnostic samples to be performed. Notable has not received any advance payments for which there are any remaining performance obligations. Accordingly, no deferred revenue is recorded as of December 31, 2023 and 2022. Notable has not recorded any contract assets as of December 31, 2023 and 2022, and as of December 31, 2023 Notable had not completed any performance obligations for which it has not been able to bill its customers. Material costs of services revenue are recorded as costs of sales and immaterial and are recorded in operating expenses.
Research and Development Expenses
Research and development expenses are charged to expense as incurred. Research and development expenses include payroll and personnel costs related to research and development activities, materials costs, external clinical drug product manufacturing costs, outside services costs, repair, maintenance and depreciation costs for research and development equipment, as well as facility costs used for research and development activities. Nonrefundable advance payments for goods or services that will be used or rendered for future research and development activities are capitalized and expensed as the goods are delivered or the related services are performed. Notable continues to evaluate whether it expects the goods to be delivered or services to be rendered and charges to expense any portion of the advance payment that has been capitalized when the entity no longer expects the goods to be delivered or services to be rendered.
Notable expects to significantly increase its research and development efforts by conducting the remaining studies necessary for the development and approval of Volasertib and Fosciclopirox. Future research and development expenses may include:
● employee-related expenses, such as salaries, bonuses and benefits, consultant-related expenses, share-based compensation, overhead related expenses and travel related expenses for Notable’s research and development personnel;
● expenses incurred under agreements with CROs, as well as consultants that support the implementation of the clinical studies described above;
● manufacturing and packaging costs in connection with conducting clinical trials and for stability and other studies required to support the NDA filing as well as manufacturing drug product for commercial launch;
● formulation, research and development expenses related to the PPMP, Volasertib and Fosciclopirox; and other products Notable may choose to develop; and
● costs for sponsored research.
Research and development activities will continue to be central to Notable’s business plan. Products in later stages of clinical development generally have higher development costs than those in earlier stages of clinical development, primarily due to the increased size and duration of later-stage clinical trials. Notable expects its research and development expenses to be significant over the next several years as personnel and compensation costs increase and Notable conducts late-stage clinical studies and prepares to seek regulatory approval for Volasertib and Fosciclopirox and any other future product.
The duration, costs and timing of clinical trials of Volasertib and Fosciclopirox and any other future product will depend on a variety of factors that include, but are not limited to:
● the number of trials required for approval;
● the per patient trial costs;
● the number of patients that participate in the trials;
● the number of sites included in the trials;
● the countries in which the trial is conducted;
● the length of time required to enroll eligible patients;
● the number of doses that patients receive;
● the drop-out or discontinuation rates of patients;
● the potential additional safety monitoring or other studies requested by regulatory agencies;
● the duration of patient follow-up;
● the timing and receipt of regulatory approvals; and
● the efficacy and safety profile of Notable’s product candidates.
General and Administrative Expenses
General and administrative expenses consist primarily of employee-related expenses, including salaries, benefits and stock-based compensation, for personnel in executive, finance, business development, facility and administrative functions. Other significant costs include facility costs not otherwise included in research and development expenses, legal fees relating to patent and corporate matters and fees for accounting, tax and consulting services.
Notable anticipates that general and administrative expenses will increase in the future to support its continued research and development activities. These increases will likely include increased costs related to the hiring of personnel, including compensation and employee-related expenses, and fees to outside consultants, lawyers and accountants. Additionally, Notable anticipates increased costs associated with being a public company, including compliance with Nasdaq Capital Market and SEC requirements, insurance and investor relations costs.
Income Taxes
For the year ended December 31, 2023 and 2022, no income tax expense or benefit was recognized. Notable’s deferred tax assets are comprised primarily of net operating loss carryforwards. At December 31, 2023, Notable had federal and state net operating loss carryforwards of approximately $120.8 million and foreign net operating loss carryforwards of $263.6 million. Notable maintains a full valuation allowance on its deferred tax assets since Notable has not yet achieved sustained profitable operations and does not expect taxable income in the near future. As a result, Notable has not recorded any income tax benefit since its inception.
Results of Operations
Comparison of the Years Ended December 31, 2023 and December 31, 2022
The following table sets forth Notable’s results of operations for the year ended December 31, 2023 compared to the year ended December 31, 2022 (in thousands):
Year ended December 31,
Increase
(Decrease)
Services revenue
$
$
$
Cost of services
-
Operating expenses:
Research and development
4,706
7,776
(3,070 )
General and administrative
10,064
5,156
4,908
Loss from operations
(14,657 )
(12,924 )
(1,733 )
Other income (expense), net
3,393
(1,483 )
4,876
Net loss
$ (11,264
)
$ (14,407 )
$ 3,143
Services Revenue
Services revenue increased from $0.0 million to $0.3 million for the year ended December 31, 2023 compared to the year ended December 31, 2022. This increase of $0.3 million was the result of Notable’s performing services for others.
Research and Development Expenses
Research and development expenses decreased to $4.7 million from $7.8 million for the year ended December 31, 2023 compared to the year ended December 31, 2022. The decrease of $3.1 million, or 66.0%, was primarily due to the increases and decreases in the following programs (in thousands):
Year ended December 31,
Increase
(Decrease)
Engineering
$
$ 2,176
$ (1,347 )
Medical Affairs
Operational
(120 )
Scientific projects
2,949
3,871
(922 )
Volasertib
(160 )
Subtotal
4,626
7,164
(2,538 )
Other
(532 )
Total
$ 4,706
$ 7,776
$ (3,070 )
Engineering expenses are costs necessary to support the PPMP platform. Engineering expenses decreased to $0.8 million from $2.2 million for the year ended December 31, 2023 compared to the year ended December 31, 2022. The decrease of $1.3 million, or 61.9%, related to a $0.7 million decrease in payroll and payroll related costs resulting from the reduction in force in during the year ended December 31, 2022 without an increase in payroll during the year ended December 31, 2023, $0.1 million decrease in technology costs, and a $0.6 million decrease in facilities costs.
Medical affairs expenses include costs of clinical planning. Medical affairs expenses remained consistent for the years ended December 31, 2023 and 2022.
Operational expenses are costs to operate the laboratory. Operational expenses decreased to $0.1 million from $0.2 million for the year ended December 31, 2023 compared to the year ended December 31, 2022. The decrease of $0.1 million, or 57.1%, resulted from a $0.1 million decrease in payroll and payroll related costs.
Scientific projects are exploratory research and development projects. Scientific project expenses decreased $0.9 million, or 23.8%, to $2.9 million for the year ended December 31, 2023 compared to $3.9 million for the year ended December 31, 2022. The decrease is primarily related to a $1.0 million decrease in payroll and payroll related costs, a $0.5 million decrease related to the Fosciclopirox project, offset by a $0.1 million increase in laboratory supplies, a $0.4 million increase in facilities costs and a $0.1 million decrease in depreciation.
Volasertib is a small molecule with certain uses related to cancer. Volasertib expenses decreased to $0.5 million from $0.6 million for the year ended December 31, 2023 compared to the year ended December 31, 2022. The decrease of $0.1 million, or 25.7%, resulted from a $0.1 million decrease in laboratory costs related to Volasertib.
General and Administrative Expenses
General and administrative expenses increased to $10.1 million from $5.2 million for the year ended December 31, 2023 compared to the year ended December 31, 2022. The increase of $4.9 million, or 95.2%, was due to a $5.3 million increase in third party contractors primarily related to the merger, a $0.3 million increase in insurance expense predominantly related to directors and officers insurance and a $0.3 million increase in stock based compensation, offset by a decrease of $0.8 million in payroll and payroll related expenses and a $0.2 million decrease in depreciation expense.
Other Income (Expense), Net
Other income (expense), net, increased from $1.5 million of other expense, net to $3.4 million of other income, net, for the year ended December 31, 2023 compared to the year ended December 31, 2022. The increase of $4.9 million, or 328.8%, was primarily due to the loss on the conversion of the Series D SAFEs of $1.7 million, the increase in the derivative fair value of the Series C SAFE and redeemable convertible preferred stock warrant liability of $7.5 million and an increase in interest income of $0.1 million, offset by the forgiveness of debt during the year ended 2022 of $1.0 million related the PPP Loan.
Net Loss
Net loss decreased to $11.3 million from $14.4 million for the year ended December 31, 2023 compared to the year ended December 31, 2022. The decrease of $3.1 million, or 21.8%, was due to the factors described above.
Liquidity, Capital Resources, and Financial Requirements
Overview
For the period from inception through December 31, 2023, Notable has incurred losses and negative cash flows from operation mainly attributable to its development efforts and has an accumulated deficit of $82.3 million. Notable has financed its operations primarily through the issuance of Preferred Shares and SAFE shares and through the cash inflow as a result of the Merger completed on October 16, 2023. Notable does not expect to have positive cash flow for the foreseeable future and does not believe the existing cash resources will be sufficient to sustain operations during the next twelve months. We currently need to generate sufficient revenues to support our cost structure to enable us to pay ongoing costs and expenses as they are incurred, finance the development of our products, and execute the business plan. If we cannot generate sufficient revenue to fund our business plan, we intend to seek to raise such financing through the sale of debt and/or equity securities. The issuance of additional equity would result in dilution to existing shareholders. If we are unable to obtain additional funds when they are needed or if such funds cannot be obtained on terms acceptable to us, we will be unable to execute upon the business plan or pay costs and expenses as they are incurred, which would have a material, adverse effect on our business, financial condition and results of operations. Even if we are successful in generating sufficient revenue or in raising sufficient capital in order commercialize our products, our ability to continue in business as a viable going concern can only be achieved when our revenues reach a level that sustains our business operations.
As of April 1, 2024, Notable has cash and cash equivalents of $8.2 million. Based on the current cash position and the Company’s planned expense run rate, management believes Notable will be able to finance its operations through November 2024. Notable has based this estimate on assumptions that may prove to be wrong and may deplete its capital resources sooner than it expects.
Notable expects to continue to incur significant and increasing operating losses at least for the foreseeable future. Notable does not expect to generate product revenue unless and until it successfully completes development of and obtains regulatory approval for Volasertib, Fosciclopirox, or any other future products. Notable’s net losses may fluctuate significantly from quarter-to-quarter and year-to-year, depending on the timing of planned clinical trials and Notable’s expenditures on other research and development activities. Notable anticipates that its expenses will increase substantially in 2024 as Notable advances the clinical development of Volasertib and Fosciclopirox, and operates as a publicly traded company. Notable does not expect positive cash flows from operations in the foreseeable future. Notable management expects to continue to incur additional substantial losses in the foreseeable future as a result of expanded research and development activities until regulatory approval is granted. Regulatory approval is not guaranteed and may never be obtained. As a result, these conditions raise substantial doubt about Notable’s ability to continue as a going concern.
The foregoing forward-looking information was prepared by us in good faith based upon assumptions that we believe to be reasonable. No assurance can be given, however, regarding the attainability of the projections or the reliability of the assumptions on which they are based. The projections are subject to the uncertainties inherent in any attempt to predict the results of our operations, especially where new products and services are involved. Certain of the assumptions used will inevitably not materialize and unanticipated events will occur. Actual results of operations are, therefore, likely to vary from the projections and such variations may be material and adverse to us. Accordingly, no assurance can be given that such results will be achieved. Moreover due to changes in technology, new product announcements and competitive pressures, we may be required to change the current plans.
Future Funding Requirements
Notable expects that it will need to obtain further funding through other public or private offerings of Notable’s capital stock, debt financing, collaboration and licensing arrangements or other sources, the requirements for which will depend on many factors, including:
● the scope, timing, rate of progress and costs of Notable’s drug development efforts, preclinical development activities, laboratory testing and clinical trials for Notable’s product candidates;
● the number and scope of clinical programs Notable decides to pursue;
● the cost, timing and outcome of preparing for and undergoing regulatory review of Notable’s product candidates;
● the scope and costs of development and commercial manufacturing activities;
● the cost and timing associated with commercializing Notable’s product candidates, if they receive marketing approval;
● the extent to which Notable acquires or in-licenses other product candidates and technologies;
● the costs of preparing, filing and prosecuting patent applications, maintaining and enforcing Notable’s intellectual property rights and defending intellectual property-related claims;
● Notable’s ability to establish and maintain collaborations on favorable terms, if at all;
● Notable’s efforts to enhance operational systems and Notable’s ability to attract, hire and retain qualified personnel, including personnel to support the development of Notable’s product candidates and, ultimately, the sale of Notable’s products, following FDA approval;
● Notable’s implementation of operational, financial and management systems; and
● the costs associated with being a public company.
A change in the outcome of any of these or other variables with respect to the development of any of Notable’s product candidates could significantly change the costs and timing associated with the development of such product candidate. Furthermore, Notable’s operating plans may change in the future, and Notable will continue to require additional capital to meet operational needs and capital requirements associated with such operating plans.
Adequate additional funding may not be available to Notable on acceptable terms, or at all. If Notable is unable to raise capital in sufficient amounts or on terms acceptable to it, Notable may have to significantly delay, scale back or discontinue the development or commercialization of Volasertib and Fosciclopirox, or any future product, or potentially discontinue operations.
To the extent that Notable raises additional capital through the sale of equity or convertible debt securities, the ownership interest of Notable shareholders will be diluted, and the terms of these securities may include liquidation or other preferences that adversely affect the rights of Notable Ordinary Shareholders. Debt financing and preferred equity financing, if available, may involve agreements that include covenants limiting or restricting Notable’s ability to take specific actions, such as incurring additional debt, making capital expenditures or declaring dividends.
If Notable raises additional funds through collaborations, strategic alliances or marketing, distribution or licensing arrangements with third parties, Notable may be required to relinquish valuable rights to Notable’s technologies, future revenue streams, research programs or proposed products, or to grant licenses on terms that may not be favorable to Notable. If Notable is unable to raise additional funds through equity or debt financings when needed, Notable may be required to delay, limit, reduce or terminate Notable’s drug development or future commercialization efforts or grant rights to develop and market any future product, that Notable would otherwise prefer to develop and market ourselves.
Because Notable is currently engaged in research at a relatively early stage, it will take a significant amount of time and resources to develop any product or intellectual property capable of generating sustainable revenues. Accordingly, Notable’s business is unlikely to generate any sustainable operating revenues in the next several years, and may never do so. In addition, to the extent that Notable is able to generate operating revenues, there can be no assurances that Notable will be able to achieve positive earnings and operating cash flows.
Cash Flows
Comparisons of the Years Ended December 31, 2023 and December 31, 2022
The following table sets forth the primary sources and uses of cash for each of the periods set forth below (in thousands):
Year ended December 31, Increase
(Decrease)
Cash used in operating activities $ (13,716 ) $ (11,642 ) $ (2,074 )
Cash provided by investing activities 15,540 14,616
Cash provided by financing activities 7,822 9,898 (2,076 )
Net increase (decrease) in cash and cash equivalents $ 9,646 $ (820 ) $ 10,466
Cash Flows used in Operating Activities
Net cash used in operating activities was $13.7 million and $11.6 million for the years ended December 31, 2023 and 2022, respectively, representing an increase of $2.1 million or approximately 17.8%. The increase was primarily due to an increase in prepaid insurance related to the directors’ and officers’ insurance of approximately $0.9 million and other working capital increases.
Cash Flows from Investing Activities
Net cash from investing activities was $15.5 million for the year ended December 31, 2023 and $0.9 million for the year ended December 31, 2022, representing an increase of $14.6 million or approximately 1,581.8%. The increase was primarily due to cash received related to the merger.
Cash Flows from Financing Activities
Net cash from financing activities was $7.8 million for the year ended December 31, 2023 and $9.9 million for the year ended December 31, 2022, representing a decrease of $2.1 million or approximately 21.0%. For 2023, the amounts represent net proceeds from issuance of convertible preferred stock and related SAFE Agreements. For 2022, such amounts represent net proceeds received from option exercises, issuance of convertible preferred stock, issuance of the Oncoheroes SAFE agreement.
Critical Accounting Policies and Use of Estimates
Notable’s discussion and analysis of its financial condition and results of operations are based on Notable’s financial statements, which have been prepared in accordance with GAAP. The preparation of these financial statements requires Notable to make estimates and judgments that affect the reported amounts of assets, liabilities, revenues, and expenses and the disclosure of contingent assets and liabilities in Notable’s financial statements. On an ongoing basis, Notable evaluates its estimates and judgments, including those related to accrued expenses, valuation allowance on deferred tax assets and valuation of intangible assets. Notable bases its estimates on historical experience, known trends and events, and various other factors that are believed to be reasonable under the circumstances, the results of which form the basis for making judgments about the carrying values of assets and liabilities that are not readily apparent from other sources. Actual results may differ from these estimates under different assumptions or conditions.
Our financial statements are impacted by the accounting policies used and the estimates and assumptions made by management during their preparation. A complete summary of these policies is included in Note 2 of the Notes to Financial Statements included elsewhere herein. We have identified below the accounting policies that are of particular importance in the presentation of our financial position, results of operations and cash flows and which require the application of significant judgment by management.
Stock-Based Compensation Expense
We have adopted the fair value recognition provisions Financial Accounting Standards Board Accounting Standards Codification (“FASB ASC”) 718. In addition, the Securities and Exchange Commission issued Staff Accounting Bulletin No. 107 “Share-Based Payment” (“SAB 107”), which provides supplemental FASB ASC 718 application guidance based on the views of the SEC. Under FASB ASC 718, compensation cost recognized includes compensation cost for all share-based payments granted, based on the grant date fair value estimated in accordance with the provisions of FASB ASC 718.
We have used the Black-Scholes option-pricing model to estimate the option fair values. The option-pricing model requires a number of assumptions, of which the most significant are, expected stock price volatility, the expected pre-vesting forfeiture rate and the expected option term (the amount of time from the grant date until the options are exercised or expire).
All issuances of stock options or other equity instruments to non-employees as consideration for goods or services received by Notable are accounted for based on the fair value of the equity instruments issued. Non-employee equity-based payments that do not vest immediately upon grant are recorded as an expense over the vesting period.
Fair Value Measurement
Fair value accounting is applied for all financial assets and liabilities that are recognized or disclosed at fair value in the financial statements on a recurring basis. Financial instruments such as cash and cash equivalents, accounts receivable, accounts payable and accrued liabilities approximate fair value due to their relatively short maturities.
Assets and liabilities recorded at fair value on a recurring basis in the balance sheet are categorized based on the level of judgment associated with the inputs used to measure their fair values. Fair value is defined as the exchange price that would be received for an asset or an exit price that would be paid to transfer a liability in the principal or most advantageous market for the asset or liability in an orderly transaction between market participants on the measurement date.
Warrants issued pursuant to equity offerings that are potentially exercisable in cash or on a cashless basis resulting in a variable number of shares being issued are considered derivative liabilities and therefore measured at fair value.
Warrants to Purchase Redeemable Convertible Preferred Stock
Notable measures its Series C Warrant liability, classified as a Level 3 liability, at fair value on a recurring basis with the change in fair value recorded in the consolidated statements of operations and comprehensive loss until the warrants are exercised, expire or other facts and circumstances lead the warrant liability to be reclassified as an equity instrument. The fair value is determined using an option-pricing backsolve method. The fair value of the Series C Warrant Liability as of December 31, 2023, was determined using the Black-Scholes option-pricing model to estimate the warrant fair values.
Accrued Research and Development Costs
Notable accrues for expenses resulting from obligations under contracts with clinical research organizations (CROs). The financial terms of these contracts are subject to negotiations, which vary from contract to contract and may result in payment flows that do not match the periods over which materials or services are provided. Notable’s objective is to reflect the appropriate trial expense in the financial statements by matching the appropriate expenses with the period in which services and efforts are expended.
Redeemable Convertible Preferred Stock
Notable records redeemable convertible preferred stock at fair value on the dates of issuance, unless an exception applies, net of issuance costs. The redeemable convertible preferred stock, as of December 31, 2022, has been classified outside of stockholders’ deficit as temporary equity on the accompanying balance sheet because the shares contain certain redemption features that are not solely within the control of the Company. The redeemable convertible preferred stock was not generally redeemable; however, upon certain change in control events including liquidation, sale or transfer of control of Notable, holders of the redeemable convertible preferred stock had the right to receive its liquidation preference under the terms of Notable’s certificate of incorporation. The carrying values of the redeemable convertible preferred stock are adjusted to their liquidation preferences if and when it becomes probable that such a liquidation event will occur.
Redeemable Convertible Preferred Stock Warrant Liabilities
Notable classifies warrants to purchase redeemable convertible preferred stock as liabilities at fair value when the underlying shares are contingently redeemable and adjusts the instruments to fair value at each reporting period. The warrants to purchase redeemable convertible preferred stock are subject to re-measurement at each balance sheet date until exercised or expired, and any change in fair value is recognized as a component of other income, net in the consolidated statements of operations and comprehensive loss. We use the Black-Scholes option-pricing model to estimate the fair value of the convertible preferred stock warrants. Offering costs associated with the issuance of redeemable convertible preferred stock warrant liabilities are allocated on a relative basis and expensed as incurred. Following the Merger, these warrants are now convertible into Ordinary Shares.
Revenue Recognition
During the year ended December 31, 2023, Notable’s central revenue generating activities and performance obligations consisted of performing diagnostic services using its proprietary platform that was utilized by entities primarily engaged in their own research and development efforts to identify therapeutic combinations in a more targeted and efficient method of drug discovery. These activities do not represent its major and ongoing central operations.
Notable recognizes revenue from diagnostic services in the amount that reflects the consideration that it expects to be entitled as Notable performs its obligation under a contract with a customer by processing diagnostic tests on laboratory samples and making the test results available to its customers. Revenue is recorded considering a five-step revenue recognition model that includes identifying the contract with a customer, identifying the performance obligations in the contract, determining the transaction price, allocating the transaction price to the performance obligations, and recognizing revenue when, or as, an entity satisfies a performance obligation. Notable generally has a contract or a purchase order from a customer with the specified required terms, including the number of diagnostic samples to be performed. Notable has not received any advance payments for which there are any remaining performance obligations. Accordingly, no deferred revenue is recorded as of December 31, 2023 and 2022. Notable has not recorded any contract assets as of December 31, 2023 and 2022 as Notable has not completed any performance obligations for which it has not been able to bill its customers. Material costs of services revenue are recorded as costs of sales and immaterial costs of services are recorded in operating expenses.
In accordance with FASB ASC 606, Revenue from Contracts with Customers, Notable recognizes revenue when it satisfies performance obligations, by transferring promised goods or services to customers, in an amount that reflects the consideration to which Notable expects to be entitled in exchange for fulfilling those performance obligations.

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ITEM 7A. QUANTITATIVE AND QUALITATIVE DISCLOSURES ABOUT MARKET RISK
Item 7A.
QUANTITATIVE AND QUALITATIVE DISCLOSURES ABOUT MARKET RISK
Not applicable.

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ITEM 8. FINANCIAL STATEMENTS AND SUPPLEMENTARY DATA
Item 8. FINANCIAL STATEMENTS AND SUPPLEMENTARY DATA
Our consolidated financial statements, together with the report of our independent registered public accounting firm, appear beginning on page of this Annual Report for the year ended December 31, 2023.

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ITEM 9. CHANGES IN AND DISAGREEMENTS WITH ACCOUNTANTS
Item 9. CHANGES IN AND DISAGREEMENTS WITH ACCOUNTANTS ON ACCOUNTING AND FINANCIAL DISCLOSURE
None

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ITEM 9A. CONTROLS AND PROCEDURES
Item 9A. CONTROLS AND PROCEDURES
Disclosure Controls and Procedures
We have performed an evaluation of the effectiveness of our disclosure controls and procedures that are designed to ensure that the material financial and non-financial information required to be disclosed to the SEC is recorded, processed, summarized and reported timely. Based on our evaluation, our management, including the Chief Executive Officer, or CEO, and the Chief Financial Officer, or CFO, has concluded that our disclosure controls and procedures (as defined in Rules 13a-15(e) and 15d-15(e) of the Securities Exchange Act of 1934, as amended) as of the end of the period covered by this report are effective. Notwithstanding the foregoing, there can be no assurance that our disclosure controls and procedures will detect or uncover all failures of persons within our company to disclose material information otherwise required to be set forth in our reports.
Management’s Annual Report on Internal Control Over Financial Reporting
Our management is responsible for establishing and maintaining adequate internal control over financial reporting, as such term is defined in Rule 13a-15(f) promulgated under the Exchange Act. Our internal control system was designed to provide reasonable assurance to our management and board of directors regarding the reliability of financial reporting and the preparation and fair presentation of published financial statements for external purposes in accordance with generally accepted accounting principles. All internal control systems, no matter how well designed, have inherent limitations. Therefore, even those systems determined to be effective can provide only reasonable assurance with respect to financial statement preparation and presentation and may not prevent or detect misstatements. Also, projections of any evaluation of effectiveness to future periods are subject to the risk that controls may become inadequate because of changes in conditions, or that the degree of compliance with policies or procedures may deteriorate.
Our management, including our CEO and CFO, conducted an evaluation, pursuant to Rule 13a-15(c) promulgated under the Exchange Act, of the effectiveness, as of the end of the period covered by this Annual Report, of our internal control over financial reporting based on the framework in Internal Control-Integrated Framework issued by the Committee of Sponsoring Organizations of the Treadway Commission (2013). Based on the results of this evaluation, management concluded that our internal control over financial reporting was effective as of December 31, 2023.
Changes in Internal Control over Financial Reporting
There were no changes in our internal control over financial reporting (as defined in Rules 13a-15(f) and 15d-15(f) under the Exchange Act) that occurred during the quarter ended December 31, 2023, that have materially affected, or are reasonably likely to materially affect, our internal control over financial reporting.

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ITEM 9B. OTHER INFORMATION
Item 9B. OTHER INFORMATION
None.

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ITEM 10. DIRECTORS, EXECUTIVE OFFICERS AND CORPORATE GOVERNANCE
Item 10. DIRECTORS, EXECUTIVE OFFICERS AND CORPORATE GOVERNANCE
The following table sets forth certain information relating to our executive officers and directors, including their ages as of April 1, 2024.
Name
Age
Position
Executive Officers and Executive Director
Thomas Bock
Chief Executive Officer and Director
Scott A. McPherson
Chief Financial Officer
Joseph Wagner
Chief Scientific Officer
Non-Executive Directors
Tuomo Pätsi (1)
Chairman of the Board of Directors
Peter Feinberg (1)
Director
Michele Galen (1)
Director
Michael Rice (1)
Director
External Directors
Thomas I. H. Dubin (1) (2)
External Director
Thomas Graney (1) (2)
External Director
(1) Independent director under the rules of Nasdaq.
(2) External director as defined under Israeli law.
Executive Officers
Dr. Thomas A. Bock, Chief Executive Officer and Director. Dr. Thomas Bock, age 59, joined Notable as a Director in October 2020, was appointed as its interim Chief Executive Officer in February 2021 and was appointed as Chief Executive Officer on a permanent basis in April 2021. Dr. Bock has more than 20 years of biotechnology industry experience plus 10 years of experience in academic medicine and research. From December 2020 to March 2021 he served as a senior advisor to Ordaos, an AI drug design and development company. From July 2020 to January 2021 he served as a founder and CEO of Tirili LLC, an early-stage health technology company. Triggered by his spouse’s inherited BRCA cancer diagnosis, Dr. Bock founded HeritX, and between March 2015 and February 2019, served as CEO and Director of HeritX Inc., a pioneer in cancer prevention through pre-cancer vaccines, immunoprevention, and gene repair. Previously, he served as Senior Vice President Medical Affairs on the executive management team of Alexion Pharmaceuticals, building a start-up into a global leader in ultra-rare disorders. Before joining Alexion, Dr. Bock built and led the worldwide Medical Affairs Departments of Novartis Oncology and Celgene as their Vice President and Global Head of Medical Affairs. Prior to Celgene, Dr. Bock served as the Medical Director of Amgen Europe for hematology and oncology. Prior to joining the biopharmaceutical industry, Dr. Bock worked in medical practice and research in the fields of cancer, stem cell biology, and gene therapy at European medical centers and the US National Human Genome Research Institute. Dr. Bock earned his M.D. at RWTH Aachen University and his M.B.A. at Columbia Business School. Dr Bock has also served as the Board Chair of Columbia Business School’s Healthcare Advisory Board. Based on his extensive management and scientific experience across the biopharmaceutical industry and academic medicine, Notable believes Dr. Bock is qualified to be on the Board.
Joseph Wagner, Chief Scientific Officer. Dr. Joseph Wagner, age 56, joined Notable in June 2020 and has more than 20 years of experience developing therapeutics and diagnostics. Dr. Wagner previously served as the Executive Director of University of California Drug Discovery Consortium from September 2017 to February 2020 and was an independent consultant from March 2020 to May 2020, prior to joining Notable. A pharmacologist by training, Dr. Wagner has spent the majority of his biotechnology industry career focused on building teams and organizations primarily focused on developing small molecule and biologic therapeutics from bench studies through to Phase 2 clinical trials at companies including BriaCell Therapeutics, OncoCyte and Cell Targeting, where he served in CEO/CTO roles. Dr. Wagner has led programs in a variety of indications, including oncology, neurology and cardiovascular disease, and has led bioinformatic efforts to develop novel targets, biomarkers and companion diagnostics. Dr. Wagner received his bachelor’s in neuroscience from the University of Rochester and his Ph.D. in pharmacology from Duke University.
Scott A. McPherson, Chief Financial Officer. Mr. McPherson, age 62, has served as Notable’s Chief Financial Officer since March 2023. Mr. McPherson previously served as Chief Financial Officer of Rego Payment Architectures, Inc., an OTC-listed provider of financial services software, from July 2015 until August 2022. Mr. McPherson was hired as a part-time controller for US Environmental, Inc. in September 2019 and upon the death of the owner has served as interim Chief Executive Officer since March 2022. US Environmental, Inc. is an environmental services company primarily involved in the transportation and disposal of environmental waste. Mr. McPherson also served as the Chief Financial Officer of VerifyMe, Inc. from December 1, 2014 through July 15, 2017 and from December 2012 to October 2013. VerifyMe, Inc. is a public company that provides high-tech solutions in the field of authenticating people and products. Mr. McPherson from April 2015 to July 2015 was the Chief Executive Officer and was the Chief Financial Officer of CannLabs, Inc. from June 2014 to July 2015. Prior to that, Mr. McPherson served as the Chief Financial Officer of Rego Payment Architectures, Inc., from August 2010 through November 2012. Mr. McPherson formed McPherson, CPA, PLLC in January 2005, which he continues to manage today. The firm performs accounting, tax and litigation support services for numerous clients in various industries. The firm has successfully assisted small public companies by developing procedures for them to implement, in order to initially comply and maintain compliance with the Sarbanes-Oxley Act. All of these services are conducted under the direction of Mr. McPherson.
External and Non-Executive Directors
Tuomo Pätsi. Mr. Pätsi, age 59, has over 30 years of experience working in the biotech and pharmaceutical industries. Since March 2022, Mr. Pätsi has served as an advisor to various biopharma companies and investors. Between July 2020 and February 2022, he served as the Executive Vice President of Seagen Inc. (Nasdaq: SGEN), a US-based cancer-focused biotechnology company. Between November 2012 and June 2020, he served in various capacities at Celgene Corp., which was later acquired by Bristol-Myers Squibb Company (NYSE: BMY), including serving as the President of the EMEA region and Worldwide Markets and President of European and International Operations, engaged primarily in the development, and commercialization of therapies for the treatment of cancer. Mr. Patsi participated in strategic deals and partnerships and co-led the international commercial integration of Celgene and Bristol-Myers Squibb Company. Prior to his work at Celgene, Mr. Pätsi served as Vice President of Europe for Human Genome Science, and over a period of 11 years he served in roles of increasing responsibility at Amgen Inc., in Europe and the United States. Mr. Pätsi has served as board member of Aqsens Health since April 2023 and as a non-executive director of Faron Pharmaceuticals Ltd. (AIM London: FARN, Nasdaq Helsinki First North: FARON), since March 2023. Mr. Pätsi is a registered pharmacist and holds an MSc in pharmacology from the School of Pharmacy, Helsinki University. Notable believes that Mr. Pätsi is qualified to serve on its board of directors due to his extensive management skills and experience in the biotechnology and pharmaceutical industries.
Thomas I. H. Dubin. Mr. Dubin, age 62, is a pharmaceutical executive and attorney. During the last five years Mr. Dubin has served as an advisor and board member to various biopharma and other companies. From 2001 through 2013 he was the Chief Legal Officer and member of the core executive team that grew Alexion Pharmaceuticals (“Alexion”) from development stage to membership in the S&P 500. At Alexion, Mr. Dubin led legal, government affairs, pricing and reimbursement, human resources, corporate communications, and other functions, and held commercial responsibility for the company’s Australasia region. Prior to Alexion, Mr. Dubin served as Vice President and General Counsel of ChiRex, Inc. and Assistant General Counsel of Warner-Lambert Company. Mr. Dubin began his career as a corporate attorney with Cravath, Swaine & Moore in New York City. Mr. Dubin currently serves as Executive Chair of Cellphire Therapeutics, Chair of Norwalk Hospital, board member of Connecticut Innovations, member of the Yale School of Public Health Leadership Council and advisory board member of Mythic Pharmaceuticals. Mr. Dubin was a board member of BioBlast Pharmaceuticals (Nasdaq: ORPN) from 2015 to 2018, and a trustee of American Jewish World Service from 2014 to 2021. Mr. Dubin received his J.D. from New York University School of Law, his M.P.H. from Yale University School of Public Health and his B.A. from Amherst College, cum laude. Notable believes that Mr. Dubin is qualified to serve on its board of directors due to his extensive legal and business skills and experience in the biotechnology industry.
Peter Feinberg. Mr. Feinberg, age 63, has over 30 years of experience in the financial services industry. Since April 2020, Mr. Feinberg has been a founder of Sporos Bioventures, Inc, a private biotechnology company focused on transforming the drug development process across oncology. Since June 2019, Mr. Feinberg has served as Partner and Founding Member of Boxcar Partners and Boxcar PMJ LP, a venture capital investment firm with a focus on biotechnology investing. Since October 2018, Mr. Feinberg has also been the co-founder of Emerging Security Solutions. Mr. Feinberg is the co-founder of BridgeBio Pharma, Inc. (Nasdaq: BBIO), a publicly traded biotechnology company focusing on genetic diseases, which he helped found in December, 2014. Previously, Mr. Feinberg served as a Managing Director and Head of Institutional Equities Trading at Oppenheimer & Co, with his tenure ranging from July 1982 to December 2015. Mr. Feinberg has served on the board of directors of Immuneering Corporation (Nasdaq: IMRX), a biotechnology company that aims to apply bioinformatics to create a new approach to drug discovery, since 2021. Mr. Feinberg received his B.S. in finance from Whittier College. Notable believes that Mr. Feinberg is qualified to serve on its board of directors due to his extensive leadership skills and experience in the financial and biotechnology industries.
Michele Galen. Ms. Galen, age 67, from July 2016 to the present, has served as an executive and leadership development coach and organizational consultant for biopharma executives. Ms. Galen was the SVP & Chief Communications Officer of Shire Pharmaceuticals PLC (now Takeda), from April 2015 to June 2016. Previously, Ms. Galen was the Global Head of Communications for Novartis AG based in Basel Switzerland, from January 2012 to January 2015. Prior to this appointment, Ms. Galen served as Vice President and Global Head Communications and Advocacy for Novartis Pharma; Vice President and Global Head, Oncology Affairs; Vice President and Global Head, Communications and External Affairs for Novartis Molecular Diagnostics; and Vice President, Corporate Communications for Novartis Pharmaceuticals Corporation (“NPC”). Prior to joining NPC, Ms. Galen was a Managing Director in the Corporate Practice at a leading global public relations firm in New York specializing in change communication, issues management and strategic philanthropy. She also is an award-winning journalist and served as Legal Affairs and Social Issues Editor at Business Week magazine. Ms. Galen was a director of Cardax, Inc. from January 2017 to October 2021 and served as a board member of the Global Health Council, and Global Oncology. Ms. Galen is a member of the New York State Bar and practiced at Stroock, Stroock + Lavan, and Skadden, Arps, Slate, Meagher & Flom. Ms. Galen received her J.D. from New York University School of Law, her M.S. in journalism from Columbia University and her bachelor’s degree in psychology from The George Washington University. Notable believes that Ms. Galen is qualified to serve on its board of directors due to her extensive communication, organizational change and business and patient advocacy experience in the biotechnology and media/public relations industry. Notable believes that Ms. Galen is qualified to serve on its board of directors due to her extensive experience in the biotechnology and pharmaceutical industries.
Thomas Graney. Mr. Graney, age 59, has extensive global finance experience that spans corporate development, commercial strategy, portfolio management and supply chain management, communication, and investor relations. Mr. Graney served as the Chief Executive Officer of Oxurion NV from May 2021 to December 2023. Prior to his promotion to Chief Executive Officer, Mr. Graney served as the Chief Financial Officer of Oxurion NV from October 2020. From February 2019 to April 2020, Mr. Graney served as the Chief Financial Officer of Generation Bio. Prior to that, Mr. Graney was Chief Financial Officer of Vertex Pharmaceuticals Inc. from September 2017 to February 2019 and the Chief Financial Officer and Senior Vice President of Corporate Strategy at Ironwood Pharmaceuticals, from September 2014 to September 2017. Prior to Ironwood pharmaceuticals, Mr. Graney spent more than 20 years working with Johnson & Johnson and its affiliates, serving for four years as worldwide Chief Financial Officer of Ethicon. Mr. Graney currently serves as a board member and chair of the Audit Committee of Mogrify Ltd. and was a board member at AC Immune SA from 2017 to 2023. Mr. Graney is a Chartered Financial Analyst charterholder; he received his B.S. in accounting from the University of Delaware, and his M.B.A. in Marketing, Finance, and International Business from the Leonard N. Stern School of Business at New York University. Notable believes that Mr. Graney is qualified to serve on its board of directors due to his extensive financial skills and experience in the biotechnology and pharmaceutical industries.
Michael Rice. Mr. Rice, age 59, has served on VBL’s board of directors since July 2021. Mr. Rice has deep experience in portfolio management, investment banking, and capital markets. Mr. Rice is a founding partner of LifeSci Advisors LLC, a life sciences investor relations consultancy, since 2010 and of LifeSci Capital LLC, a research-driven investment bank, since 2013. Previously, Mr. Rice was the co-head of Health Care Investment Banking at Canaccord Adams, where he was involved in debt and equity financing. Mr. Rice was also a managing director at Think Equity Partners, where he was responsible for managing Healthcare Capital Markets, which included structuring and executing numerous transactions. Prior to that, he served as a managing director at Bank of America serving large hedge funds and private equity healthcare funds while working closely with Investment Banking. Previously, he was a managing director at JP Morgan/Hambrecht & Quist. Mr. Rice graduated from the University of Maryland with a degree in Economics and currently sits on the board of 9 Meters Biopharma Inc. (Nasdaq: NMTR) and Navidea Biopharmaceuticals, Inc. (NYSE: NAVB). Notable believes Mr. Rice is qualified to serve on its board of directors because of his extensive financial and industry background.
Committees of the Board of Directors
Notable has three standing committees to assist in fulfilling its responsibilities to its shareholders: the Audit Committee, the Compensation Committee, and the Nominating Committee. The committees of Notable’s board of directors will operate pursuant to and apply Notable’s written charters and corporate governance policies.
Notable’s board of directors has an Audit Committee which supervises the audit and financial procedures of the Notable and is responsible for the selection of the Notable’s independent registered public accounting firm. The members of the Audit Committee are Thomas Graney (Chair), Thomas Dubin, Peter Feinberg and Michael Rice. Notable’s board of directors has determined that each member of the Audit Committee is an “independent director” within the meaning of the applicable NASDAQ Listing Rules and applicable SEC rules under the Exchange Act.
Notable’s board of directors has a Compensation Committee, which is responsible for, among other things, assisting the board of directors in overseeing the executive compensation strategy and reviewing and approving the compensation of our executive officers and for the administration of the employee benefit plans. The Compensation Committee will also be responsible for reviewing and approving the compensation of Notable’s directors. Except as specified in “Compensation Discussion and Analysis” below, the executive officers do not determine executive or director compensation but provide information and recommendations to the Compensation Committee upon its request. The members of the Compensation Committee are Thomas Dubin (Chair), Michele Galen, Thomas Graney and Michael Rice. Notable’s board of directors has determined that each member of the Compensation Committee is an “independent director” within the meaning of the applicable NASDAQ Listing Rules and applicable SEC rules under the Exchange Act.
Notable’s board of directors has a Nominating Committee which is responsible for recommending to the independent directors the nominees for election to Notable’s board of directors at the annual meeting of the shareholders. When reviewing candidates for Notable’s board of directors, the Nominating Committee and the independent members of Notable’s board of directors consider the evolving needs of Notable’s board of directors and seek candidates that fill any current or anticipated future needs. The members of the Nominating Committee are Tuomo Patsi (Chair), Peter Feinberg and Thomas Graney. Notable’s board of directors has determined that each member of the Nominating Committee is an “independent director” within the meaning of the applicable NASDAQ Listing Rules and applicable SEC rules under the Exchange Act.
Code of Ethics
We have adopted a Code of Business Conduct and Ethics applicable to all of our directors and employees, including our CEO and CFO, or other persons performing similar functions. The full text of the Code of Business Conduct and Ethics can be obtained, without charge, upon request addressed to: Corporate Secretary, Notable Labs, Ltd., 320 Hatch Drive, Foster City, CA 94404. If we make any substantive amendments to, or grant any waivers from, our Code of Business Conduct and Ethics for any officer or director, we will disclose the nature of such amendment or waiver on our website or in a current report on Form 8-K.
Compliance with Section 16(a) of the Exchange Act
Section 16(a) of the Exchange Act requires the Company’s officers and directors and persons who own more than 10% of a registered class of the Company’s equity securities (collectively, the “Reporting Persons”) to file reports of ownership and changes in ownership with the SEC. Reporting Persons are required by SEC regulations to furnish the Company with copies of all Section 16(a) forms they file.
Based solely on Notable’s review of copies of such forms received by Notable, and on representations made to us, we believe that during the year ended December 31, 2023, all filing requirements applicable to all officers, directors and greater than 10% beneficial shareholders were timely complied with.

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ITEM 11. EXECUTIVE COMPENSATION
Item 11. EXECUTIVE COMPENSATION
The disclosure required by Items 402 and 407(e)(4) and (e)(5) of Regulation S-K contained in the Registrant’s definitive proxy statement filed with the Securities and Exchange Commission on February 16, 2024 is incorporated by reference herein.

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ITEM 12. SECURITY OWNERSHIP OF CERTAIN BENEFICIAL OWNERS
Item 12. SECURITY OWNERSHIP OF CERTAIN BENEFICIAL OWNERS AND MANAGEMENT AND RELATED STOCKHOLDER MATTERS
The disclosure required by Item 403 of Regulation S-K contained in the Registrant’s definitive proxy statement filed with the Securities and Exchange Commission on February 16, 2024 is incorporated by reference herein.
Equity Compensation Plans
The following table provides certain information with respect to all of the Company’s equity compensation plans as of December 31, 2023.
Number of
securities
remaining
available for
future
issuance
under equity
Number of
compensation
securities to
Weighted-
plans
be
average
(excluding
issued upon
exercise
securities
exercise of
price of
reflected
outstanding
outstanding
in column
options and stock appreciation rights
options
(a))
Plan Category
(a)
(b)
(c)
Equity compensation plans approved by security holders
284,437
$ 49.67
305,626
Equity compensation plans not approved by security holders
-
$ -
-

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ITEM 13. CERTAIN RELATIONSHIPS AND RELATED TRANSACTIONS
Item 13. CERTAIN RELATIONSHIPS AND RELATED TRANSACTIONS, AND DIRECTOR INDEPENDENCE
Described below are all transactions occurring since January 1, 2022 and all currently proposed transactions to which Notable was a party and in which:
● the amount involved exceeded, or will exceed, $120,000 (or, if less, 1% of the average of the total assets of either Notable at December 31, 2023 and 2022); and
● any director, executive officer, holder of 5% or more of any class of the outstanding capital stock of Notable, or any member of the immediate family of, or entities affiliated with, any of the foregoing persons, had, or will have, a direct or indirect material interest.
In February 2023, Notable entered into a master service agreement with LifeSci Advisors for investor relations services, with an approximate monthly retainer of $20,000. Pursuant to the master service agreement, Notable can terminate LifeSci Advisors agreement (as can LifeSci Advisors) for any reason by giving six (6) months prior written notice of termination. Michael Rice, a director of Notable, is a principal of LifeSci Advisors.
In February 2022, Notable Labs, Inc. commenced an offering of simple agreements for future equity (“Series C SAFEs”). From February through March 2022, Notable Labs Inc. received an aggregate of approximately $4.0 million from the sale of the Series C SAFEs. Approximately 64.9% of the financing from the sale of the Series C SAFEs was received from parties who are related to or affiliated with members of Notable Labs, Inc.’s former board of directors.
Beginning on February 21, 2023, Notable Labs, Inc. sold an aggregate of approximately $4.4 million of Series D SAFEs to the SAFE Investors as part of the Pre-Closing Financing. Approximately 46.0% of the financing was received from parties who were related to or affiliated with members of Notable Labs, Inc.’s former board of directors. The Series D SAFEs converted into shares of Notable’s Series D-1 Preferred Stock at a 30% discount to the price to be paid by the Investors in the Series D Financing.
During 2023, prior to the closing of the Merger, Notable Labs, Inc. sold an aggregate of approximately $6.0 million in Series D-2 Preferred Stock. Approximately 34.3% of such financing (not including amounts received from the sale of the Series D SAFEs) was committed from parties who are related to or affiliated with members of Notable Labs, Inc.’s former board of directors.
Director Independence
As required under Nasdaq listing standards, a majority of the members of a listed company’s board of directors must qualify as “independent”, as affirmatively determined by the board of directors. The Notable Board has determined that the directors are expected to be independent within the meaning of the applicable listing standards. Each of the 7 directors, other than Thomas A. Bock, qualifies as “independent” under applicable Nasdaq rules.
External Directors
Under the Companies Law, an Israeli company whose shares have been offered to the public or whose shares are listed for trading on a stock exchange in or outside of Israel is required to appoint at least two external directors to serve on its Board of Directors. Such external directors are not required to be Israeli residents in case of a company listed on a foreign stock exchange (such as NASDAQ). External directors must meet stringent standards of independence. Our external directors are Mr. Dubin and Mr. Graney.
The Companies Law provides that an individual person is not qualified to be nominated and appointed or to serve as an external director if (i) the nominee is a relative of a “controlling shareholder” of the company, or (ii) if the nominee or the nominee’s relative, partner, employer, other person to whom the nominee is a subordinate, directly or indirectly, or a corporation under the control of the above has or had any prohibited affiliation or other disqualifying relationship (as defined below), at the time of the appointment or during the two years preceding the date of appointment as an external director, with: (a) the company, with any person who owns control over the company (i.e. a “controlling shareholder”) or a relative of such controlling shareholder, or with any corporation that at the time of the appointment or during the two years preceding the date of appointment is controlled by the company or its controlling shareholder; or (b) in the case of a company with no controlling shareholder or a shareholder holding at least 25% of its voting rights, a person then serving as the Chairman of the board, the Chief Executive Officer of the company, a holder of 5% or more of the issued share capital or voting power in the company, or the chief financial officer of the Company.
The term “controlling shareholder” means a shareholder with the ability to direct the activities of the company, other than by virtue of being an office holder. A shareholder is presumed to have “control” of the company and thus to be a controlling shareholder of the company if the shareholder holds 50% or more of the “means of control” of the company. “Means of control” is defined as (1) the right to vote at a general meeting of a company or a corresponding body of another corporation; or (2) the right to appoint directors of the corporation or its general manager. For the purpose of determining the holding percentage stated above, two or more shareholders who have a personal interest in a transaction that is brought for the company’s approval are deemed as joint holders.
The term “relative” is defined under the Companies Law as a spouse, sibling, parent, grandparent, or descendant; spouse’s sibling, parent, or descendant; and the spouse of each of the foregoing persons.
Under the Companies Law, the term “(prohibited) affiliation” and the similar types of prohibited relationships include (subject to certain exceptions regarding relationships deemed negligible under the Companies Law and the regulations promulgated thereunder):
● an employment relationship;
● a business or professional relationship maintained on a regular basis or by means of control (and with respect to an already serving external director - even if such relations are not maintained on a regular basis (excluding insignificant relationships), and including if one had accepted consideration not in compliance with the Companies Law and regulations promulgated thereunder; and
● Serving as an office holder, excluding serving as a director in a private company prior to the initial public offering of its shares if such director were appointed as a director of the private company in order to serve as an external director following the initial public offering.
The term “office holder” is defined under the Companies Law as the Chief Executive Officer, general manager, chief business manager, deputy general manager, vice general manager, any other person assuming the responsibilities of any of the above positions regardless of that person’s title, and a director, or a manager directly subordinate to the Chief Executive Officer or general manager.
In addition, no person may serve as an “external director” if that person’s position or professional or other activities create, or may create, a conflict of interest with that person’s responsibilities as a director or otherwise interfere with that person’s ability to serve as an external director or if the person is an employee of the Israel Securities Authority or of an Israeli stock exchange.
A person may furthermore not continue to serve as an external director if he or she received direct or indirect compensation from the company including amounts paid pursuant to his or her service as an external director, other than as permitted by the Companies Law and the regulations promulgated thereunder.
Following the termination of an external director’s service on a Board of Directors, the company, its controlling shareholder, or any entity under its controlling shareholder’s control may not provide such former external director and his or her spouse and children with a direct or indirect benefit. This includes engagement as an office holder or director of the company or a company controlled by its controlling shareholder or employment by, or provision of services to, any such company for consideration, either directly or indirectly, including through a corporation controlled by the former external director. This restriction extends for a period of two years with regard to the former external director and his or her spouse or children, and for one year with respect to other relatives of the former external director.
If, at the time at which an external director is appointed, all members of the Board of Directors, who are not controlling shareholders or relatives of controlling shareholders of the company are of the same gender, the external director to be appointed must be of the other gender.
According to regulations promulgated under the Companies law, at least one of the external directors is required to have “financial and accounting expertise,” unless another member of the audit committee, who is an independent director under the NASDAQ Stock Market rules, has “financial and accounting expertise,” and the other external director or directors are required to have “professional expertise”.
An external director may not be appointed to an additional term unless: (1) such director has “accounting and financial expertise;” or (2) he or she has “professional proficiency,” and on the date of appointment for another term there is another external director who has “accounting and financial expertise” and the number of “accounting and financial experts” on the Board of Directors is at least equal to the minimum number determined appropriate by the Board of Directors. We have determined that both Mr. Dubin and Mr. Graney have accounting and financial expertise (and the remaining directors have professional proficiency).
A director has “professional expertise” if he or she satisfies one of the following requirements: (1) the director holds an academic degree in either economics, business administration, accounting, law or public administration, (2) the director either holds an academic degree in any other field or has completed another form of higher education in the company’s primary field of business or in an area which is relevant to his or her office as an external director in the company, or (3) the director has at least five years of experience serving in any one of the following, or at least five years of cumulative experience serving in two or more of the following capacities: (a) a senior business management position in a company with a substantial scope of business, (b) a senior position in the company’s primary field of business or (c) a senior position in public administration.
Under the Companies Law, external directors are elected by a majority vote at a shareholders’ meeting, so long as either:
● at least a majority of the shares held by shareholders who are not controlling shareholders and do not have personal interest in the appointment (excluding a personal interest that did not result from the shareholder’s relationship with the controlling shareholder) have voted in favor of the proposal (shares held by abstaining shareholders shall not be considered); or
● the total number of shares of such shareholders voted against the election of the external director does not exceed 2% of the aggregate voting rights of our Company.
The Companies Law provides for an initial three-year term for an external director. Thereafter, an external director may be reelected by shareholders to serve in that capacity for up to two additional three-year terms, with certain exceptions as explained below, provided that:
(1) his or her service for each such additional term is recommended by one or more shareholders holding at least one percent of the company’s voting rights and is approved at a shareholders meeting by a disinterested majority, where the total number of shares held by non-controlling, disinterested shareholders voting for such reelection exceeds two percent of the aggregate voting rights in the company and subject to additional restrictions set forth in the Companies Law with respect to affiliation of the external director nominee;
(2) his or her service for each such additional term is recommended by the Board of Directors and is approved at a shareholders meeting by the same disinterested majority required for the initial election of an external director (as described above); or
(3) the external director offered his or her service for each such additional term and was approved in accordance with the provisions of section (1) above.
The term of office for external directors for Israeli companies traded on certain foreign stock exchanges, including the NASDAQ Stock Market, may be extended indefinitely in increments of additional three-year terms, in each case provided that the audit committee and the Board of Directors of the company confirm that, in light of the external director’s expertise and special contribution to the work of the Board of Directors and its committees, the reelection for such additional period(s) is beneficial to the company, and provided that the external director is reelected subject to the same shareholder vote requirements as if elected for the first time (as described above). Prior to the approval of the reelection of the external director at a general shareholders meeting, the company’s shareholders must be informed of the term previously served by him or her and of the reasons why the Board of Directors and audit committee recommended the extension of his or her term.
External directors may be removed only by the same special majority of shareholders required for their election or by a court, and in both cases only if the external directors cease to meet the statutory qualifications for their appointment or if they violate their duty of loyalty to our company. In the event of a vacancy created by an external director which causes the company to have fewer than two external directors, the Board of Directors is required under the Companies Law to call a shareholders meeting as soon as possible (and within three months) to appoint such number of new external directors in order that the company thereafter has two external directors.
External directors may be compensated only in accordance with regulations adopted under the Companies Law. Compensation of an external director is determined prior to his or her appointment and, subject to certain exceptions, may not be changed during his or her term.
The definition of “independent director” under NASDAQ Listing Rules and the definition of “external director” under the Companies Law overlap to a significant degree such that we would generally expect any director serving as external directors under the Companies Law to satisfy the requirements to be independent under NASDAQ Listing Rules. However, it is possible for a director to qualify as an “external director” under the Companies Law without qualifying as an “independent director” under NASDAQ Listing Rules, or vice-versa. The definition of “external director” under the Companies Law includes a set of statutory criteria that must be satisfied, including criteria whose aim is to ensure that there is no factor that would impair the ability of the external director to exercise independent judgment. The definition of “independent director” under NASDAQ Listing Rules specifies similar, if slightly less stringent, requirements in addition to the requirement that the Board of Directors consider any factor which would impair the ability of the independent director to exercise independent judgment. In addition, external directors serve for a period of three years (and for no more than two additional three-year terms) pursuant to the requirements of the Companies Law. However, a special majority of shareholders must elect “external directors” while “independent directors” may be elected by an ordinary majority.
Each committee of the Board of Directors that exercises the powers of the Board of Directors must include at least one external director. The audit committee and the compensation committee must include all external directors then serving on the Board of Directors and the audit committee should be comprised of a majority of directors who are defined as independent under Israeli law; the external directors must be the majority of the members of the compensation committee. The Chairman of the audit committee and of the compensation committee must be an external director.
Under the regulations pursuant to the Companies Law, certain exemptions and reliefs with respect to external directors and independent directors are granted to companies whose securities are traded outside of Israel. Notable may use these exemptions and reliefs.

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ITEM 14. PRINCIPAL ACCOUNTING FEES AND SERVICES
Item 14. PRINCIPAL ACCOUNTANT FEES AND SERVICES
The disclosure set forth in the proposal regarding the approval of the Registrant’s independent registered public accounting firm contained in the Registrant’s definitive proxy statement, filed with the Securities and Exchange Commission on February 16, 2024, is incorporated herein by reference.
PART IV

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ITEM 15. EXHIBITS, FINANCIAL STATEMENT SCHEDULES
Item 15. EXHIBITS AND FINANCIAL STATEMENT SCHEDULES
Exhibit No.
Description
(A)(1)
Financial Statements
The consolidated financial statements of Notable Labs, Ltd. appear after Item 16 of this report.
(A)(2)
Financial Statement Schedules
None.
(A)(3)
Exhibits
2.1++
Agreement and Plan of Merger, dated as of February 22, 2023, by and among Vascular Biogenics, Ltd., Vibrant Merger Sub, Inc. and Notable Labs, Inc. (incorporated by reference to Exhibit 2.1 to the Registration Statement on Form S-4 filed with the SEC on September 5, 2023.
3.1
Articles of Association of the Registrant (incorporated by reference to Exhibit 3.1 of the Annual Report on Form 10-K filed with the SEC on March 14, 2023).
3.2
Memorandum of Association of the Registrant (incorporated by reference to Exhibit 3.2 of the Annual Report on Form 10-K filed with the SEC on March 14, 2023).
3.3
Amendment to Articles of Association of the Registrant, dated October 16, 2023 (incorporated by reference to Exhibit 3.1 to the Current Report on Form 8-K filed with the SEC on October 16, 2023).
4.1
Form of Certificate for Ordinary Shares (incorporated by reference to Exhibit 4.2 of Registration Statement on Form filed with the SEC on July 29, 2014).
10.1*
Employee Ownership and Share Option Plan (2011) of Vascular Biogenics Ltd., and form of agreement thereunder (incorporated by reference to Exhibit 10.1 of the Registration Statement on Form filed with the SEC on June 6, 2014).
10.2*
Employee Share Ownership and Option Plan (2014) of Vascular Biogenics Ltd., and form of Capital Gains Option Agreement thereunder (incorporated by reference to Exhibit 10.17 of the Registration Statement on Form filed with the SEC on June 25, 2014).
10.3*
Vascular Biogenics Ltd. Inducement Plan (2022) of Vascular Biogenics Ltd. and form of award agreements thereunder (incorporated by reference to Exhibit 99.1 of the Current Report on Form 6-K filed with the SEC on February 15, 2022).
10.4*
Form of Release and Indemnification Agreement entered into between Vascular Biogenics Ltd. and its officers and directors (incorporated by reference to Exhibit 10.2 of the Registration Statement on Form filed with the SEC on June 25, 2014).
10.5*
Restated Executive Employment Agreement between Vascular Biogenics Ltd. and Dror Harats, dated January 20, 2022 (incorporated by reference to Exhibit 10.5 of the Annual Report on Form 10-K filed with the SEC on March 14, 2023).
10.6*
Restated Consulting and Services Agreement between Vascular Biogenics Ltd. and Grand H Services Ltd., dated January 20, 2022, as amended on August 23, 2022 (incorporated by reference to Exhibit 10.6 of the Annual Report on Form 10-K filed with the SEC on March 14, 2023).
10.7*
Employment Offer Letter between Vascular Biogenics Ltd. and Sam Backenroth, dated October 4, 2021 (incorporated by reference to Exhibit 10.7 of the Annual Report on Form 10-K filed with the SEC on March 14, 2023).
10.8
Form of Pre-Funded Warrant (incorporated by reference to Exhibit 4.1 of the Current Report on Form 6-K filed with the SEC on April 12, 2021).
10.9+
Exclusive License Agreement by and between Notable Labs, Inc. and Oncoheroes Biosciences Inc. dated October 1, 2021 (incorporated by reference to Exhibit 10.9 to the Registration Statement on Form S-4 filed with the SEC on September 5, 2023).
10.10
Side Letter by and between Boehringer Ingelheim International GmbH and Oncoheroes Biosciences Inc. dated August 1, 2019, as amended by Amendment #1 effective on April 5, 2020 (incorporated by reference to Exhibit 10.10 to the Registration Statement on Form S-4 filed with the SEC on September 5, 2023).
10.11+
Co-Development and Profit-Sharing Agreement between Notable Labs, Inc. and CicloMed LLC dated July 20, 2021 (incorporated by reference to Exhibit 10.11 to the Registration Statement on Form S-4 filed with the SEC on September 5, 2023).
10.12
Standard Industrial/Commercial Single-Tenant Lease by and between Hatch Drive Associates and the Notable Labs, Inc., dated as of March 25, 2019 (incorporated by reference to Exhibit 10.12 to the Registration Statement on Form S-4 filed with the SEC on September 5, 2023).
10.13
First Amendment to Lease Agreement by and between Hatch Drive Associates, LLC and Notable Labs, Inc., dated as of April 27, 2023 (incorporated by reference to Exhibit 10.13 to the Registration Statement on Form S-4 filed with the SEC on September 5, 2023).
10.14*
2015 Stock Plan of Notable Labs, Inc. (incorporated by reference to Exhibit 10.17 to the Registration Statement on Form S-4 filed with the SEC on September 5, 2023).
10.15
Form of Series C Warrant Agreement between Notable Labs, Inc. and purchasers of Series C-1 Preferred Stock, dated June 2021 (incorporated by reference to Exhibit 10.18 to the Registration Statement on Form S-4 filed with the SEC on September 5, 2023).
10.16
Form of Stock Option Award Agreement between Notable Labs, Inc. and purchasers of Series C-1 Preferred Stock, dated June 2021 (incorporated by reference to Exhibit 10.19 to the Registration Statement on Form S-4 filed with the SEC on September 5, 2023).
10.17++
Stock Purchase Agreement between Notable Labs, Inc. and investors party thereto dated February 22, 2023 (incorporated by reference to Exhibit 10.20 to the Registration Statement on Form S-4 filed with the SEC on September 5, 2023).
10.18*
Amended and Restated Employment Agreement by and between Notable Labs, Inc. and Thomas Bock dated April 30, 2021 (incorporated by reference to Exhibit 10.14 to the Registration Statement on Form S-4 filed with the SEC on September 5, 2023).
10.19*
Employment Agreement by and between Notable Labs, Inc. and Joseph Wagner dated June 15, 2020 (incorporated by reference to Exhibit 10.15 to the Registration Statement on Form S-4 filed with the SEC on September 5, 2023).
10.20*
Engagement Letter by and between Notable Labs, Inc. and Scott A. McPherson dated March 1, 2023 (incorporated by reference to Exhibit 10.16 to the Registration Statement on Form S-4 filed with the SEC on September 5, 2023).
10.21*
Form of Release and Indemnification Agreement (incorporated by reference to Exhibit 10.4 to the Current Report on Form 8-K filed with the SEC on October 16, 2023).
10.22+
Asset Purchase Agreement by and between Immunewalk Therapeutics Inc. and Vascular Biogenics Ltd., dated as of October 1, 2023 (incorporated by reference to Exhibit 10.1 to the Current Report on Form 8-K filed with the SEC on October 2, 2023).
21.1
Subsidiaries of the Registrant
23.1
Consent of Withum Smith+Brown, PC
23.2
Consent of Deloitte & Touche LLP
31.1
Certification of Chief Executive Officer pursuant to Section 302 of the Sarbanes-Oxley Act of 2002.
31.2
Certification of Chief Financial Officer pursuant to Section 302 of the Sarbanes-Oxley Act of 2002.
32.1
Certification of the Chief Executive Officer and Chief Financial Officer pursuant to 18 U.S.C. Section 1350, as adopted pursuant to Section 906 of Sarbanes-Oxley Act of 2002.
Clawback Policy
101.INS
Inline XBRL Instance Document - the instance document does not appear in the Interactive Data File because XBRL tags are embedded within the Inline XBRL document.
101.SCH
Inline XBRL Taxonomy Extension Schema Document.
101.CAL
Inline XBRL Taxonomy Extension Calculation Linkbase Document.
101.DEF
Inline XBRL Taxonomy Extension Definition Linkbase Document.
101.LAB
Inline XBRL Taxonomy Extension Label Linkbase Document.
101.PRE
Inline XBRL Taxonomy Extension Presentation Linkbase Document.
Cover Page Interactive Data File.
* Denotes management compensation plan, agreement or arrangement.
+ Portions of this Exhibit (indicated with [****]) have been omitted as the Registrant has determined that (i) the omitted information is not material and (ii) the omitted information would likely cause competitive harm to the Registrant if publicly disclosed.
++ Certain schedules and exhibits have been omitted pursuant to Item 601(b)(2) of Regulation S-K. A copy of any omitted schedule and/or exhibit will be furnished to the SEC upon request.