Safety and Antiviral Activity of BLD-2660 in COVID-19 Hospitalized Subjects

Study Overview
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Brief Summary
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BLD-2660 is a novel, synthetic, orally active, small molecule inhibitor of calpain (CAPN) 1, 2, and 9 that is selective over the cathepsins as well as other protease families, displays good metabolic stability and permeability, oral bioavailability and low cytochrome P450 (CYP) inhibition. It is under development for the treatment of coronavirus disease-19 (COVID-19) resulting from infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV2), where there is significant unmet medical need.

Detailed Description
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Interleukin 6 (IL-6), a proinflammatory cytokine, is a key driver of a cytokine storm that plays a significant role in clinical complications and acute lung injury. Emerging data indicate that serum levels of IL-6 are elevated in COVID-19 patients and are predictive of respiratory failure and mortality. IL-6 has been shown to contribute to lung damage during SARS-CoV infection and the virus itself is capable of directly inducing its expression. Suppression of pro-inflammatory IL-6 have been shown to have a therapeutic effect in many inflammatory diseases, including viral infections. In a mouse model of lung injury employing bleomycin, BLD-2660, at therapeutic doses of 30 and 100 mg/kg twice per day (BID), reduced IL-6 levels in bronchoalveolar lavage (BAL) fluid. BLD-2660 also attenuated fibrosis damage as measured by significant reductions in the alpha smooth muscle actin and collagen 1 in lung tissue. BLD-2660 also demonstrated target engagement by inhibiting cleavage of one of its substrates, spectrin, in bronchoalveolar cells. BLD-2660 was also evaluated in a mouse model of NASH fibrosis, demonstrating an anti-fibrotic effect. A significant decrease in IL-6 transcription was also observed. This suggests that the effect of BLD-2660 on IL-6 is independent of the injury, or the affected organ. It has been shown that the receptor for SARS-CoV-1 and -2 entry into the cell is angiotensin-converting enzyme 2 (ACE-2). ACE-2 and the dimeric calpains (data on file) are co-expressed in respiratory epithelial cells, the site of both viral entry and predominant early lung injury in COVID-19. Inhibition of dimeric calpain activity has not been associated with impairment of normal immune function. The safety and tolerability of BLD-2660 has been demonstrated in the recently completed Phase 1 single ascending dose (SAD)/multiple ascending dose (MAD) B-2660-101 study. As BLD-2660 has been demonstrated to (1) reduce tissue IL-6 levels and (2) attenuate lung fibrosis damage, it could therefore, potentially reduce the nonproductive IL-6 mediated host-response to infection, which contribute to morbidity and mortality in COVID-19. In addition, data suggest that survivors of SARS-CoV-2 infection are at risk for chronic impairment of pulmonary function, likely attributable to pulmonary fibrosis secondary to lung injury and inflammation. Although there is not yet available data documenting numbers of patients infected with SARS CoV2 pneumonia who progress to pulmonary fibrosis, epidemiology, viral immunology, and current clinical evidence support that pulmonary fibrosis may become one of the serious long-term complications of survivors of COVID-19 related pneumonia. Thus, BLD-2660 could not only potentially downregulate the nonproductive host-response to infection, which contributes to morbidity and mortality in COVID-19 but also could reduce potential long-term fibrosis and loss of pulmonary function resulting from SARS-CoV pneumonia. This study will evaluate BLD-2660 as an add-on therapy to standard of care (SOC) in hospitalized subjects with recent diagnosis of COVID-19.

Official Title
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Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Antiviral Activity of BLD-2660 in Hospitalized Subjects With Recently Diagnosed COVID-19 Compared to Standard of Care Treatment

Conditions
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Sars-CoV-2, Covid19

Intervention / Treatment
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* Drug: BLD-2660


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At least 18 years of age at the time of signing the ICF. Hospitalized for COVID-19. Diagnosed with COVID-19 as defined by having at least 2 of the following signs or symptoms within the past 2 days: Fever defined as a body temperature of ≥ 38.0 °C oral, or ≥ 38.3 °C rectal, ≥37.7 °C forehead or ≥38.7°C aural (axillary temperatures are not allowable); Cough; Fatigue; Shortness of breath. Radiographic evidence (chest x-ray or CT scan) of one the following: Ground-glass opacities, or Local or bilateral patchy infiltrates, or Interstitial pulmonary infiltrates. Oxygen requirements: SpO2 ≤ 94% on ambient air OR Requires supplemental oxygen administration by nasal cannula, simple face mask, or other similar oxygen delivery device. Male and/or female subjects. - Contraception use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. All subjects (male or female) who are of childbearing potential must agree to use highly effective contraception during the study. Female subjects and male partners of female subjects must continue to use highly effective contraception for 30 days after the last dose of study drug. Female subjects should not donate oocytes during this time. Male subjects and female partners of male subjects must continue to use highly effective contraception for 90 days. Male subjects must agree not to donate sperm during this time. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. Note: Ethinyl estradiol is the primary estrogen used in hormonal contraceptives. The progestin component consists of norethindrone, levonorgestrel, norgestrel, norethindrone acetate, ethynodiol diacetate, norgestimate, desogestrel, and drospirenone. As BLD-2660 is a weak CYP3A4 inducer, exposure to both the estrogen and progestin components in hormonal contraceptives may be decreased, resulting in an increased risk of pregnancy. As such, it is recommended that subjects who are on hormonal contraceptives for birth control should use an alternate means of contraception (condoms, diaphragms, intrauterine device (IUD), other barrier methods, sexual abstinence, etc.) during participation in the study. Women of childbearing potential must have a negative serum pregnancy test at Screening within 72 hours prior to first administration of study drug. Women not of childbearing potential must be postmenopausal (defined as cessation of regular menstrual periods for at least 1 year Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol Exclusion Criteria: Active bacterial pneumonia infection Known active tuberculosis (TB). History of Child-Pugh B or C cirrhosis. History of ischemic heart disease or myocardial infarction or acute coronary syndrome. Subjects requiring supplemental oxygen ≥0.75 FiO2. It is not in the best interest of the subjects to participate, in the opinion of the treating Investigator. Female subjects who are pregnant or breastfeeding or expecting to conceive within the projected duration of the study, starting with the screening visit through 90 days after the last dose of study drug. The following laboratory parameters are excluded: Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 x upper limit of normal (ULN); Creatinine clearance < 50 mL/min. Requiring, or expected to require mechanical ventilation at screening. Treatment with chloroquine or hydroxychloroquine at study entry. Treatment with anti-IL 6, anti-IL-6 receptor antagonists, or with Janus kinase inhibitors (JAKi) in the past 30 days or plans to receive during the study period. Participation in any other clinical study of an experimental drug treatment for COVID-19 within 6 half-lives of the experimental treatment. Note: Subjects participating in an observational study are an exception to this criterion and may qualify for the study with Sponsor approval. Note: Subjects who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent. Unable to swallow solid oral medication or known malabsorption disorder. Subjects who have allergy to BLD-2660 or inactive components of BLD-2660.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active (BLD-2660) Group<br> | Drug: BLD-2660<br>* BLD-2660 is a novel, synthetic, orally active, small molecule inhibitor of calpain (CAPN) 1, 2, and 9.<br>|
| Placebo Comparator: Placebo Group<br> | Drug: BLD-2660<br>* BLD-2660 is a novel, synthetic, orally active, small molecule inhibitor of calpain (CAPN) 1, 2, and 9.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Recovery | To evaluate time to recovery as defined by no longer requiring oxygen support or hospital discharge, whichever occurs first. | Course of study; 28 days | 
| Change in Oxygenation | To evaluate change in oxygenation in hospitalized adults with COVID-19 treated with BLD-2660. Measured by change from baseline to Day 10 or hospital discharge, if sooner, in the ratio of peripheral hemoglobin oxygen saturation to fraction of inspired oxygen (SpO2/FiO2) | 10 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety & Tolerability: Incidence of TEAEs and Serious Adverse Events (SAEs) | To evaluate the safety and tolerability of BLD-2660 in the same population. Measured by incidence of TEAEs and serious adverse events (SAEs) | Course of study; 28 days |