A Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of VEL-101

Study Overview
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Brief Summary
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This study is primarily designed to assess the safety and tolerability of single doses of VEL-101 when administered subcutaneously (via injection into an area under the skin) or intravenously (via infusion into a vein). As each new group of participants is enrolled into the study, the dose administered to that group may be higher than a previous dose shown to be safe in other participants. The study is also designed to determine blood levels of VEL-101 and some substances produced by the immune system following VEL-101 administration. This information can provide insight into how quickly VEL-101 is eliminated from the body and some if its effects on the body.

Official Title
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A Phase 1, Randomized, Double Blind, Placebo Controlled, Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of VEL-101 Administered Intravenously or Subcutaneously in Healthy Subjects.

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: VEL-101
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to understand the key components of the study as described in the written informed consent document, and willing and able to provide written informed consent; Self-described healthy male or female, 18 to 65 years of age, inclusive, at Screening; Body mass index (BMI) within the range of 18.5 to <35 kg/m2 at Screening; If female, is surgically sterile, 2 years postmenopausal, or, if of childbearing potential, is using a medically accepted method of contraception (abstinence, the simultaneous use of 2 barrier methods, or the use of an intrauterine device [in place at least 3 months prior to dosing], or oral contraceptives), and agrees to continued use of this method until study Day 50; If male, agrees to use an approved method of contraception (abstinence, 2 barrier methods, female partner's use of an intrauterine device [in place at least 3 months prior to dosing], oral contraceptives or female partner who is surgically sterile or 2 years postmenopausal) and agrees to use this method until study Day 50; Able to comply with all study procedures, including the required overnight stays in the clinical research center and the food, beverage, and medication restrictions during the study; In the opinion of the Investigator, is able to adhere to the requirements of the study. Exclusion Criteria: Known allergy to study medication or its components (non-medicinal ingredients) or a history of a severe allergic reaction to any drug or history of multiple food/drug allergies; Use of tobacco, smoking cessation products, or products containing nicotine within 3 months prior to Screening; History of alcohol or illicit drug use disorder, marijuana consumption as defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, or a reported habitual alcohol intake greater than 1.5 oz (ethanol equivalent) per day (eg, 24 oz of beer, 10 oz of wine, or 3 oz of hard liquor) for the past two years; Positive urine screen for drugs of abuse including tetrahydrocannabinol or has a positive breathalyzer test on admission to the study center, at Screening and at Baseline for each treatment cohort; Positive serologic test for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis C virus (HCV) antibody, human immunodeficiency virus (HIV), or positive for EBV polymerase chain reaction [PCR] at Screening; Negative for Epstein-Barr Virus ([EBV], viral capsid antigen [VCA IgG], Epstein-Barr nuclear antigen antibody [EBNA],); History of inadequately treated active or latent mycobacterium tuberculosis (TB) infection or positive QuantiFERON® TB Gold at Screening; History of diabetes, clinically significant cardiovascular, pulmonary, hepatic, renal, or malabsorptive disease, as determined by the Principal Investigator (PI); Clinically significant abnormality upon physical examination at Screening, as determined by the Investigator; Clinically significant abnormality on 12-lead ECG at Screening, as determined by the Investigator; Clinically significant abnormal laboratory values (clinical chemistry, hematology, coagulation, or urinalysis) outside the reference values established by the laboratory, as determined by the Investigator at Screening; Positive pregnancy test or lactating at Screening or at Day -1; Participation in an investigational study within 30 days or within 5 half-lives of the investigational drug, whichever is longer, prior to the Screening Visit; Receiving any antibody or biologic medicinal product within 90 days prior to Screening; Blood or plasma donation within 72 hours prior to Screening or planned up to study Day 50; Positive test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen testing or equivalent testing on Day -1; Subjects fully recovered from coronavirus disease 2019 (COVID-19) infection are eligible. Subjects with a past history of hospitalization due to COVID-19 infection will be excluded; History of infection or vaccination within 90 days prior to the Screening, or planned vaccination within 90 days of dosing, with the exception of vaccination against SARS CoV-2; History or presence, upon clinical evaluation, of any illness that, in the opinion of the Investigator, would interfere with the ability to provide informed consent or comply with study instructions, or that might confound the interpretation of the study results or put the subject at undue risk.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Subcutaneous (SQ) Dose A<br>Single dose of VEL-101 by SQ injection | Drug: VEL-101<br>* Intervention administered via subcutaneous injection or 1-hour intravenous infusion on Day 1<br>|
| Experimental: Intravenous (IV) Dose A<br>Single dose of VEL-101 by IV infusion | Drug: VEL-101<br>* Intervention administered via subcutaneous injection or 1-hour intravenous infusion on Day 1<br>|
| Experimental: SQ Dose B<br>Single dose of VEL-101 by SQ injection | Drug: VEL-101<br>* Intervention administered via subcutaneous injection or 1-hour intravenous infusion on Day 1<br>|
| Experimental: SQ Dose C<br>Single dose of VEL-101 by SQ injection | Drug: VEL-101<br>* Intervention administered via subcutaneous injection or 1-hour intravenous infusion on Day 1<br>|
| Experimental: IV Dose C<br>Single dose of VEL-101 by IV infusion | Drug: VEL-101<br>* Intervention administered via subcutaneous injection or 1-hour intravenous infusion on Day 1<br>|
| Experimental: SQ Dose D<br>Single dose of VEL-101 by SQ injection | Drug: VEL-101<br>* Intervention administered via subcutaneous injection or 1-hour intravenous infusion on Day 1<br>|
| Experimental: SQ Dose E<br>Single dose of VEL-101 by SQ injection | Drug: VEL-101<br>* Intervention administered via subcutaneous injection or 1-hour intravenous infusion on Day 1<br>|
| Placebo Comparator: SQ or IV Placebo<br>Single dose of Placebo by SQ injection or IV infusion | Drug: Placebo<br>* Intervention administered via subcutaneous injection or 1-hour intravenous infusion on Day 1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Percentage of Participants with Treatment-emergent Adverse Events (TEAEs) | Number and percentage of participants experiencing one or more adverse events which occurred or worsened in severity after initiation of investigational product (IP) dosing | Day 1 through Day 50 | 
| Number and Percentage of Participants with Serious TEAEs | Number and percentage of participants experiencing one or more serious TEAEs | Day 1 through Day 50 | 
| Number and Percentage of Participants with Grade 3 or Higher TEAEs | Number and percentage of participants experiencing one or more grade 3 TEAEs | Day 1 through Day 50 | 
| Number and Percentage of Participants with TEAEs Leading to Withdrawal from the Study | Number of participants experiencing one or more TEAEs directly resulting in withdrawal from the study | Day 1 through Day 50 | 
| Number and Percentage of Participants with TEAEs Leading to Death | Number and percentage of participants experiencing TEAEs that resulted in death | Day 1 through Day 50 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Percentage of Participants with Abnormal Chemistry Panel Results | Descriptive statistics will summarize results (including change from baseline, as appropriate) of the following at each time point: sodium, potassium, chloride, calcium, bicarbonate, glucose, phosphorus, blood urea nitrogen, creatinine, creatine kinase, C-reactive protein, estimated glomerular filtration rate (eGFR), magnesium, amylase, uric acid, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), albumin, alkaline phosphatase, direct bilirubin, total bilirubin, indirect bilirubin, total protein, and lactate dehydrogenase | Days -1, 2 (24 hours), 3, 5, 8, 15, 22, 29, 50 | 
| Number and Percentage of Participants with Abnormal Hematology Panel Results | Descriptive statistics will summarize results (including change from baseline, as appropriate) of the following at each time point: hematocrit, hemoglobin, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW), red blood cells (RBC), white blood cells (WBC) and differential, and platelets | Days -1, 2 (24 hours), 3, 5, 8, 15, 22, 29, 50 | 
| Number and Percentage of Participants with Abnormal Coagulation Panel Results | Descriptive statistics will summarize results (including change from baseline, as appropriate) of the following at each time point: prothrombin time (PT), international normalized ratio (INR), partial thromboplastin time (PTT), and fibrinogen | Days -1, 2 (24 hours), 3, 5, 8, 15, 22, 29, 50 | 
| Number and Percentage of Participants with Abnormal Urinalysis Results | Descriptive statistics will summarize results (including change from baseline, as appropriate) of the following at each time point: specific gravity, pH, leukocytes, erythrocytes, protein, glucose, nitrite, urobilinogen, bilirubin, ketones, and additional microscopic examination if blood or protein are abnormal | Days -1, 2 (24 hours), 3, 5, 8, 15, 22, 29, 50 | 
| Number and Percentage of Participants with Abnormal 12-lead Electrocardiogram (ECG) Results | Descriptive statistics will summarize results (including change from baseline, as appropriate) of the following at each time point: PR interval, QRS duration, QT interval, corrected QT interval (QTc), and corrected QT interval using Fridericia's formula (QTcF) | Days 1 (0, 1, 2, 3, 4, 5, 8, 12, 12, 16, and 20 hours), 2 (24, 30, 36, and 42 hours), 3, 4, 5, 8, 29, 50 | 
| Number and Percentage of Participants with Abnormal Vital Signs Results | Descriptive statistics will summarize results (including change from baseline, as appropriate) of the following at each time point: heart rate (HR), respiratory rate (RR), blood pressure (BP), temperature, and oxygen saturation | Days -1, 1 (0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 8, 12, 16, 20 hours), 2 (24, 30, 36, 42 hours), 3, 4, 5, 6, 7, 8, 15, 22, 29, 50 | 
| CD28 Receptor Occupancy | Proportion of target receptors occupied by VEL-101 | Day 1 (0, 1, 3, 5, 8 hours) and Days 2 (24 hours), 3, 15, 22, 29, 50 | 
| Number and Percentage of Participants with Anti-drug Antibody (ADA) Formation | Presence of detectable anti-VEL-101 antibodies; neutralizing antibody assessments to be performed in samples positive for ADA | Days 1 (0 hour), 15, 29, 50 | 
| Number and Percentage of Participants with Detectable Systemic Cytokine Concentrations | Interferon-gamma, interleukin-1 beta, interleukin-2, interleukin-4, interleukin-5, interleukin-6, interleukin-8, interleukin-10, interleukin-13, interleukin-17, interleukin-12 p70 (heterodimer composed of p40 and p35 subunits), tumor necrosis factor-alpha | Day 1 (0, 1, 3, 5, 8 hours) and Days 2 (24 hours), 3, 15, 50 | 
| Maximum Plasma Concentration (Cmax) | The observed maximum plasma concentration | Day 1 (0, 1, 3, 5, 8 hours) and Days 2 (24 hours), 3, 4, 5, 6, 7, 8, 15, 22, 29, 50 | 
| Time of Observed Maximum Plasma Concentration (Tmax) | Time at which the observed maximum plasma concentration occurred | Day 1 (0, 1, 3, 5, 8 hours) and Days 2 (24 hours), 3, 4, 5, 6, 7, 8, 15, 22, 29, 50 | 
| Terminal Elimination Rate Constant | Terminal elimination rate constant, determined using the linear least squares regression of the terminal phase of the log plasma concentration time profile | Day 1 (0, 1, 3, 5, 8 hours) and Days 2 (24 hours), 3, 4, 5, 6, 7, 8, 15, 22, 29, 50 | 
| Terminal Elimination Half-life | Elimination half-life calculated using terminal phase plasma concentration data | Day 1 (0, 1, 3, 5, 8 hours) and Days 2 (24 hours), 3, 4, 5, 6, 7, 8, 15, 22, 29, 50 | 
| Area Under the Plasma Concentration Versus Time Curve (AUC) from Time Zero to Time of Last Observed Quantifiable Concentration | Area under the plasma concentration versus time curve (AUC) from time zero to time of last observed quantifiable concentration (different from AUC from time zero to infinity) | Day 1 (0, 1, 3, 5, 8 hours) and Days 2 (24 hours), 3, 4, 5, 6, 7, 8, 15, 22, 29, 50 | 
| AUC from Time Zero to Infinity | Area under the plasma concentration versus time curve from time zero to infinity | Day 1 (0, 1, 3, 5, 8 hours) and Days 2 (24 hours), 3, 4, 5, 6, 7, 8, 15, 22, 29, 50 | 
| Total Clearance (CL) | Total clearance from plasma | Day 1 (0, 1, 3, 5, 8 hours) and Days 2 (24 hours), 3, 4, 5, 6, 7, 8, 15, 22, 29, 50 | 
| Terminal Volume of Distribution (Vz) | Apparent volume of distribution in the terminal phase | Day 1 (0, 1, 3, 5, 8 hours) and Days 2 (24 hours), 3, 4, 5, 6, 7, 8, 15, 22, 29, 50 | 
| Bioavailability (F) | Absolute bioavailability | Day 1 (0, 1, 3, 5, 8 hours) and Days 2 (24 hours), 3, 4, 5, 6, 7, 8, 15, 22, 29, 50 |