Safety and Pharmacokinetics of a Human Monoclonal Antibody, VRC-EBOMAB092-00-AB (MAb114), Administered Intravenously to Healthy Adults

VRC 608: A Phase I, Open-Label, Dose-Escalation Study of the Safety and Pharmacokinetics of a Human Monoclonal Antibody, VRC-EBOMAB092-00-AB (MAb114), Administered Intravenously to Healthy Adults

Study Design: VRC 608 is the first-in-human Phase I study to examine safety, tolerability and pharmacokinetics of the monoclonal antibody (MAb), VRC-EBOMAB092-00-AB (MAb114). MAb114 will be administered as a single dose. The hypotheses are: 1) MAb114 administration to healthy adults will be safe by the intravenous (IV) route; and 2) MAb114 will be detectable in human sera with a definable half-life. The primary objectives are to evaluate the safety and tolerability of MAb114 in healthy adults. Secondary objectives will evaluate the pharmacokinetics of MAb114 and the potential to detect an anti-drug antibody response to MAb114.

Product Description: MAb114 is a human IgG1 MAb targeted to the Zaire ebolavirus (EBOV) glycoprotein (GP). It was developed by the VRC/NIAID/NIH and manufactured at Cook Pharmica LLC d.b.a. Catalent Indiana, LLC (Bloomington, IN) under current Good Manufacturing Practice (cGMP) regulations. MAb114 is supplied as a lyophilized product in a glass vial at 400 mg per vial with target overfill to 425 mg per vial.

Subjects: Up to 30 healthy adults, 18-60 years of age.

Study Plan: This is an open-label, dose-escalation study of MAb114 administered by IV infusion at dosages of 5, 25 and 50 mg/kg (Groups 1-3). Enrollment will begin with the lowest dose group. Following the first product administration in each group, the study team will wait at least 3 days before administering MAb114 to a second subject within the same group. Dose-escalation evaluations will occur to ensure the safety data support proceeding to the higher doses. Solicited reactogenicity following product administration will be evaluated using a 3-day diary. Assessment of safety will include clinical observation and monitoring of serum hematological and chemical parameters at defined timepoints throughout the study.

• Group 1: 3 subjects; 5 mg/kg IV
• Group 2: 5 subjects; 25 mg/kg IV
• Group 3: 10 subjects; 50 mg/kg IV
• Total* 18 subjects

• A minimum of 18 subjects will be enrolled. Enrollment up to a total of 30 subjects is permitted if additional subjects are necessary for safety or pharmacokinetic (PK) evaluations.

Study Duration: Subjects will be followed for 24 weeks after the study product administration.

Inclusion criteria

A volunteer must meet all of the following criteria:

• Able and willing to complete the informed consent process.
• Available for clinical follow-up through the last study visit.
• 18 to 60 years of age.
• In good general health without clinically significant medical history.
• Willing to have blood samples collected, stored indefinitely, and used for research purposes.
• Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process.
• Physical examination without clinically significant findings within the 84 days prior to enrollment.
• Have screening laboratory values within 84 days prior to enrollment that meet the following criteria:

• White Blood Cell (WBC) 2,500-12,000/mm^3
• WBC differential either within institutional normal range or accompanied by the Principal Investigator (PI) or designee approval
• Platelets = 125,000 - 400,000/mm^3
• Hemoglobin within institutional normal range or accompanied by the PI or designee approval
• Creatinine less than or equal to 1.1 x upper limit of normal (ULN)
• Alanine aminotransferase (ALT) less than or equal to 1.25 x ULN
• Negative for human immunodeficiency virus (HIV) infection by a Food and Drug Administration (FDA) approved method of detection
• Negative for Hepatitis B core antibody (HBcAb) and Hepatitis C virus antibody (HCV Ab)
• Criteria applicable to women of childbearing potential:

• If a woman is of reproductive potential and sexually active with a male partner, then she agrees to use an effective means of birth control from the time of study enrollment until the last study visit, or to be monogamous with a partner who has had a vasectomy.
• Negative human chorionic gonadotropin (beta-HCG) pregnancy test (urine or serum) on day of enrollment and product administration.

Exclusion criteria

A volunteer will be excluded from study participation if one or more of the following conditions apply:

• Previous receipt of a licensed or investigational monoclonal antibody or Ebola vaccine.
• Weight >100 kg.
• Any history of a severe allergic reaction with generalized urticaria, angioedema or anaphylaxis prior to enrollment that has a reasonable risk of recurrence during the study.
• Hypertension that is not well controlled.
• Woman who is breast-feeding, or planning to become pregnant during study participation.
• Receipt of any investigational study product within 28 days prior to enrollment.
• Any other chronic or clinically significant medical condition that in the opinion of the investigator would jeopardize the safety or rights of the volunteer, including but not limited to: diabetes mellitus type I, chronic hepatitis; OR clinically significant forms of: drug or alcohol abuse, asthma, autoimmune disease, psychiatric disorders, heart disease, or cancer.
• Bleeding disorder diagnosed by a doctor (e.g. factor deficiency, coagulopathy, or platelet disorder requiring special precautions) or significant bruising or bleeding difficulties with intramuscular (IM) injections or blood draws.
• Use of angiotensin-converting enzyme (ACE) inhibitors or other potential nephrotoxins.