Phase 1, Open-label, Single Dose Study to Examine Safety, Tolerability, Pharmacokinetics and Virologic Impact of VRC01LS or VRC07-523LS in HIV-infected Viremic Adults

Study Design:

Open-label, single dose study to examine safety, tolerability, pharmacokinetics and virologic impact of VRC01LS or VRC07-523LS in HIV-infected viremic adults.

Study Hypotheses:

This is the first study of VRC01LS or VRC07-523LS in HIV-infected viremic adults. The primary hypothesis is that both VRC01LS and VRC07-523LS will be safe for intravenous administration to HIV-1-infected adults. The secondary hypothesis is that VRC01LS and VRC07-523LS will be detectable in human sera with a definable half-life.

Product Description:

VRC-HIVMAB080-00-AB (VRC01LS) and VRC-HIVMAB075-00-AB (VRC07-523LS) are human monoclonal antibodies (MAbs) targeted to the CD4+ binding site of HIV-1. Both MAbs are modifications of the VRC01 MAb (which has been shown to be safe and to have antiviral activity in human studies) with the addition of the "LS", a 2-amino acid mutation designed to improve the half-life of the antibody. These MAbs were developed and manufactured by VRC/NIAID/NIH under current Good Manufacturing Practice (cGMP) at the VRC Vaccine Pilot Plant operated under contract by the Vaccine Clinical Materials Program (VCMP), Leidos Biomedical Research, Inc., Frederick, MD. Vials were provided at 100 mg/mL.

Participants:

HIV-1-infected viremic adults; 18-70 years of age.

Study Plan:

This study assessed VRC01LS or VRC07-523LS administered at 40 mg/kg IV in HIV-infected viremic participants. Participants enrolled in one of two parts: Part A (VRC01LS) or Part B (VRC07-523LS). A total of 7 participants were enrolled in Part A and received VRC01LS and a total of 9 participants were enrolled in Part B and received VRC07-523LS. Safety lab samples, HIV viral load, CD4+ lymphocyte count, pharmacokinetic (PK) samples, and blood samples for detection of human anti-VRC01LS antibody (Part A) and human anti-VRC07-523LS antibody (Part B) were drawn at baseline and intervals throughout the study. Participants recorded in a daily diary reactogenicity symptoms for 3 days after study product administration and were queried at each study visit for adverse events. Participants were strongly encouraged to initiate 3-drug anti-retroviral therapy (ART), prescribed by their primary HIV clinician; not study-provided, any time after completing the day 14 study evaluations.

VRC 607/A5378 Study Schema:

• Part: A; Participants: 7; Product: VRC01LS; Administration Schedule (Day 0): 40 mg/kg IV.
• Part: B; Participants: 9; Product: VRC07-523LS; Administration Schedule (Day 0): 40 mg/kg IV.

• Total Participants: 16

Study Duration:

Participants were followed for 48 weeks after study product administration.

Inclusion criteria

A participant must meet all of the following criteria:

• Able and willing to complete the informed consent process.
• 18-70 years old
• Available for clinic visits for 48 weeks after study product administration.
• HIV-1 infected and clinically stable. [Note: Documented HIV-1 infection by HIV enzyme immunoassay (EIA) performed by a Clinical Laboratory Improvement Amendments (CLIA) certified outside lab within 28 days of enrollment is acceptable.]
• At least one plasma viral load >=500 copies/mL within 28 days of enrollment. A plasma viral load within 28 days and closest to the day of enrollment, that is detectable but not greater than 100,000 copies/mL. [Note: outside laboratory results will be acceptable].
• A CD4+ count >=350 cells/microliter (mcL) on 2 of 3 consecutive testing occasions (or on 2 of 2 sequential tests) within 28 days prior to enrollment. [Note: outside laboratory results will be acceptable].
• In general good health as assessed by a study clinician and under the care of a primary health care provider for medical management of HIV infection while participating in the study. Willing to give consent to contact and send laboratory results to the participant's primary health provider.
• Willing to have blood samples collected, stored indefinitely, and used for various research purposes.
• Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process.
• Screening laboratory values within 28 days prior to enrollment must meet the following criteria:

• Absolute neutrophil count >=800/mcL
• Platelets >=100,000/mcL
• Hemoglobin >=10.0 g/dL
• Creatinine less than or equal to 1.31 mg/dL
• Alanine aminotransferase (ALT) less than or equal to 2.5 x upper limit of normal (ULN)
• Negative Hepatitis B Surface Antigen (HBsAg)
• Undetectable Hepatitis C Viral Load (HCV RNA)

[Note: Documented negative HBsAg and HCV RNA performed by an outside CLIA certified lab within 28 days of enrollment are acceptable.]

Female-Specific Criteria:

• If a woman is sexually active with a male partner and has no history of hysterectomy, tubal ligation, or menopause, she must agree to use either a prescription birth control method or a barrier birth control method from the time of study enrollment until the last study visit, or have a monogamous partner who has had a vasectomy.
• Negative beta-HCG (human chorionic gonadotropin) pregnancy test (urine or serum) on day of enrollment for women presumed to be of reproductive potential.

Exclusion criteria

A participant will be excluded if one or more of the following conditions apply:

• Previous receipt of humanized or human monoclonal antibody whether licensed or investigational.
• Prior use of antiretroviral therapy.
• Ongoing AIDS-related opportunistic infection (including oral thrush).
• Active drug or alcohol use or dependence in the opinion of the site investigator that would interfere with adherence to study requirements.
• Any history of a severe allergic reaction, including generalized urticaria, angioedema or anaphylaxis prior to enrollment, that has a reasonable risk of recurrence during the study.
• Physical finding on examination considered clinically significant.
• Hypertension that is not well controlled.
• Weight >115 kg (253 pounds).
• Breast-feeding.
• 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.