There are 4 study Arms as it is possible that pharmacokinetics (PK) may differ between HIV-1-uninfected individuals (Arms 1, 2 and 4) and HIV-1-infected and viremic individuals (Arm 3). Safety and tolerability as well as PK may differ between the IV and SC routes, Arms 1, 2 and 4.
A dose escalation design has been used to establish safety and tolerability at very low doses of 10E8.4/iMab as this is a first in man study. Once demonstrated, dose levels would be increased to dosing levels thought to be more clinically relevant.
The numbers of subjects receiving active antibody in each study arm are relatively balanced such that an initial evaluation of the primary endpoint with additional dosing to provide insights into both PK and antiviral activity as well as some exploratory endpoints such as immunogenicity will be possible.
This study is a phase 1 clinical trial to evaluate the safety and tolerability, pharmacokinetics and the antiretroviral activity of the bispecific monoclonal antibody 10E8.4/iMab in HIV-infected and HIV-uninfected individuals.
HIV uninfected, healthy volunteers will be administered either one intravenous infusion of 10E8.4/iMab at one of five increasing dose levels (0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg and 30 mg/kg) or one SC injection of 1 mg/kg, 2.5 mg/kg or 10 mg/kg or placebo and will be followed for 24 weeks after 10E8.4/iMab administration. HIV-infected volunteers will be administered one intravenous infusion of 10E8.4/iMab at one of three increasing dose levels (3 mg/kg, 10 mg/kg and 30 mg/kg).
Arm 1 consists of 3 groups: Group A: 0.3 mg/kg IV, N=3; Group B: 1mg/kg SC, N=3; and Group C: 1mg/kg IV, N=3. All HIV-1 uninfected, dosed once.
Arm 2 consists of 3 groups: Group D: 3mg/kg, N=6; Group E: 10mg/kg, N=6; and Group F: 30 mg/kg, N=6. All HIV-1 uninfected, dosed IV once.
Arm 3 consists of 2 groups: H: 10mg/kg, N=4 and Group I: 30 mg/kg, N=4. All HIV-1 infected, dosed IV once.
Arm 4 consists of 2 groups: Group J: 2.5 mg/kg, N=9, 6 active, 3 placebo; Group K: 10mg/kg, N=9, 6 active, 3 placebo, dosed SC once.
Since the safety and tolerability profiles, as well as the PK profile might differ between HIV-infected and HIV-uninfected individuals, dose-escalation is planned in both study populations. Dosing in Arm 1 Groups A, B and C; Arm 2 Groups D and E; and Arm 4 Groups J and K will be done prior to initiation of dosing in Arm 3 due to safety considerations.
Arm 3 will include HIV-infected individuals off antiretroviral therapy (ART) for at least 4 weeks with plasma HIV-1 RNA levels \< 100,000 copies/ml (both ART naïve and individuals that discontinued ART due to intolerance or by choice can be included in this group), or HIV-infected individuals on stable ART with plasma HIV-1 RNA levels \> 1000 copies/ml.
The stated numbers of participants are the minimal number per dosing group. A safety monitoring committee may request additional enrollment in a specific Arm or Group based on the occurrence of dose limiting toxicities defined as any Grade 3 or greater adverse event that is probably or definitely related to the investigational product.
Study visits are all outpatient and include:
1. a screening phase of up to 2 visits
2. an administration visit at which 10E8.4/iMab is given either IV or SC in doses based on body weight and specific Arm and Group assignment.
3. follow up visits that will occur at days 2, 7, 10 and weeks 2, 3, 4, 6, 8, 12 and 24. Subjects who received placebo SC may not be required to return for the week 24 visit.
