TMB-365 and TMB-380 in Suppressed HIV-1 Infected Individuals

This study is a phase 1b / 2 adaptive open-label dose escalation study of the combination of TMB-365 and TMB-380. This adaptive study design will be comprised of Sentinel Groups (N=10) and Core Groups (N=20). Safety and pharmacokinetic (PK) data obtained from Sentinel group participants will guide the conduct of Core Group execution.

Participants will be HIV-infected and suppressed for at least 6 months on continuous daily oral combination antiretroviral therapy (cART). Continuous is defined as no more than 3 consecutive days of missed cART. There are three doses of each antibody being explored, 2400 mg, 3200 mg, and 4800 mg.

Sentinel Groups Sentinel Groups will be comprised of 10 cART suppressed HIV-1 infected volunteers who receive a single IV dose of the combination of TMB-365 and TMB-380 while continuing cART.

Sentinel Group 1 will be dosed with 2400 mg of each antibody and will continue daily oral cART throughout the screening, infusion, and post-infusion observation period of 12 and be assessed for safety and pharmacokinetics.

Sentinel group 2 will dose both antibodies at 3200 mg. The third sentinel group will dose both antibodies at 4800 mg.

Criteria for safety of a dose of either TMB-365 or TMB-380 include:

1. No SAEs probably or definitely due to TMB-365 or TMB-380 ii) No more than one Grade 3 or Grade 4 adverse event probably or definitely related to TMB-365 or TMB-380 at any dose level.

Toxicity evaluations will be guided by the DAIDS Table for Grading Severity of Adult and Pediatric Adverse Events Version 2.1. The Common Terminology Criteria for Adverse Events (CTCAE) v. 5.0 scale will be used for assessment of any infusion reactions, or anaphylactic events.

PK targets:

1. TMB-365: serum levels >0.3 μg/mL ii. TMB-380: serum levels >65 μg/mL Should a dose of either antibody prove safe and at least 80% of subjects studied in a given Sentinel dose group meet specified safety and PK criteria, then a Core group of 20 subjects will be enrolled and treated with that dose of TMB-365 and TMB-380 as a stand-alone complete maintenance regimen for 24 weeks.

Safety must be established prior to any request for dose escalation to the next higher Sentinel dose group. A review of 14-day safety data in 7 of 10 subjects after infusion must be available for review prior to any request for dose escalation. Dose escalation may only occur with the approval of an independent Data Monitoring Committee (DMC).

The maximum dose of TMB-365 and TMB-380 that will be tested in Sentinel groups is 4800 mg.

The first 3 subjects in each Sentinel group will be treated at designated sites selected for demonstration of expertise in the use of monoclonal antibody therapy. Subjects will remain at the study site for 3 hours post-infusion for monitoring of vital signs every 15 minutes beginning 15 minutes prior to the infusion of TMB-365 and TMB-380 as well as observation for the presence of infusion reactions. Should the infusions be well tolerated and no Grade 3 or 4 AEs, or SAE's occur due to study drugs within 7 days of infusion, then the remaining 7 subjects in that group may be recruited/treated. These subjects will remain at study sites for 1 hour post-infusion for monitoring of vital signs and the presence of infusion reactions.

Core Group Subjects There will be one Core Group comprised of 40 cART suppressed HIV-1 infected volunteers and will receive multiple IV doses of the combination of TMB-365 and TMB-380 as a stand-alone maintenance regimen for 24 weeks. Oral cART will be restarted in the clinic at the Week 24 visit.

Core group participants will complete the study at Day 196, 4 weeks after reinstituting oral cART. Sentinel group participants at the same dosing level may be enrolled in a Core group if infusions are well tolerated and the subject is willing to discontinue oral cART.

Core Group study group 1 will begin with the doses of each antibody that prove safe and meet PK targets.

Regimen in Core Group participants based on PK modeling include:

TMB-365: 4800 mg q 8 weeks. TMB-380: 4800 mg q 8weeks. Sentinel Group participants that wish to participate in Core Groups must repeat all screening procedures including signing a second Informed Consent Form.