Treatment Substitution With PRO 140 Monotherapy in Adult Subjects With HIV-1 Infection

A Phase 2b Study to Assess Suppression of HIV-1 Replication Following Substitution of Stable Combination Antiretroviral Therapy With a PRO 140 (Monoclonal CCR5 Antibody) Monotherapy in Adult Subjects With HIV-1 Infection

This study is a Phase 2b study designed to evaluate the efficacy, safety, and tolerability of PRO 140 monotherapy for the maintenance of viral suppression in subjects who are stable on combination antiretroviral therapy. Consenting subjects will be shifted from their combination antiretroviral regimen to PRO 140 monotherapy for 12 weeks. Total treatment duration with PRO 140 will be 14 weeks with the one week overlap of existing retroviral regimen and PRO 140 at the beginning of the study treatment, and one week overlap at the end of the treatment in subjects who do not experience virologic failure.

This study is a Phase 2b, multi-center study designed to evaluate the efficacy, safety, and tolerability of PRO 140 monotherapy for the maintenance of viral suppression in patients who are stable on combination antiretroviral therapy. Patient enrollment will be staggered in this study to facilitate adequate safety monitoring. A lead cohort will include 12 subjects. Enrollment of additional 28 subjects will not be initiated until it is approved by the independent Data Monitoring Committee (DMC). Consenting patients will be shifted from combination antiretroviral regimen to PRO 140 monotherapy for 12 weeks. Total treatment duration with PRO 140 will be up to 14 weeks with the one week overlap of existing retroviral regimen and PRO 140 at the beginning of the study treatment and also one week overlap at the end of the treatment in subjects who do not experience Virologic Failure. PRO 140 will be administered as a 350 mg subcutaneous injection weekly for up to 14 weeks. Study participants will be monitored for viral rebound on a weekly basis following initiation of PRO 140 monotherapy and will re-initiate their previous antiretroviral regimen if plasma HIV-1 RNA levels rise above 400 copies/ml on two consecutive blood draws at least 3 days apart. The study will have three phases: Screening Phase, Treatment Phase and Follow-up Phase. The primary objective is to assess efficacy of PRO 140 monotherapy for the maintenance of viral suppression following substitution of antiretroviral therapy in patients who are stable on combination antiretroviral therapy. The secondary objective of the trial is to assess the clinical safety and tolerability parameters following substitution of antiretroviral therapy in patients who are stable on combination antiretroviral therapy.

Time to virologic failure after initiating PRO 140 monotherapy. Virologic failure was defined as two (2) consecutive HIV-1 RNA levels of ≥ 400 copies/mL.

Proportion of Participants with Virologic Failure after initiating PRO 140 monotherapy at or prior to Week 14.

Mean change in Viral Load (HIV-1 RNA levels - log 10 copies/ml)), at each visit within the 14-week treatment phase.

Mean Change from Baseline in viral load at the last virologic failure visit from Week 1 to Week 14. VF can occur at any time during the treatment phase from week 1 to week 14. Subjects who experience Virologic Failure will be followed up every 4 weeks until the viral load suppression is achieved (i.e., plasma HIV-1 RNA levels to return back to <50 copies/mL)

Quality of Life Q1 Current General Health Status, is collected from base line to virologic failure (VF can occur at any time from any time during the treatment phase from week 1 to week 14). Subjects who experience Virologic Failure will be followed up every 4 weeks until the viral load suppression is achieved (i.e., plasma HIV-1 RNA levels to return back to <50 copies/mL)

From baseline to virologic failure (VF occurring at any time from Week 1 to Week 12 or virologic failure which ever comes first)

Subjects will rate their current state of health via Visual Analog Scale (VAS) using the line as a guide, with 0 as death or worst possible health and 100 as perfect or best possible health. A higher score indicates best outcome. Subjects may experience Virologic Failure (VF) any time during the treatment phase from week 1 to week 14. Subjects who experience VF will be followed up every 4 weeks until the viral load suppression is achieved (i.e., plasma HIV-1 RNA levels to return back to <50 copies/mL)

Injection site reaction pain assessment @ injection site 1. Each subject received half the total dose of the IP into two separate injection sites. (injection site 1 and injection site 2) at each treatment visit. The information is reported under separate outcomes measures for each injection site.

Injection site reaction pain assessment @ injection site 2. Each subject received half the total dose of the IP into two separate injection sites. (injection site 1 and injection site 2) at each treatment visit. The information is reported under separate outcomes measures for each injection site.

Summary of injection site reaction assessment - Injection site status @ injection site 1. Each subject received half the total dose of the IP into two separate injection sites. (injection site 1 and injection site 2) at each treatment visit. The information is reported under separate outcomes measures for each injection site.

Summary of injection site reaction assessment - Injection site status @ injection site 2. Each subject received half the total dose of the IP into two separate injection sites. (injection site 1 and injection site 2) at each treatment visit. The information is reported under separate outcomes measures for each injection site.

Summary of injection site reaction assessment - Pruritus with injection @Site 1. Each subject received half the total dose of the IP into two separate injection sites. (injection site 1 and injection site 2) at each treatment visit. The information is reported under separate outcomes measures for each injection site.

Summary of injection site reaction assessment - Pruritus with injection @ Site 2. Each subject received half the total dose of the IP into two separate injection sites. (injection site 1 and injection site 2) at each treatment visit. The information is reported under separate outcomes measures for each injection site.

Summary of injection site reaction assessment - bleeding @ Site 1. Each subject received half the total dose of the IP into two separate injection sites. (injection site 1 and injection site 2) at each treatment visit. The information is reported under separate outcomes measures for each injection site.

Summary of injection site reaction assessment - bleeding @ Site 2. Each subject received half the total dose of the IP into two separate injection sites. (injection site 1 and injection site 2) at each treatment visit. The information is reported under separate outcomes measures for each injection site.

Summary of injection site reaction assessment - drug absorption @ Site 1. Each subject received half the total dose of the IP into two separate injection sites. (injection site 1 and injection site 2) at each treatment visit. The information is reported under separate outcomes measures for each injection site.

Summary of injection site reaction assessment - drug absorption @ Site 2. Each subject received half the total dose of the IP into two separate injection sites. (injection site 1 and injection site 2) at each treatment visit. The information is reported under separate outcomes measures for each injection site.

Summary of injection site pain assessment (VAS) post injection mean change from baseline. Subject-perceived injection site pain was assessed using the Pain Visual Analog Scale (VAS) post study treatment administration assessing average pain. Higher score is worse outcome. Each subject received half the total dose of the IP into two separate injection sites. (injection site 1 and injection site 2) at each treatment visit. The information is reported under separate outcomes measures for each injection site.

Summary of injection site pain assessment (VAS) post injection @ Site 2. Subject-perceived injection site pain was assessed using the Pain Visual Analog Scale (VAS) post study treatment administration assessing average pain. A higher score is a worse outcome. Each subject received half the total dose of the IP into two separate injection sites. (injection site 1 and injection site 2) at each treatment visit. The information is reported under separate outcomes measures for each injection site.

Summary of injection site pain assessment (VAS) pre injection @ Site 1 Subject-perceived injection site pain was assessed using the Pain Visual Analog Scale (VAS) prior to study treatment administration assessing average pain since last treatment. Higher score is a worse outcome. Each subject received half the total dose of the IP into two separate injection sites. (injection site 1 and injection site 2) at each treatment visit. The information is reported under separate outcomes measures for each injection site.

Summary of injection site pain assessment (VAS) pre injection @ Site 2. Subject-perceived injection site pain was assessed using the Pain Visual Analog Scale (VAS) prior to study treatment administration assessing average pain since last treatment. Higher score is a worse outcome. Each subject received half the total dose of the IP into two separate injection sites. (injection site 1 and injection site 2) at each treatment visit. The information is reported under separate outcomes measures for each injection site.

Summary of Pro 140 Concentration. Subjects may experience Virologic Failure (VF) any time during the treatment phase from week 1 to week 14. Subjects who experience VF will be followed up every 4 weeks until the viral load suppression is achieved (i.e., plasma HIV-1 RNA levels to return back to <50 copies/mL).

Inclusion Criteria: Males and females, age ≥18 years Exclusive CCR5-tropic virus at Screening Visit as determined by Trofile™ DNA Assay On stable antiretroviral therapy for last 12 months Subject has two or more potential alternative antiretroviral regimen options to consider. No documented detectable viral loads (HIV-1 RNA <50 copies/ml) within the last 12 months prior to Screening Visit Nadir CD4 cell count of >200 cells/mm3 Exclusion Criteria: CXCR4-tropic virus or dual/mixed tropic (R5X4) virus determined by the Trofile™ DNA Assay at the Screening Visit Hepatitis B infection as manifest by the presence of Hepatitis B surface antigen (HBsAg) Any acquired immune deficiency syndrome (AIDS)-defining illness according to the 1993 Centers for Disease Control and Prevention (CDC) AIDS surveillance definition Prior use of any entry, attachment, CCR5 co-receptor, or fusion inhibitor, including PRO 140. Any other clinical condition that, in the Investigator's judgment, would potentially compromise study compliance or the ability to evaluate safety/efficacy

Chang XL, Reed JS, Webb GM, Wu HL, Le J, Bateman KB, Greene JM, Pessoa C, Waytashek C, Weber WC, Hwang J, Fischer M, Moats C, Shiel O, Bochart RM, Crank H, Siess D, Giobbi T, Torgerson J, Agnor R, Gao L, Dhody K, Lalezari JP, Bandar IS, Carnate AM, Pang AS, Corley MJ, Kelly S, Pourhassan N, Smedley J, Bimber BN, Hansen SG, Ndhlovu LC, Sacha JB. Suppression of human and simian immunodeficiency virus replication with the CCR5-specific antibody Leronlimab in two species. PLoS Pathog. 2022 Mar 31;18(3):e1010396. doi: 10.1371/journal.ppat.1010396. eCollection 2022 Mar.