577. Week 48 Results of a Phase 2 Study Evaluating Once-weekly Oral Islatravir Plus Lenacapavir
Authors: Colson Amy E , Crofoot Gordon E , Ruane Peter J , Ramgopal Moti N , Dretler Alexandra W , Nahass Ronald G , Sinclair Gary I , Berhe Mezgebe , Shihadeh Fadi , Liu Shan-Yu , Klopfer Stephanie , Madera Sharline , Dvory-Sobol Hadas , Rhee Martin , Rhee Elizabeth G , Baeten Jared , Eron Joseph J 
Published: January 2025

Abstract

Background
Both islatravir (ISL), a nucleotide reverse transcriptase translocation inhibitor, and lenacapavir (LEN), a capsid inhibitor, have potent anti-HIV-1 activity and pharmacokinetic profiles permitting once-weekly oral dosing. Week (W) 24 data (primary endpoint) from the current Phase 2 study were previously reported (CROI 2024); weekly oral ISL 2 mg + LEN 300 mg maintained high rates of viral suppression (HIV-1 RNA &lt; 50 copies/mL) with no clinically relevant decreases in CD4+ T-cells or lymphocytes, which had been previously observed with higher ISL doses. Here, we report W48 results.Table:Week 48 Virologic Outcome Data by FDA Snapshot AlgorithmaAEs leading to study discontinuation included large intestine perforation and renal colic (n=1); and hepatitis B (n=1).bLast available on-treatment HIV-1 RNA &lt;50 copies/mL.AE, adverse event; B/F/TAF, bictegravir/emtricitabine/tenofovir alafenamide; FDA, Food and Drug Administration; ISL, islatravir; LEN, lenacapavir; W, week.

Methods
In this Phase 2, randomized, open-label, active-controlled study (NCT05052996), virologically suppressed adults on bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) were randomized 1:1 to receive weekly oral ISL 2 mg + LEN 300 mg or to continue daily B/F/TAF. Virologic outcomes (using FDA-defined snapshot algorithm), adverse events (AEs), CD4+ T-cells, and lymphocytes were assessed.

Results
Overall, 104 participants were randomized and dosed; median age (range) was 40 (26–76) years, and 19 (18.3%) were assigned female at birth. At W48, 49/52 (94.2%) participants in the ISL + LEN group had HIV-1 RNA &lt; 50 copies/mL vs 48/52 (92.3%) participants in the B/F/TAF group (Table). No participants had HIV-1 RNA ≥50 copies/mL at W48. The most common AEs in ISL + LEN participants (≥10%) were upper respiratory tract infection (n=7; 13.5%), COVID-19 (n=6; 11.5%), and diarrhea (n=6; 11.5%). No Grade ≥3 AEs, serious AEs, or AEs leading to study drug discontinuation were related to study drug. Two (3.8%) participants discontinued ISL + LEN due to AEs unrelated to study drug (both reported at W24: large intestine perforation and renal colic [n=1]; hepatitis B [n=1]). At W48, there were no significant differences between ISL + LEN vs B/F/TAF groups in mean change from baseline in CD4+ T-cells (–12 vs –29/µL; P=0.88) or lymphocytes (–0.07 vs –0.03 x 103/µL; P=0.23).

Conclusion
Oral weekly ISL + LEN maintained high rates of viral suppression at W48 and was well tolerated. There were no statistically significant between-group differences in CD4+ T-cell or lymphocyte changes. ISL + LEN has the potential to become the first weekly oral complete regimen for the treatment of HIV-1 infection.

Disclosures
Amy E. Colson, Gilead Sciences, Inc.: Advisor/Consultant|ViiV: Honoraria Gordon E. Crofoot, n/a, AbbVie: Grant/Research Support|Gilead Sciences, Inc.: Grant/Research Support|Janssen: Grant/Research Support|Merck: Grant/Research Support|ViiV: Grant/Research Support Peter J. Ruane, n/a, Gilead Sciences, Inc.: Advisor/Consultant|Gilead Sciences, Inc.: Honoraria|ViiV: Advisor/Consultant|ViiV: Honoraria Moti N. Ramgopal, n/a, AbbVie: Honoraria|Gilead Sciences, Inc: Advisor/Consultant|Gilead Sciences, Inc: Honoraria|Merck: Advisor/Consultant|ViiV: Advisor/Consultant|ViiV: Honoraria Alexandra W. Dretler, n/a, AbbVie: Grant/Research Support|Gilead Sciences, Inc.: Grant/Research Support|ViiV: Advisor/Consultant|ViiV: Grant/Research Support Ronald G. Nahass, MD, Abbvie: Honoraria|Arbutus: Grant/Research Support|Gilead Sciences, Inc.: Grant/Research Support|Merck: Grant/Research Support|Vir: Grant/Research Support Gary I. Sinclair, n/a, Abbvie: Advisor/Consultant|Abbvie: Grant/Research Support|Abbvie: Honoraria|Gilead Sciences, Inc.: Advisor/Consultant|Gilead Sciences, Inc.: Grant/Research Support|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Janssen: Honoraria|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Honoraria|Theratechnologies: Advisor/Consultant|Theratechnologies: Grant/Research Support|Theratechnologies: Honoraria|ViiV: Advisor/Consultant|ViiV: Grant/Research Support|ViiV: Honoraria Fadi Shihadeh, n/a, Gilead Sciences, Inc: employee and shareholder Shan-Yu Liu, PhD, Gilead Sciences, Inc.: employee and shareholder Stephanie Klopfer, n/a, Merck & Co., Inc.: subsidiary and shareholder|Merck Sharp & Dohme LLC: employee Sharline Madera, MD, PhD, Gilead Sciences, Inc.: employee and shareholder Hadas Dvory-Sobol, PhD, Gilead Sciences, Inc.: employee and shareholder Martin Rhee, MD, Gilead Sciences, Inc.: employee and shareholder Elizabeth G. Rhee, n/a, Merck & Co., Inc.: subsidiary and shareholder|Merck Sharp & Dohme LLC: employee Jared Baeten, MD, PhD, Gilead Sciences, Inc.: employee and shareholder Joseph J. Eron, MD, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Invivyd: Safety Monitoring Board|Merck & Co: Advisor/Consultant