lenacapavir pro-drug (GS‑4182) / Gilead - LARVOL DELTA

Standardisation of monitoring routines for new long-acting antiretrovirals in development. (PubMed, Lancet HIV) - "The US Food and Drug Administration's clinical hold on Gilead Sciences' once-weekly combination of GS-1720 and GS-4182 due to unexpected CD4 T-cell and lymphocyte count declines represents a key safety signal in long-acting HIV therapy development. This event parallels the earlier islatravir trials, in which similar immunological effects led to a downsized development programme with lower doses of the drug...As GS-4182 is a prodrug that converts to lenacapavir, the parent compound warrants careful evaluation, particularly given lenacapavir's anticipated widespread use for HIV prevention...Future trials should implement standardised monitoring protocols with individual participant trajectories, predefined decline thresholds, and clear discontinuation criteria. As long-acting antiretroviral therapy advances, maintaining rigorous immunological surveillance becomes essential to balance dosing convenience against potential immunological risks."

Journal • Review • Human Immunodeficiency Virus • Infectious Disease • CD4

FDA slaps clinical hold on multiple Gilead HIV combo therapy trials, shares fall (FierceBiotech) - "Gilead has been hit with a clinical hold from the FDA for five tests of its experimental HIV combination treatment amid safety concerns...the California Big Pharma said trials of GS-1720, an investigational integrase strand transfer inhibitor, and/or GS-4182, an investigational capsid inhibitor, had been put on a full FDA hold. The drugs had been in two phase 2/3 tests known as WONDERS-1 and WONDERS-2, as well as three earlier phase 1 studies...The hold comes after “the identification of a safety signal of decreases in CD4+T-cell (CD4) and absolute lymphocyte counts in a subset of participants receiving the combination of GS-1720 and GS-4182,” Gilead said in its statement."

FDA event • Trial suspension • Human Immunodeficiency Virus • Infectious Disease

Study of Oral Weekly GS-1720 and GS-4182 Compared With Biktarvy in People With HIV-1 Who Have Not Been Treated (clinicaltrials.gov) - P2/3 | N=675 | Active, not recruiting | Sponsor: Gilead Sciences | Recruiting ➔ Active, not recruiting

Enrollment closed • Human Immunodeficiency Virus • Infectious Disease

Study of Oral Weekly GS-1720 and GS-4182 Versus Biktarvy in People With HIV-1 Who Are Virologically Suppressed (clinicaltrials.gov) - P2/3 | N=675 | Active, not recruiting | Sponsor: Gilead Sciences | Recruiting ➔ Active, not recruiting

Enrollment closed • Human Immunodeficiency Virus • Infectious Disease

Effect of acid‐reducing agents on the pharmacokinetics of oral GS‐4182 (HIV-Glasgow 2024) - "LEN exposure with and without esomeprazole Plasma LEN PK parameter GS-4182 400 mg + esomeprazole 40 mg (n = 12) GS-4182 400 mg (reference cohort) (n = 9) GLSM ratio, % (90% CI) Geometric mean AUC0-168h (%GCV), hour*ng/ml 6080 (45.1) 4810 (85.1) 126% (81.2−197) Geometric mean Cmax (%GCV), ng/ml 50.7 (54.4) 44.7 (141) 113% (62.5−206) Median Tmax (Q1, Q3), hours 12.0 (10.0, 48.0) 12.0 (4.0, 24.1) − Abbreviations: AUC0-168h, area under the concentration versus time curve from 0 to 168 hours; Cmax, maximum observed concentration; CI, confidence interval; GCV, geometric coefficient of variation; GLSM, geometric-least squares means; LEN, lenacapavir; PK, pharmacokinetics; Tmax, time to maximum concentration. LEN exposure following a single oral dose of GS-4182 400 mg was similar with and without esomeprazole coadministration. Therefore, GS-4182 could be administered without regard to ARA use."

PK/PD data • Gastrointestinal Disorder • Human Immunodeficiency Virus • Infectious Disease

Study of Oral Weekly GS-1720 and GS-4182 Compared With Biktarvy in People With HIV-1 Who Have Not Been Treated (clinicaltrials.gov) - P2/3 | N=675 | Recruiting | Sponsor: Gilead Sciences | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Human Immunodeficiency Virus • Infectious Disease

Study of Oral Weekly GS-1720 and GS-4182 Compared With Biktarvy in People With HIV-1 Who Have Not Been Treated (clinicaltrials.gov) - P2/3 | N=675 | Not yet recruiting | Sponsor: Gilead Sciences

Combination therapy • New P2/3 trial • Human Immunodeficiency Virus • Infectious Disease

Study of Oral Weekly GS-1720 and GS-4182 Versus Biktarvy in People With HIV-1 Who Are Virologically Suppressed (clinicaltrials.gov) - P2/3 | N=675 | Recruiting | Sponsor: Gilead Sciences | Not yet recruiting ➔ Recruiting

Enrollment open • Human Immunodeficiency Virus • Infectious Disease

Study of Oral Weekly GS-1720 and GS-4182 Versus Biktarvy in People With HIV-1 Who Are Virologically Suppressed (clinicaltrials.gov) - P2/3 | N=675 | Not yet recruiting | Sponsor: Gilead Sciences

Combination therapy • New P2/3 trial • Human Immunodeficiency Virus • Infectious Disease

Safety and pharmacokinetic profile of single and multiple ascending doses of GS-4182, an oral prodrug of lenacapavir, in participants without HIV-1 (AIDS 2024) - "GS-4182 demonstrated favorable LEN PK, with LEN exposure following oral GS-4182 600 mg administration approximately double compared with the equivalent dose of oral LEN. GS-4182 was well tolerated with a favorable safety profile, supporting its further development as a QW oral agent for HIV-1 treatment."

Clinical • PK/PD data • Human Immunodeficiency Virus • Infectious Disease

Nonclinical profile of GS-4182, a once-weekly oral prodrug of the HIV-1 capsid inhibitor lenacapavir in clinical development (AIDS 2024) - "LEN prodrug GS-4182 exhibits a favorable nonclinical profile that supports its continued clinical development as a component of an optimized once-weekly oral regimen for the treatment of HIV-1 infection."

Clinical • Gastrointestinal Disorder • Human Immunodeficiency Virus • Infectious Disease