GS-1720 / 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

In Vitro Resistance Profile for GS-1720, a Potent Once-Weekly Oral InSTI in Clinical Development (CROI 2025) - "Results GS-1720 retained potent antiviral activity, defined as an EC50 fold-change (FC) 300, 140 and 119 days in culture, respectively...In a fixed-dose viral breakthrough assay, clinically relevant concentrations of GS-1720 or BIC prevented viral breakthrough while EVG and raltegravir, when tested at their equivalent clinical trough plasma concentrations, showed breakthrough with resistance in 45% and 18% of PBMC cultures (n=44-48/condition), respectively. Conclusions GS-1720 exhibits an in vitro resistance profile comparable to the best-in-class INSTI bictegravir, including high barrier to resistance and minimal cross-resistance within the INSTI class. These observations support the ongoing clinical development of GS-1720 as a novel once-weekly oral INSTI."

Preclinical • Human Immunodeficiency Virus • Infectious Disease

(H-01) HIV Resistance to bNAbs, Cabotegravir, GS 1720, and Other Agents (CROI 2025) - No abstract available

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

Pharmacokinetic/pharmacodynamic and resistance analyses of GS‐1720, a once‐weekly oral integrase strand transfer inhibitor (HIV-Glasgow 2024) - "GS-1720 showed robust antiviral activity with D11 concentrations above IQ2. There were no observed cases of treatment-emergent IN resistance, including participants with low GS-1720 concentrations. The robust pharmacokinetics/pharmacodynamics data and lack of resistance support further clinical development and dose selection for GS-1720."

PK/PD data • 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

Pharmacokinetics and Safety of GS-1720 Following Multiple Ascending Doses in a Phase 1a Study in People Without HIV-1 (IDWeek 2024) - No abstract available

Clinical • P1 data • PK/PD data • 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

Nonclinical pharmacology profile of GS-1720, a novel highly potent once-weekly oral HIV-1 integrase strand transfer inhibitor in clinical development (AIDS 2024) - "When tested against a panel of INSTI-resistant HIV-1 mutants, the EC50 fold-change range relative to wild-type virus for GS-1720, bictegravir, and elvitegravir was 0.9 to 8.5, 0.6 to 4.0, and 5.1 to >86, respectively...GS-1720 demonstrated no antiviral antagonism when combined with other antiretrovirals, including lenacapavir, and showed no activity against HBV, HCV, HSV-2 or SARS-CoV-2 and low cytotoxicity in all tested human cell types. GS-1720 is a novel oral INSTI with significantly improved antiviral potency compared to bictegravir and a similar nonclinical virology, pharmacology and safety profile. Overall, these data support the ongoing clinical development of GS-1720 as a component of a novel once-weekly oral regimen for HIV-1 treatment."

Clinical • Human Immunodeficiency Virus • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • CD4

Phase 1a safety and pharmacokinetics of single ascending doses of oral GS-1720 in people without HIV-1 (AIDS 2024) - "GS-1720 was well tolerated across the doses tested and exhibited a nonlinear PK with a half-life supportive of once-weekly oral dosing. The emerging safety and PK data from this study were used to inform dose selection for Phase 1b and Phase 2 studies."

Clinical • P1 data • PK/PD data • Fatigue • Human Immunodeficiency Virus • Infectious Disease

Study of Novel Antiretrovirals in Participants With HIV-1 (clinicaltrials.gov) - P1 | N=49 | Completed | Sponsor: Gilead Sciences | Active, not recruiting ➔ Completed | Trial completion date: Mar 2027 ➔ Mar 2024 | Trial primary completion date: Mar 2027 ➔ Mar 2024

Trial completion • Trial completion date • Trial primary completion date • Human Immunodeficiency Virus • Infectious Disease • CD4

Study of Novel Antiretrovirals in Participants With HIV-1 (clinicaltrials.gov) - P1 | N=49 | Active, not recruiting | Sponsor: Gilead Sciences | Recruiting ➔ Active, not recruiting | N=110 ➔ 49 | Trial completion date: Dec 2024 ➔ Mar 2027 | Trial primary completion date: Dec 2024 ➔ Mar 2027

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Human Immunodeficiency Virus • Infectious Disease • CD4

Study of Novel Antiretrovirals in Participants With HIV-1 (clinicaltrials.gov) - P1 | N=110 | Recruiting | Sponsor: Gilead Sciences | Trial completion date: May 2024 ➔ Dec 2024 | Trial primary completion date: May 2024 ➔ Dec 2024

Trial completion date • Trial primary completion date • Human Immunodeficiency Virus • Infectious Disease • CD4

Antiviral Activity, Safety, and Pharmacokinetics of GS-1720: A Novel Weekly Oral InSTI (CROI 2024) - "GS-1720 demonstrated potent antiviral activity and PK supportive of once weekly oral dosing while being well-tolerated. The observed >2 log…10 copies/mL decline in HIV-1 RNA and half-life >1 week in this cohort demonstrates the potential of GS-1720 as part of an oral weekly INSTI-based regimen."

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

Study of Novel Antiretrovirals in Participants With HIV-1 (clinicaltrials.gov) - P1 | N=110 | Recruiting | Sponsor: Gilead Sciences | Phase classification: P1b ➔ P1

Phase classification • Human Immunodeficiency Virus • Infectious Disease • CD4