GS CA1 / Gilead - LARVOL DELTA

Lenacapavir: A Twice-Yearly Injectable for HIV Preexposure Prophylaxis. (PubMed, Ann Pharmacother) - "Lenacapavir provides a long-acting injectable option for people seeking a pharmacologic prevention agent against HIV-1. Despite injection-site reactions being relatively common, these did not present a barrier to treatment continuation among trial participants."

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

HIV-1 capsid stability and reverse transcription are finely balanced to minimize sensing of reverse transcription products via the cGAS-STING pathway. (PubMed, mBio) - "At low concentrations that allowed the accumulation of reverse transcription products, CA-targeting compounds GS-CA1 and lenacapavir measurably impacted CA lattice stability in cells and modestly enhanced innate immune sensing of HIV. Unexpectedly, due to increased levels of reverse transcription and cytosolic accumulation of the resulting viral cDNA, capsid mutants with hyperstable cores also resulted in the potent induction of type I interferon-mediated innate immunity. Our findings suggest that HIV-1 capsid lattice stability and reverse transcription are finely balanced to minimize exposure of reverse transcription products in the cytosol of host cells."

Journal • Human Immunodeficiency Virus • Infectious Disease • STING

GS-CA1 and lenacapavir stabilize the HIV-1 core and modulate the core interaction with cellular factors. (PubMed, iScience) - "GS-CA1 stabilized the HIV-1 core, possibly by inducing a conformational shift in the core; in agreement, HIV-1 cores bearing N74D regained their ability to bind CPSF6 in the presence of GS-CA1. We showed that GS-CA1 binds to the HIV-1 core, changes its conformation, stabilizes the core, and thereby prevents viral uncoating and infection."

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

Long Acting Capsid Inhibitor Protects Macaques From Repeat SHIV Challenges. (PubMed, Nature) - "Pharmacokinetic analysis showed a correlation between GS-CA1 plasma concentration and protection from SHIV challenges, with GS-CA1 levels >2-fold the rhesus plasma protein-adjusted 95% effective concentration conferring 100% protection in this model. These proof-of-concept data support the development of capsid inhibitors as a novel long-acting PrEP strategy in humans."

Journal • Human Immunodeficiency Virus • Infectious Disease

[VIRTUAL] Long-acting capsid inhibitor effective as PrEP against vaginal SHIV transmission in macaques (IAS-HIV 2021) - "These preclinical data demonstrate that a long-acting GS-CA1 formulation can effectively protect against vaginal SHIV transmission in nonhuman primates and together with the rectal challenge study results support the clinical development of lenacapavir for HIV prevention in both males and females."

Late-breaking abstract • Human Immunodeficiency Virus

[VIRTUAL] LONG-ACTING HIV CAPSID INHIBITOR EFFECTIVE AS PrEP IN A SHIV RHESUS MACAQUE MODEL (CROI 2021) - "Lenacapavir (LEN), an investigational small molecule inhibitor of HIV capsid function with picomolar antiviral potency and long-acting subcutaneous (s.c.) dosing potential (twice yearly), is in clinical development for HIV treatment. These preclinical data provide a proof of concept for the prophylactic efficacy of a long-acting capsid inhibitor in a nonhuman primate SHIV challenge model and support the clinical development of LEN for HIV prevention."

Late-breaking abstract • Human Immunodeficiency Virus • Infectious Disease

Advances in Long-Acting Agents for the Treatment of HIV Infection. (PubMed, Drugs) - "This review provides an outline of the current landscape of long-acting antiretroviral therapy for HIV treatment, both approved and under development, including cabotegravir, rilpivirine, leronlimab, islatravir, albuvirtide, GS-6207, and broadly neutralizaing antibodies. However, there are a number of research gaps for long-acting antiretroviral therapy including issues regarding resistance and understudied populations, and this review highlights some of the challenges that will need to be addressed for clinical implementation of these novel treatment modalities."

Journal • Fatigue • Gene Therapies • Human Immunodeficiency Virus • Immunology • Infectious Disease • Long-acting Reversible Contraceptives • Psychiatry

[VIRTUAL] Novel ART compounds (HIV-Glasgow 2020) - "The author will review the clinical data presented in 2020 on the most advanced novel compounds in the pipeline such as islatravir and lenacapavir and explore the mode of delivery, frequency and possible partner compounds for these drugs. As science advances, new questions of social justice evolve around when, where, how and to whom we offer these drugs. These must be considered in parallel with drug development to ensure that people with HIV remain at the heart of all we do."

Human Immunodeficiency Virus • Infectious Disease

[VIRTUAL] DOSE-RESPONSE RELATIONSHIP OF SUBCUTANEOUS LONG-ACTING HIV CAPSID INHIBITOR GS-6207 (CROI 2020) - "One participant experienced a serious AE (Grade 3) of atrial fibrillation after using methamphetamine; no other SAEs, Grade 3 or 4 AEs, AEs leading to discontinuation, or clinically relevant Grade 3 or 4 laboratory abnormalities were reported. In PLWH, GS-6207 demonstrated potent antiviral activity, with up to a 2.2 log10 copies/mL decline at Day 10, and was generally safe and well tolerated. These results support further clinical evaluation of GS-6207 as a long-acting antiretroviral agent."

Atrial Fibrillation • Cardiovascular • Human Immunodeficiency Virus • Infectious Disease

DOSE-RESPONSE RELATIONSHIP OF SUBCUTANEOUS LONGACTING HIV CAPSID INHIBITOR GS-6207 (CROI 2020) - No abstract available

Gene Therapies • Infectious Disease

[VIRTUAL] Lenacapavir resistance analysis in a phase Ib clinical proof-of-concept study (HIV-Glasgow 2020) - "Overall, emergence of resistance to LEN was rare and only occurred well below exposures expected to be achieved in PhII/III studies, with the emergence of a single mutation Q67H. Notably, previous in vitro characterization identified that Q67H mutation had the least impact on fitness and susceptibility to LEN, which may explain its emergence at lower LEN exposures. These results support further evaluation of LEN as a long-acting antiretroviral agent in PLWH."

Clinical • P1 data • Human Immunodeficiency Virus • Infectious Disease

[VIRTUAL] Lenacapavir resistance analysis in a phase Ib clinical proof-of-concept study (HIV-Glasgow 2020) - No abstract available

Clinical • P1 data

Single doses of long-acting capsid inhibitor GS-6207 administered by subcutaneous injection are safe and efficacious in people living with HIV (EACS 2019) - "These preliminary data demonstrate proof-of-concept for in vivo antiviral activity via capsid inhibition. Following a single SC dose, potent antiviral activity was observed in all participants who received GS-6207 at 50, 150, or 450 mg through D10. GS-6207 was generally safe and well tolerated."

Gene Therapies • Infectious Disease

Single doses of long-acting capsid inhibitor GS-6207 administered by subcutaneous injection are safe and efficacious in people living with HIV (EACS 2019) - "These preliminary data demonstrate proof-of-concept for in vivo antiviral activity via capsid inhibition. Following a single SC dose, potent antiviral activity was observed in all participants who received GS-6207 at 50, 150, or 450 mg through D10. GS-6207 was generally safe and well tolerated."

Gene Therapies • Infectious Disease

Single doses of long-acting capsid inhibitor GS-6207 administered by subcutaneous injection are safe and efficacious in people living with HIV (EACS 2019) - "These preliminary data demonstrate proof-of-concept for in vivo antiviral activity via capsid inhibition. Following a single SC dose, potent antiviral activity was observed in all participants who received GS-6207 at 50, 150, or 450 mg through D10. GS-6207 was generally safe and well tolerated."

Gene Therapies • Infectious Disease

Off-Pathway Assembly: A Broad-Spectrum Mechanism of Action for Drugs That Undermine Controlled HIV-1 Viral Capsid Formation. (PubMed, J Am Chem Soc) - "Intriguingly, a few CIs, such as PF-3450074 (PF74) and GS-CA1, exhibit effects at multiple stages of the viral lifecycle at effective concentrations in the pM to nM regimes, while the majority of CIs target a single stage of the viral lifecycle and are effective at nM to μM concentrations...Two relevant phenotypes are observed: (1) eccentric capsid formation that may fail to encase the viral genome and (2) rapid disassembly of the capsid, which express at late and early stages of infection, respectively. Finally, our study emphasizes the importance of adopting a dynamical perspective on inhibitory mechanisms and provides a basis for the design of future therapeutics that are effective at low stoichiometric ratios of drug to protein."

Journal • Human Immunodeficiency Virus • Immunology • Infectious Disease

Cell type-dependent escape of capsid inhibitors by simian immunodeficiency virus SIVcpz. (PubMed, J Virol) - "The related Pan troglodytes schweinfurthii is the host of a similar virus, SIVcpzPts, which did not spread to humans.We tested these viruses with small-molecule capsid inhibitors (PF57, PF74, and GS-CA1) that interact with a binding groove in the capsid that is also used by CPSF6...Cyclosporin A treatment, mutating the CYPA-binding loop in the capsid or CYPA-knockout eliminated SIVcpzPts' resistance to PF74 in HeLa cells...These results indicate that early cytoplasmic infection events of SIVcpzPts may differ between cell types and affect, in an unknown manner, the antiviral activity of capsid inhibitors. Thus, capsid inhibitors depend on the activity or interaction of currently uncharacterized cellular factors."

Journal • Immunology • Infectious Disease

[VIRTUAL] Targeting HIV capsid assembly by long-acting small molecule modulators (ACS-Fall 2020) - "GS-6207 is currently in Phase II clinical trials as first-in-class HIV capsid inhibitor. This small molecule disrupts capsid functions and it is suitable to long-acting therapy due to its superb antiviral potency, low in vivo clearance and slow drug release kinetics. This talk will highlight some of the structure-based modeling and crystallography efforts that went into our HIV capsid inhibitor discovery program, helping to optimize the antiviral activities and to understand the MOA."

Human Immunodeficiency Virus • Infectious Disease

[VIRTUAL] Targeting HIV capsid assembly by long-acting small molecule modulators (ACS-Fall 2020) - "GS-6207 is currently in Phase II clinical trials as first-in-class HIV capsid inhibitor. This small molecule disrupts capsid functions and it is suitable to long-acting therapy due to its superb antiviral potency, low in vivo clearance and slow drug release kinetics. This talk will highlight some of the structure-based modeling and crystallography efforts that went into our HIV capsid inhibitor discovery program, helping to optimize the antiviral activities and to understand the MOA."

Human Immunodeficiency Virus • Infectious Disease

Study to Evaluate the Safety and Efficacy of Lenacapavir in Combination With Other Antiretroviral Agents in People Living With HIV (clinicaltrials.gov) - P2; N=175; Recruiting; Sponsor: Gilead Sciences; Trial primary completion date: Jul 2021 ➔ Oct 2021

Clinical • Combination therapy • Trial primary completion date • Gene Therapies • Human Immunodeficiency Virus • Infectious Disease

Safety, Pharmacokinetics, and Antiviral Activity of Lenacapavir Administered Subcutaneously in HIV-1 Infected Adults (clinicaltrials.gov) - P1b; N=53; Completed; Sponsor: Gilead Sciences; Active, not recruiting ➔ Completed

Clinical • Trial completion • Gene Therapies • Human Immunodeficiency Virus • Infectious Disease

[VIRTUAL] GS-6207 sustained delivery formulation supports 6-month dosing interval (AIDS 2020) - No abstract available

Study to Evaluate the Safety and Efficacy of GS-6207 in Combination With Other Antiretroviral Agents in People Living With HIV (clinicaltrials.gov) - P2; N=175; Recruiting; Sponsor: Gilead Sciences; Trial primary completion date: Apr 2021 ➔ Jul 2021

Clinical • Combination therapy • Trial primary completion date

Frequency of capsid substitutions associated with GS-6207 in vitro resistance in HIV-1 from antiretroviral-naive and -experienced patients. (PubMed, J Antimicrob Chemother) - "Out of the seven HIV capsid substitutions previously selected in vitro and shown to confer phenotypic resistance to GS-6207, none of these seven mutations was observed in this large dataset, suggesting that neither PLWH with previous PI failure nor PLWH with emergence of PI resistance mutations are anticipated to impact GS-6207 activity in these diverse HIV-infected populations."

Journal

[VIRTUAL] ABSENCE OF GS-6207 PHENOTYPIC RESISTANCE IN HIV Gag CLEAVAGE SITE AND OTHER MUTANTS (CROI 2020) - "Finally, the activity of GS-6207 was not affected by the presence of resistance mutations to the 4 main ARV classes. These data support the evaluation of GS-6207 in PLWH with multi-class resistance."