Antiviral Activity, Safety, and Exposure–Response Relationships of GSK3532795, a Second-Generation Human Immunodeficiency Virus Type 1 Maturation Inhibitor, Administered as Monotherapy or in Combination With Atazanavir With or Without Ritonavir in a Phase 2a Randomized, Dose-Ranging, Controlled Trial (AI468002)

Hwang, Carey; Schürmann, Dirk; Sobotha, Christian; Boffito, Marta; Sevinsky, Heather; Ray, Neelanjana; Ravindran, Palanikumar; Xiao, Hong; Keicher, Christian; Hüser, Andreas; Krystal, Mark; Dicker, Ira B.; Grasela, Dennis M.; Lataillade, Max

doi:10.1093/cid/cix239

Cited by 21 publications

(34 citation statements)

References 18 publications

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“…At the GSK3532795 120 mg and 180 mg doses, efficacy at Week 24 was similar in participants with or without a baseline Gag substitution at position 370. Furthermore, these response rates were similar to EFV and generally corroborate data from the prior proof-of-concept study [ 14 ]. However, participants receiving the GSK3532795 60 mg dose displayed reduced efficacy at Week 24 in the presence of Gag polymorphic variation at position 370.…”

Section: Discussionsupporting

confidence: 88%

“…The second-generation MI, GSK3532795, provided a potent antiviral response in a Phase IIa dose-ranging clinical trial, regardless of the presence of baseline Gag polymorphisms, a notable difference relative to bevirimat [ 14 ]. Based on the findings from this proof-of-concept study, 205891 was conducted to investigate the efficacy, safety, and dose response of GSK3532795.…”

Section: Introductionmentioning

confidence: 99%

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Safety, efficacy, and dose response of the maturation inhibitor GSK3532795 (formerly known as BMS-955176) plus tenofovir/emtricitabine once daily in treatment-naive HIV-1-infected adults: Week 24 primary analysis from a randomized Phase IIb trial

et al. 2018

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GSK3532795 (formerly known as BMS-955176) is a second-generation maturation inhibitor targeting a specific Gag cleavage site between capsid p24 and spacer peptide 1 of HIV-1. Study 205891 (previously AI468038) investigated the efficacy, safety, and dose response of GSK3532795 in treatment-naive, HIV-1-infected participants. Study 205891 (NCT02415595) was a Phase IIb, randomized, active-controlled, double-blind, international trial. Participants were randomized 1:1:1:1 to one of three GSK3532795 arms at doses 60 mg, 120 mg or 180 mg once daily (QD), or to efavirenz (EFV) at 600 mg QD, each in combination with tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) (300/200 mg QD). Primary endpoint was proportion of participants with plasma HIV-1 RNA <40 copies/mL at Week 24. Between May 2015 and May 2016, 206 participants received treatment. At Week 24, 76–83% participants receiving GSK3532795 and 77% receiving EFV achieved HIV-1 RNA <40 copies/mL. Fifteen participants receiving GSK3532795 and one receiving EFV met resistance testing criteria; 10/15 receiving GSK3532795 had emergent substitutions at reverse transcriptase positions M184, and one at position K65, while the participant receiving EFV did not have any nucleoside reverse transcriptase inhibitor (NRTI)/non-NRTI mutations. EFV, relative to GSK3532795, had more serious adverse events (9% versus 5%) and adverse events leading to discontinuation (17% versus 5%). However, 3–4-fold higher rates of gastrointestinal adverse events were observed with GSK3532795 relative to EFV. GSK3532795 combined with TDF/FTC is efficacious with 24 weeks of therapy. However, GSK3532795 showed a higher rate of gastrointestinal intolerability and treatment-emergent resistance to the NRTI backbone relative to EFV.Trial registration: ClinicalTrials.gov NCT02415595.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Safety, efficacy, and dose response of the maturation inhibitor GSK3532795 (formerly known as BMS-955176) plus tenofovir/emtricitabine once daily in treatment-naive HIV-1-infected adults: Week 24 primary analysis from a randomized Phase IIb trial

et al. 2018

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“…AI468002 (NCT01803074) was a Phase 2a, randomized, dose-ranging multipart study that investigated GSK3532795 in HIV-1 subtype B- and C-infected individuals [20]. In part A of the study, HIV-1 subtype B-infected individuals received 5–120 mg GSK3532795 (or placebo) once daily (QD, quaque die) for 10 days.…”

Section: Methodsmentioning

confidence: 99%

“…However, higher rates of gastrointestinal intolerability and treatment-emergent resistance to the nucleoside reverse transcriptase inhibitor (NRTI) backbone relative to EFV prevented further development and discontinuation of GSK3532795 [19]. Here we report on the in vitro and clinical genotypic resistance profile of GSK3532795; clinical data were obtained from the Phase 2a clinical study (AI468002) [20].…”

Section: Introductionmentioning

confidence: 99%

Resistance profile of the HIV-1 maturation inhibitor GSK3532795 in vitro and in a clinical study

Dicker¹,

Zhang²,

Ray

et al. 2019

PLoS ONE

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GSK3532795 (formerly BMS955176) is a second-generation maturation inhibitor (MI) that progressed through a Phase 2b study for treatment of HIV-1 infection. Resistance development to GSK3532795 was evaluated through in vitro methods and was correlated with information obtained in a Phase 2a proof-of-concept study in HIV-1 infected participants. Both low and high concentrations of GSK3532795 were used for selections in vitro, and reduced susceptibility to GSK3532795 mapped specifically to amino acids near the capsid/ spacer peptide 1 (SP1) junction, the cleavage of which is blocked by MIs. Two key substitutions, A364V or V362I, were selected, the latter requiring secondary substitutions to reduce susceptibility to GSK3532795. Three main types of secondary substitutions were observed, none of which reduced GSK3532795 susceptibility in isolation. The first type was in the capsid C-terminal domain and downstream SP1 region (including (Gag numbering) R286K, A326T, T332S/N, I333V and V370A/M). The second, was an R41G substitution in viral protease that occurred with V362I. The third was seen in the capsid N-terminal domain, within the cyclophilin A binding domain (V218A/M, H219Q and G221E). H219Q increased viral replication capacity and reduced susceptibility of poorly growing viruses. In the Phase 2a study, a subset of these substitutions was also observed at baseline and some were selected following GSK35323795 treatment in HIV-1-infected participants.

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“…Although high protein binding and poor solubility continue to present challenges for this class of molecules, the second-generation molecules display improvements in these properties relative to BVM. The BVM analog GSK-3532795/BMS-955176, was recently taken into clinical trials with largely favorable outcomes in terms of its ability to suppress viral replication [ 84 , 101 , 102 , 103 ]. However, clinical development of this compound was halted because of gastrointestinal intolerability and the emergence of the SP1-A1V resistance mutation, which is often observed with this class of molecules in vitro [ 103 ].…”

Section: Mis That Block Ca-sp1 Processingmentioning

confidence: 99%

HIV-1 Maturation: Lessons Learned from Inhibitors

Kleinpeter

Freed

2020

Viruses

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Since the emergence of HIV and AIDS in the early 1980s, the development of safe and effective therapies has accompanied a massive increase in our understanding of the fundamental processes that drive HIV biology. As basic HIV research has informed the development of novel therapies, HIV inhibitors have been used as probes for investigating basic mechanisms of HIV-1 replication, transmission, and pathogenesis. This positive feedback cycle has led to the development of highly effective combination antiretroviral therapy (cART), which has helped stall the progression to AIDS, prolong lives, and reduce transmission of the virus. However, to combat the growing rates of virologic failure and toxicity associated with long-term therapy, it is important to diversify our repertoire of HIV-1 treatments by identifying compounds that block additional steps not targeted by current drugs. Most of the available therapeutics disrupt early events in the replication cycle, with the exception of the protease (PR) inhibitors, which act at the virus maturation step. HIV-1 maturation consists of a series of biochemical changes that facilitate the conversion of an immature, noninfectious particle to a mature infectious virion. These changes include proteolytic processing of the Gag polyprotein by the viral protease (PR), structural rearrangement of the capsid (CA) protein, and assembly of individual CA monomers into hexamers and pentamers that ultimately form the capsid. Here, we review the development and therapeutic potential of maturation inhibitors (MIs), an experimental class of anti-HIV-1 compounds with mechanisms of action distinct from those of the PR inhibitors. We emphasize the key insights into HIV-1 biology and structure that the study of MIs has provided. We will focus on three distinct groups of inhibitors that block HIV-1 maturation: (1) compounds that block the processing of the CA-spacer peptide 1 (SP1) cleavage intermediate, the original class of compounds to which the term MI was applied; (2) CA-binding inhibitors that disrupt capsid condensation; and (3) allosteric integrase inhibitors (ALLINIs) that block the packaging of the viral RNA genome into the condensing capsid during maturation. Although these three classes of compounds have distinct structures and mechanisms of action, they share the ability to block the formation of the condensed conical capsid, thereby blocking particle infectivity.

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Cited by 21 publications

References 18 publications

Safety, efficacy, and dose response of the maturation inhibitor GSK3532795 (formerly known as BMS-955176) plus tenofovir/emtricitabine once daily in treatment-naive HIV-1-infected adults: Week 24 primary analysis from a randomized Phase IIb trial

Safety, efficacy, and dose response of the maturation inhibitor GSK3532795 (formerly known as BMS-955176) plus tenofovir/emtricitabine once daily in treatment-naive HIV-1-infected adults: Week 24 primary analysis from a randomized Phase IIb trial

Resistance profile of the HIV-1 maturation inhibitor GSK3532795 in vitro and in a clinical study

HIV-1 Maturation: Lessons Learned from Inhibitors

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