Drugs

GSK3532795

Other Names: BMS-176, BMS-955176 Drug Class: Maturation Inhibitors Registry Number: S900006910 (ChemID) Organization: ViiV Healthcare Phase of Development: Phase IIb (discontinued)

(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 GlaxoSmithKline press release,3 and HIV i-Base website4)

NOTE: The development of GSK3532795 for HIV treatment has been discontinued.


The study of GSK3532795 (formerly BMS-955176) as a maturation inhibitor (MI) HIV medicine was discontinued in 2016. The company developing the drug announced that this decision was based on high rates of gastrointestinal adverse events and treatment-emergent drug resistance observed during the Phase IIb AI468-038 study.4,5


Pharmacology


Mechanism of Action: MI. GSK3532795 is a second-generation HIV-1 MI that binds tightly and reversibly to HIV-1 Gag, inhibiting the final protease-mediated cleavage event at the capsid/spacer peptide 1 (CA/SP1) junction within Gag. Prevention of CA/SP1 separation to p24 (CA) and SP1 results in the release of immature, noninfectious virions.6,7

GSK3532795 has been shown to dissociate slowly from Gag polymorphs known to be resistant to the discontinued first-generation investigational MI bevirimat. Thus, compared to bevirimat, GSK3532795 has improved antiviral activity.6,7

Half-life (T½): In participants with subtype B HIV receiving once daily doses of GSK3532795 (5 mg to 120 mg) under fasted conditions over 10 days, the mean half-life of GSK3532795 was approximately 30 to 35 hours and supports once-daily dosing.8

Metabolism/Elimination: GSK3532795 is eliminated primarily via CYP3A4 metabolism, followed by biliary excretion. Renal excretion of GSK3532795 is minor.9,10

Resistance: GSK3532795 has demonstrated in vitro antiviral activity against subtype B HIV with naturally occurring Gag polymorphisms that are associated with bevirimat resistance (including polymorphisms at positions 362, 369, 370, and 371). GSK3532795 has also shown antiviral activity against mutations conferring resistance to other classes of ARVs, including NRTIs, NNRTIs, PIs, and INSTIs.6,7 In an in vitro selection experiment using MT-2 cells infected with wild-type virus and recombinant virus with Gag polymorphisms, GSK3532795 mainly selected for A364V or V362I mutations in Gag. Certain combinations of changes—secondary mutations R286K, A326T, T332S/N and I333V with V362I or V370A alone or with V362I/V370A—led to reduced GSK3532795 susceptibility relative to wild-type virus. The A364V substitution, arising under GSK3532795 pressure, resulted in high-level resistance.11,12 In vitro, GSK3532795 has not displayed cross-resistance to other ARV classes.13

A Phase IIa study (NCT01803074) evaluated GSK3532795 monotherapy administered once-daily at doses ranging from 5 mg to 120 mg to participants with subtype B HIV-1 for 10 days. In this study, GSK3532795 demonstrated similar antiviral activity against both wild-type HIV-1 and HIV-1 with Gag polymorphisms resistant to bevirimat.14,15 In addition, GSK3532795 administered as monotherapy at the 40-mg and 120-mg dose levels for 10 days demonstrated potent antiviral activity in participants with subtype C HIV-1 and at least 1 Gag polymorphism at baseline.15,16 Treatment-emergent changes in Gag occurred mainly at positions A364 and V362. Suboptimal clinical responses to GSK3532795 were seen in participants having certain baseline double polymorphisms in Gag, such as V362/V370. The clinical response to GSK3532795 was further reduced in participants with the baseline R286K polymorphism in addition to the V362 or V370 baseline Gag polymorphisms.12

A Phase IIb trial (NCT02415595) compared 3 different doses of GSK3532795 to efavirenz with each drug administered with tenofovir DF/emtricitabine. An analysis at Week 24 found that treatment-emergent NRTI resistance developed in 10 out of 153 (6.5%) participants receiving GSK3532795. No participants in the efavirenz group developed NRTI resistance. Among participants receiving GSK3532795, 4 (2.6%) developed treatment-emergent Gag mutations at positions 362 and/or 364. The high rate of NRTI resistance among participants receiving GSK3532795 was one of the reasons that the GSK3532795 clinical development program was discontinued.5,17


Clinical Trials


Study Identifiers: AI468-002; NCT01803074

Sponsor: ViiV Healthcare

Phase: IIa

Status: This study has been completed.

Study Purpose: The purpose of this study was to evaluate the safety and antiviral activity of GSK3532795 monotherapy and GSK3532795 administered with atazanavir (with or without ritonavir).

Study Population: Participants were treatment-naive adults or treatment-experienced (but PI- and MI-naive) adults with subtype B or C HIV. Participants had HIV RNA ≥ 5,000 copies/mL and CD4 counts ≥ 200 cells/mm3.

Dosing: AI468-002 was a multipart trial. All doses of GSK3532795 were administered once daily as an oral solution.

Part A: Participants with subtype B HIV were randomized to 1 of 4 GSK3532795 dose groups: 5 mg, 10 mg, 20 mg, or 40 mg. Later additional participants were randomized to GSK3532795 80 mg and 120 mg dose groups. Within each dose group, participants received either GSK3532795 monotherapy or placebo for 10 days.

Part B: Participants with subtype B HIV were randomized to 1 of 4 groups to receive the following regimens for 28 days:

  • Tenofovir DF/emtricitabine 300/200 mg + atazanavir 300 mg boosted with ritonavir 100 mg
  • GSK3532795 40 mg + atazanavir 300 mg boosted with ritonavir 100 mg
  • GSK3532795 40 mg + atazanavir 400 mg
  • GSK3532795 80 mg + atazanavir 400 mg

Part C: Participants with subtype C HIV were randomized to receive either GSK3532795 monotherapy (40 mg or 120 mg) or placebo for 10 days.14-16,18-20

Selected Study Results:

Study Identifiers: AI468-048; NCT02386098

Sponsor: ViiV Healthcare

Phase: IIb

Status: This study has been terminated.

Study Purpose: The purpose of this open-label study was to evaluate the safety and efficacy of GSK3532795 administered with dolutegravir and atazanavir (with or without ritonavir).

Study Population: Participants were treatment-experienced adults with HIV with documented failure of 1 or 2 ART regimens that included ARVs from 2 or 3 different drug classes. Participants had CD4 counts >50 cells/mm3.

Dosing: Participants received 1 of the following regimens:

  • GSK3532795 120 mg + atazanavir 300 mg boosted with ritonavir 100 mg + dolutegravir 50 mg
  • GSK3532795 120 mg + atazanavir 400 mg + dolutegravir 50 mg
  • GSK3532795 180 mg + atazanavir 400 mg + dolutegravir 50 mg
  • Tenofovir DF 300 mg + atazanavir 300 mg boosted with ritonavir 100 mg + dolutegravir 50 mg

All doses were given once daily over 96 weeks, with the primary outcome analysis at Week 24. GSK3532795 was administered as an oral tablet.21

Study Identifiers: AI468-038; NCT02415595

Sponsor: ViiV Healthcare

Phase: IIb

Status: This study has been terminated.

Study Purpose: This was a dose-finding safety and efficacy study of GSK3532795 administered with tenofovir DF/emtricitabine.

Study Population: Participants were treatment-naive adults with HIV. Participants had HIV RNA ≥1000 copies/mL and CD4 counts >200 cells/mm3.

Dosing: Participants were randomized to 1 of the following 4 groups:
  • GSK3532795 60 mg + tenofovir DF/emtricitabine 300/200 mg
  • GSK3532795 120 mg + tenofovir DF/emtricitabine 300/200 mg
  • GSK3532795 180 mg + tenofovir DF/emtricitabine 300/200 mg
  • Efavirenz 600 mg + tenofovir DF/emtricitabine 300/200 mg

Matching placebos were also administered in each group, and all doses were given once daily. A primary outcome analysis was performed at Week 24.5,17

Selected Study Results:


Adverse Events


AI468-002 (NCT01803074):

In this Phase IIa, 3-part study (A, B, C), 107 participants (Part A = 60; Part B = 28; Part C = 19) were randomized, treated, and completed the study. No deaths, discontinuations due to an adverse event (AE), or serious adverse events (SAEs) were reported during the study. In Parts A and C of the study (GSK3532795 monotherapy), AEs were mild to moderate in intensity and affected a similar proportion of participants receiving GSK3532795 and placebo. The most common AEs were transient headache, abnormal dreams, and night sweats in Part A and headache in Part C. The frequency of diarrhea increased as GSK3532795 doses increased. In Part A, there was 1 Grade 3-4 laboratory abnormality (transient neutropenia) that was considered GSK3532795-related. No cases of elevated bilirubin occurred in participants receiving GSK3532795 monotherapy in Parts A or C.15

In Part B of the Phase IIa trial, AEs were mild to moderate in intensity except for 1 case of neutropenia not related to GSK3532795. The most common study drug-related AEs in Part B were elevated bilirubin, headache, and diarrhea. Ten participants in Part B had Grade 3-4 hyperbilirubinemia with more of the cases reported in participants receiving GSK3532795 plus ritonavir-boosted atazanavir than in those receiving GSK3532795 plus unboosted atazanavir. Median changes in bilirubin levels from baseline were lower in participants receiving unboosted atazanavir than in those receiving ritonavir-boosted atazanavir.15

AI468-038 (NCT02415595):

In this Phase IIb trial comparing 3 different doses of GSK3532795 to efavirenz, each administered with tenofovir DF/emtricitabine, 206 participants were treated (n = 153 GSK3532795 groups; n = 53 efavirenz group). An analysis at Week 24 found that SAEs occurred in 2.0% to 3.8% of participants across the GSK3532795 arms versus in 9.4% of participants in the efavirenz arm. The proportion of participants experiencing an AE that led to study discontinuation was 2.0% to 7.8% across the GSK3532795 groups and 17.0% in the efavirenz group. All the AEs that led to study discontinuation in the GSK3532795 groups were gastrointestinal-related. The rate of treatment-related gastrointestinal disorders of any grade (mostly diarrhea and abdominal pain) was higher in the GSK3532795 groups (42.0% to 60.8%) than in the efavirenz group (13.2%). The high rate of gastrointestinal AEs among participants receiving GSK3532795 was the reason that the GSK3532795 clinical development program was discontinued.5,17


Drug Interactions


In vitro data indicate that GSK3532795 is a substrate of CYP3A4 and P-gp; it is also a weak inhibitor of CYP3A4, CYP2C8, and UGT1A1.9

The effects of ritonavir or atazanavir coadministered with GSK3532795 (spray-dried dispersion formulation) versus GSK3532795 administered alone were assessed in healthy participants. A single-dose of GSK3532795 40 mg coadministered with 2 ritonavir 100 mg doses given 12 hours apart increased GSK3532795 Cmax by 11% and AUCinf by 48%. Fourteen days of GSK3532795 40 mg once daily coadministered with atazanavir 400 mg once daily increased GSK3532795 AUCtau by 26%.22

In a multiple-dose pharmacokinetic interaction study between GSK3532795 40 mg once daily (spray-dried dispersion formulation) and tenofovir DF 300 mg once daily in healthy participants, no clinically relevant interactions were seen. Coadministration of GSK3532795 and tenofovir DF at the doses studied does not require dose adjustments.23


References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/S900006910. Last accessed on November 7, 2017.
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Available at: https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on November 7, 2017.
  3. GlaxoSmithKline: Press Release, dated February 22, 2016. GSK’s global HIV business ViiV Healthcare completes transactions to acquire Bristol-Myers Squibb’s R&D HIV assets. Available at: http://us.gsk.com/en-us/media/press-releases/2016/gsk-s-global-hiv-business-viiv-healthcare-completes-transactions-to-acquire-bristol-myers-squibb-s-randd-hiv-assets/. Last accessed on November 7, 2017.
  4. HIV i-Base website. GSK discontinues development of maturation inhibitor BMS-955176. Available at: http://i-base.info/htb/30865. Last accessed on November 7, 2017.
  5. Morales-Ramirez J, Bogner J, Molina J-M, et al. Safety, efficacy, and dose-response of GSK3532795/BMS-955176 plus tenofovir/emtricitabine in treatment-naive HIV-1-infected adults: Week 24 primary analysis. International AIDS Society (IAS) Conference on HIV Science; July 23–26, 2017; Paris, France. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2017. Available at: http://www.natap.org/2017/IAS/IAS_132.htm. Last accessed on November 7, 2017.
  6. Nowicka-Sans B, Protack T, Lin Z, et al. BMS-955176: characterization of a second-generation HIV-1 maturation inhibitor. Poster presented at: International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention; July 19-22, 2015; Vancouver, Canada. Poster TUPEA078. Available at: http://pag.ias2015.org/PAGMaterial/eposters/1723.pdf. Last accessed on November 7, 2017.
  7. Lin Z, Cantone J, Protack T, et al. Maturation inhibitor mechanistic studies - understanding and modeling differential inhibition of Gag polymorphs. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 23-26, 2015; Seattle, WA. Poster 539. Available at: http://www.croiconference.org/sites/default/files/posters-2015/539.pdf. Last accessed on November 7, 2017.
  8. Sevinsky H, Ravindran P, Vakkalagadda B, et al. HIV-1 maturation inhibitor BMS-955176: pharmacokinetic and exposure-response analysis. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 22-25, 2016; Boston, MA. Poster 425. Available at: http://www.croiconference.org/sites/default/files/posters-2016/425.pdf. Last accessed on November 7, 2017.
  9. Sevinsky H, Chang M, Karkas J, Hawthorne D, Ravindran P, Eley T. Open-label, drug-drug interaction study between second-generation HIV-1 maturation inhibitor BMS-955176 and tenofovir in healthy subjects. International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy; June 8-10, 2016; Washington, DC. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2016. Available at: http://www.natap.org/2016/Pharm/Pharm_46.htm. Last accessed on November 7, 2017.
  10. Sevinsky H, Gandhi Y, Vakkalagadda B, et al. Pharmacokinetics and exploratory interactions of HIV maturation inhibitor BMS-955176 in healthy subjects: single- and multiple-ascending dose studies. International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy; June 8-10, 2016; Washington, DC. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2016. Available at: http://www.natap.org/2016/Pharm/Pharm_47.htm. Last accessed on November 7, 2017.
  11. Dicker I, Nowicka-Sans B, Zhang S, et al. Resistance profile of GSK3532795. Abstract presented at: International AIDS Society (IAS) Conference on HIV Science; July 23–26, 2017; Paris, France. Abstract MOPEB0347. Available at: http://programme.ias2017.org/Abstract/Abstract/3190. Last accessed on November 7, 2017.
  12. Dicker I, Nowicka-Sans B, Zhang S, et al. Resistance profile of HIV-1 maturation inhibitor GSK3532795. Poster presented at: International AIDS Society (IAS) Conference on HIV Science; July 23–26, 2017; Paris, France. Poster MOPEB0347. Available at http://programme.ias2017.org//PAGMaterial/eposters/3190.pdf. Last accessed on November 7, 2017.
  13. Nowicka-Sans B, Protack T, Lin Z, et al. Identification and characterization of BMS-955176, a second-generation HIV-1 maturation inhibitor with improved potency, antiviral spectrum, and Gag polymorphic coverage. Antimicrob Agents Chemother. 2016 Jul; 60(7): 3956–3969. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914680/. Last accessed on November 7, 2017.
  14. Hwang C, Schurmann D, Sobotha C, et al. BMS-955176: antiviral activity and safety of a second-generation HIV-1 maturation inhibitor. Conference on Retroviruses and Opportunistic Infections (CROI); February 23-26, 2015; Seattle, WA. Levin: Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2015. Available at: http://www.natap.org/2015/CROI/croi_36.htm. Last accessed on November 7, 2017.
  15. Hwang C, Schürmann D, Sobotha C, et al. 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). Clin Infect Dis. 2017 Aug 1;65(3):442–452. Available at: https://academic.oup.com/cid/article/65/3/442/3078562/Antiviral-Activity-Safety-and-Exposure-Response. Last accessed on November 7, 2017.
  16. Hwang C, Schürmann D, Sobotha C, et al. Second-generation HIV-1 maturation inhibitor BMS-955176: overall antiviral activity and safety results from the Phase IIa proof-of-concept study (AI468002). European AIDS Conference (EACS); October 21-24, 2015; Barcelona, Spain. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2015. Available at: http://www.natap.org/2015/EACS/EACS_09.htm. Last accessed on November 7, 2017.
  17. ViiV Healthcare. A Phase 2b randomized, active-controlled, double-blind trial to investigate safety, efficacy, and dose-response of BMS-955176, given on a backbone of tenofovir/emtricitabine, in treatment-naive HIV-1 infected adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 11, 2015. NLM Identifier: NCT02415595. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02415595. Last accessed on November 7, 2017.
  18. ViiV Healthcare. Randomized, placebo-controlled, multiple-dose study to evaluate the pharmacodynamics, safety and pharmacokinetics of BMS-955176 (double-blinded) and BMS-955176 with atazanavir +/- ritonavir (open-labeled) in HIV-1 infected subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 1, 2013. NLM Identifier: NCT01803074. Available at: https://clinicaltrials.gov/ct2/show/NCT01803074. Last accessed on November 7, 2017.
  19. Bristol-Myers Squibb: Press Release, dated October 23, 2015. Complete Phase 2a study of HIV-1 investigational maturation inhibitor demonstrates positive results for therapy designed to attack virus differently than existing treatments. Available at: http://news.bms.com/press-release/complete-phase-2a-study-hiv-1-investigational-maturation-inhibitor-demonstrates-positi. Last accessed on November 7, 2017.
  20. Hwang C, Schürmann D, Sobotha C, et al. Second-generation HIV-1 maturation inhibitor BMS-955176: antiviral activity and safety with atazanavir ± ritonavir. International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention; July 19-22, 2015; Vancouver, Canada. Levin: Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2015. Available at: http://www.natap.org/2015/IAS/IAS_25.htm. Last accessed on November 7, 2017.
  21. ViiV Healthcare. A Phase 2b randomized, active-controlled, staged, open-label trial to investigate safety and efficacy of BMS-955176 in combination with dolutegravir and atazanavir (with or without ritonavir) in treatment-experienced HIV-1 infected adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 6, 2015. NLM Identifier: NCT02386098. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02386098. Last accessed on November 7, 2017.
  22. Sevinsky H, Gandhi Y, Vakkalagadda B, et al. Pharmacokinetics and exploratory interactions of HIV maturation inhibitor BMS-955176 in healthy subjects: single- and multiple-ascending dose studies. Abstract presented at: International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy; June 8-10, 2016; Washington, DC. Abstract P_63. Available at: http://regist2.virology-education.com/Abstractbook/2016_6.pdf. Last accessed on November 7, 2017.
  23. Sevinsky H, Chang M, Karkas J, Hawthorne D, Ravindran P, Eley T. Open-label, drug-drug interaction study between second-generation HIV-1 maturation inhibitor BMS-955176 and tenofovir in healthy subjects. Abstract presented at: International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy; June 8-10, 2016; Washington, DC. Abstract P_50. Available at: http://regist2.virology-education.com/Abstractbook/2016_6.pdf. Last accessed on November 7, 2017.


Last Reviewed: December 6, 2017