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BMS-955176

Other Names: BMS-176
Drug Class: Maturation Inhibitors
Registry Number: S900006910 (ChemID)
Company: ViiV Healthcare
Phase of Development: Phase II
Patent Version Content

Pharmacology


Mechanism of Action: Maturation inhibitor. BMS-955176 is a second-generation HIV-1 maturation inhibitor (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.4,5

BMS-955176 has been shown to dissociate slowly from Gag polymorphs known to be resistant to the discontinued first-generation investigational maturation inhibitor bevirimat. This leads BMS-955176 to have improved antiviral activity over bevirimat.4,5

Half-life (T½): In HIV subtype B-infected participants receiving once daily doses of BMS-955176 (5 mg to 120 mg) under fasted conditions over 10 days, the mean half-life of BMS-955176 was approximately 30 to 35 hours and supports once-daily dosing.6

Metabolism/Elimination: BMS-955176 is eliminated primarily via CYP3A4 metabolism, followed by biliary excretion. Renal excretion of BMS-955176 is minor.7,8

Resistance: In vitro, BMS-955176 demonstrates 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). BMS-955176 also shows antiviral activity against mutations conferring resistance to other classes of antiretrovirals (ARVs), including NRTIs, NNRTIs, PIs, and INSTIs. The A364V substitution, however, leads to high-level resistance to BMS-955176.4,5 In vitro, BMS-955176 displays no cross-resistance to other ARV classes.9

A 10-day monotherapy study (NCT01803074) involved once-daily BMS-955176 administered at multiple dose levels ranging from 5 mg to 120 mg to HIV-1, subtype B-infected participants. In this study, BMS-955176 demonstrated similar antiviral activity against both wild-type HIV-1 and HIV-1 with Gag polymorphisms resistant to bevirimat.10,11 In addition, BMS-955176 monotherapy administered at the 40-mg dose level over 10 days in HIV-1, subtype C-infected participants demonstrated potent antiviral activity.12


Clinical Trials


Study Identifiers: AI468-002; NCT01803074
Sponsor: Bristol-Myers Squibb
Phase: IIa
Study Purpose: The purpose of this study was to evaluate the safety and antiviral activity of BMS-955176 administered as monotherapy and administered in combination with atazanavir (with or without ritonavir).
Study Population: The participants were HIV-1-infected (clade B and C), treatment-naive adults or treatment-experienced (but protease inhibitor-naive and maturation inhibitor-naive) adults.
Dosing: AI468-002 was a multipart trial. All doses of BMS-955176 were administered once daily as an oral solution.

Part A: HIV-1 clade B-infected participants were randomized to one of the following four BMS-955176 dose groups: 5 mg, 10 mg, 20 mg, or 40 mg. At a later time, additional participants were randomized to BMS-955176 80 mg and 120 mg. Within each dose group, participants received either BMS-955176 monotherapy or placebo for 10 days.

Part B: HIV-1 clade B-infected participants were randomized to one of the following four groups for 28 days:

  • Tenofovir DF/emtricitabine 300/200 mg + atazanavir 300 mg boosted with ritonavir 100 mg
  • BMS-955176 40 mg + atazanavir 300 mg boosted with ritonavir 100 mg
  • BMS-955176 40 mg + atazanavir 400 mg
  • BMS-955176 80 mg + atazanavir 400 mg

Part C: HIV-1 clade C-infected participants were randomized to receive either BMS-955176 monotherapy (40 mg or 120 mg) or placebo for 10 days.10-14

Selected Study Results:

 

Study Identifiers: AI468-048; NCT02386098
Sponsor: Bristol-Myers Squibb
Phase: IIb
Study Purpose: The purpose of this study is to evaluate the safety and efficacy of BMS-955176 administered in combination with dolutegravir and atazanavir (with or without ritonavir).
Study Population: The participants are HIV-infected, treatment-experienced adults who have evidence of failure of one or two ART regimens that included drugs from two or three different drug classes.
Dosing: Participants will receive one of the following regimens:

  • BMS-955176 120 mg + atazanavir 300 mg boosted with ritonavir 100 mg + dolutegravir 50 mg
  • BMS-955176 120 mg + atazanavir 400 mg + dolutegravir 50 mg
  • BMS-955176 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 will be given once daily over 96 weeks, with the primary outcome analysis at Week 24. BMS-955176 will be administered as an oral tablet.15

* This study is currently recruiting participants.

 

Study Identifiers: AI468-038; NCT02415595
Sponsor: Bristol-Myers Squibb
Phase: IIb
Study Purpose: This is a dose-finding safety and efficacy study of BMS-955176 administered in combination with tenofovir DF/emtricitabine.
Study Population: Participants are HIV-infected, treatment-naive adults with HIV RNA ≥1000 copies/mL and CD4 counts >200 cells/mm3.
Dosing: Participants are randomized to one of the following four groups:

  • BMS-955176 60 mg + BMS-955176 placebo matching 120 mg + efavirenz placebo matching 600 mg + tenofovir DF/emtricitabine 300/200 mg
  • BMS-955176 placebo matching 60 mg + BMS-955176 120 mg + efavirenz placebo matching 600 mg + tenofovir DF/emtricitabine 300/200 mg
  • BMS-955176 60 mg + BMS-955176 120 mg + efavirenz placebo matching 600 mg + tenofovir DF/emtricitabine 300/200 mg
  • BMS-955176 placebo matching 60 mg + BMS-955176 placebo matching 120mg + efavirenz 600 mg + tenofovir DF/emtricitabine 300/200 mg

All doses will be given once daily over 96 weeks, with the primary outcome analysis at Week 24.16

* This study is currently ongoing, but not recruiting participants.

 


Adverse Events


In the Phase IIa, multipart study (NCT01803074), there were no deaths, discontinuations due to an adverse event (AE), or serious AEs reported in the study overall (Parts A, B, and C). In Part A, Grade 1-2 diarrhea was more common in participants receiving BMS-955176 than in participants receiving placebo. The most frequently reported AEs were headache and abnormal dreams in Part A and headache and constipation in Part C.12,13

In Part B, a Grade 3-4 AE occurred in 1 participant receiving BMS-955176 80 mg plus atazanavir 400 mg. Grade 3-4 lab abnormalities occurred in each of the four Part B treatment groups. All of the Grade 3-4 lab abnormalities were attributed to elevated bilirubin levels except one, which was related to neutropenia (occurring in the BMS-955176 80-mg group). Grade 3-4 lab abnormalities were more common in the standard of care tenofovir DF/emtricitabine group (3 out of 4 participants) and in the BMS-955176 40 mg plus atazanavir and ritonavir group (5 out of 8 participants) than in the BMS-955176 groups receiving unboosted atazanavir. Bilirubin levels were lower in participants receiving BMS-955176 plus unboosted atazanavir than in participants receiving BMS-955176 40 mg plus atazanavir and ritonavir or the standard of care tenofovir DF/emtricitabine regimen. The most common AEs occurring in more than 10% of participants across all treatment groups included elevated bilirubin levels, headache, and abnormal dreams.12-14


Drug Interactions


In vitro data indicate that BMS-955176 is a substrate of CYP3A4 and P-gp; it is also a weak inhibitor of CYP3A4, CYP2C8, and UGT1A1.7

The effects of ritonavir or atazanavir co-administered with BMS-955176 (spray-dried dispersion formulation) versus BMS-955176 administered alone were assessed in healthy participants. A single-dose of BMS-955176 40 mg co-administered with two ritonavir 100 mg doses given 12 hours apart increased BMS-955176 Cmax by 11% and AUCinf by 48%. Fourteen days of BMS-955176 40 mg once daily co-administered with atazanavir 400 mg once daily increased BMS-955176 AUCtau by 26%.17

In a multiple-dose pharmacokinetic study between BMS-955176 40 mg once daily (spray-dried dispersion formulation) and tenofovir DF 300 mg once daily in healthy participants, no clinically relevant interactions were seen. Co-administration of BMS-955176 and tenofovir DF at the doses studied does not require dose adjustments.18


References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/S900006910. Last accessed on September 15, 2016.
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Available at: http://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on September 15, 2016.
  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://www.gsk.com/en-gb/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 September 15, 2016.
  4. Nowicka-Sans B, Protack T, Lin Z, et al. BMS-955176: Characterization of a Second-Generation HIV-1 Maturation Inhibitor. Poster presented at: 8th 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 September 15, 2016.
  5. Lin Z, Cantone J, Protack T, et al. Maturation Inhibitor Mechanistic Studies - Understanding and Modeling Differential Inhibition of Gag Polymorphs. Poster presented at: 22nd 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 September 15, 2016.
  6. Sevinsky H, Ravindran P, Vakkalagadda B, et al. HIV-1 Maturation Inhibitor BMS-955176: Pharmacokinetic and Exposure-Response Analysis. Poster presented at: 23rd 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 September 15, 2016.
  7. 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. 17th 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 September 15, 2016.
  8. 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. 17th 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 September 15, 2016.
  9. 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 September 15, 2016.
  10. Hwang C, Schurmann D, Sobotha C, et al. BMS-955176: Antiviral Activity and Safety of a Second-Generation HIV-1 Maturation Inhibitor. 22nd 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 September 15, 2016.
  11. Bristol-Myers Squibb. 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 September 15, 2016.
  12. 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). 15th 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 September 15, 2016.
  13. 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 September 15, 2016.
  14. Hwang C, Schürmann D, Sobotha C, et al. Second-Generation HIV-1 Maturation Inhibitor BMS-955176: Antiviral Activity and Safety with Atazanavir ± Ritonavir. 8th 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 September 15, 2016.
  15. Bristol-Myers Squibb. 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 September 15, 2016.
  16. Bristol-Myers Squibb. 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 September 15, 2016.
  17. 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: 17th 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 September 15, 2016.
  18. 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: 17th 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 September 15, 2016.


Last Reviewed: September 15, 2016