Drugs

GSK3532795

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.

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

The study of GSK3532795 as a maturation inhibitor for HIV treatment was discontinued in 2016. The company developing GSK3532795 based this decision on the high rate of diarrhea, abdominal pain, and other gastrointestinal disorders among participants receiving GSK3532795 in a study of the drug.4,18

What is an investigational drug?

What is an investigational drug?

An investigational drug is one that is under study and is not approved by the U.S. Food and Drug Administration (FDA) for sale in the United States. Medical research studies are conducted to evaluate the safety and effectiveness of an investigational drug. These research studies are also called clinical trials. Once an investigational drug has been proven safe and effective in clinical trials, FDA may approve the drug for sale in the United States.

To learn more about investigational drugs, read the AIDSinfo What is an Investigational HIV Drug? fact sheet.

What is GSK3532795?

What is GSK3532795?

GSK3532795 is an investigational drug that has been studied for the treatment of HIV infection.

GSK3532795 belongs to a class (group) of HIV drugs called maturation inhibitors.2 Maturation inhibitors act during the last step of the HIV life cycle to prevent HIV from multiplying and infecting other cells.

At the beginning of the last step in the HIV life cycle, the newly formed HIV particles are still immature and can't infect other cells in the body. In this form, HIV has long chains of proteins that need to be cut into smaller proteins. The smaller HIV proteins can then combine to form mature HIV that is capable of infecting other cells. An HIV enzyme called protease breaks up the long protein chains into the smaller HIV proteins. (An enzyme is a protein that starts or increases the speed of a chemical reaction.)

Maturation inhibitors bind to a specific long HIV protein chain called Gag. This binding blocks protease from breaking up the Gag protein chain into smaller HIV proteins. Without the smaller HIV proteins, HIV cannot change into its mature, infectious form. Instead, HIV remains immature and not infectious, preventing the virus from multiplying and reducing the amount of HIV in the body.5-7

The very first maturation inhibitor that was tested in clinical trials was called bevirimat. Bevirimat did not work well on HIV that had certain naturally occurring genetic variations, which are also called polymorphisms. In vitro studies have shown that GSK3532795 works better than bevirimat against some types of HIV with certain polymorphisms. (In vitro studies are studies done in test tubes or other laboratory equipment and not on animals or humans.)8-11

How are clinical trials of investigational drugs conducted?

How are clinical trials of investigational drugs conducted?

Clinical trials are conducted in phases. Each phase has a different purpose and helps researchers answer different questions.12

  • Phase I trials: Researchers test an investigational drug in a small group of people (20–80) for the first time. The purpose is to evaluate its safety and identify side effects.
  • Phase II trials: The investigational drug is administered to a larger group of people (100–300) to determine its effectiveness and to further evaluate its safety.
  • Phase III trials: The investigational drug is administered to large groups of people (1,000–3,000) to confirm its effectiveness, monitor side effects, compare it with standard or equivalent treatments, and collect information that will allow the investigational drug to be used safely.12

In most cases, an investigational drug must be proven effective and must show continued safety in a Phase III clinical trial to be considered for approval by FDA for sale in the United States. Some drugs go through FDA’s accelerated approval process and are approved before a Phase III clinical trial is complete. After a drug is approved by FDA and made available to the public, researchers track its safety in Phase IV trials to seek more information about the drug’s risks, benefits, and optimal use.12

Some clinical trials are categorized as “a” or “b,” such as “Phase Ia” or “Phase IIb.” These different subphases typically mean that a study is researching certain types of information or using a certain type of participant population.

In what phase of testing is GSK3532795?

In what phase of testing is GSK3532795?

GSK3532795 was being studied in Phase IIb clinical trials, but the study was terminated and development of the drug for HIV treatment discontinued.4

What are some studies on GSK3532795?

What are some studies on GSK3532795?

Study Names: AI468-002; NCT01803074
Sponsor: ViiV Healthcare
Phase: IIa
Status: This study has been completed.
Location: Germany
Participants:

  • Participants were adults with subtype B HIV and subtype C HIV.
  • Some participants had never taken HIV medicines before entering the study. Other participants had taken HIV medicines previously but never a protease inhibitor or maturation inhibitor.

Purpose: The purpose of this study was to evaluate the safety and antiviral activity of GSK3532795.13,14

Study Names: AI468-048; NCT02386098
Sponsor: ViiV Healthcare
Phase: IIb
Status: This study has been terminated.
Location: Multiple countries, including the United States
Participants:

  • Participants were adults living with HIV who have taken HIV medicines previously.
  • Participants had previous treatment failure with 1 or 2 antiretroviral therapy (ART) regimens that included HIV medicines from 2 or 3 different HIV drug classes. (Treatment failure is when an ART regimen is unable to control HIV infection.)
Purpose: The purpose of this study was to look at the safety and effectiveness of GSK3532795.15

Study Names: AI468-038; NCT02415595
Sponsor: ViiV Healthcare
Phase: IIb
Status: This study has been terminated.
Location: Multiple countries, including United States
Participants:
  • Participants were adults with HIV who have taken HIV medicines previously.
  • Participants had viral load levels (the amount of HIV in a blood sample) of at least 1,000 copies/mL. Participants also have CD4 counts of more than 200 cells/mm3. (A CD4 count is a laboratory test that measures the number of CD4 cells in a sample of blood and is an important indicator of immune function.)
Purpose: The purpose of this study was to find a safe and effective dose of GSK3532795 for adults who have taken HIV medicines previously.16

For more details on the studies listed above, see the Health Professional version.

What side effects might GSK3532795 cause?

What side effects might GSK3532795 cause?

One goal of HIV research is to identify new drugs that have fewer side effects. The following side effects were observed in the studies of GSK3532795 listed above.

AI468-002 (NCT01803074):

Some participants in this study were assigned to receive either GSK3532795 or placebo. (A placebo is an inactive drug that is identical in appearance to the active drug being studied.) The most common side effects reported by these participants were headaches, abnormal dreams, and night sweats. These side effects were mild to moderate in intensity and affected a similar number of participants receiving GSK3532795 and placebo.

Another group of participants received GSK3532795 along with HIV medicines or only HIV medicines. Among these participants, the most common GSK3532795-related side effects were signs of liver damage, headache, and diarrhea. In this group, all side effects were mild to moderate in intensity except for 1 case of low white blood cells, which was not related to GSK3532795.17

AI468-038 (NCT02415595):

This study was stopped early due to the high rate of diarrhea, abdominal pain, and other gastrointestinal disorders among participants receiving GSK3532795. These side effects are the reason GSK3532795 is no longer being studied for HIV treatment.18

If testing of GSK3532795 resumes, additional information on possible side effects will be gathered.

Where can I get more information about clinical trials studying GSK3532795?

Where can I get more information about clinical trials studying GSK3532795?

More information about GSK3532795-related research studies is available from the AIDSinfo database of ClinicalTrials.gov study summaries. Click on the title of any trial in the list to see the ClinicalTrials.gov trial summary and more information about the study.

How can I find more information about participating in a clinical trial?

How can I find more information about participating in a clinical trial?

Participating in a clinical trial can provide benefits. For example, a volunteer participant can benefit from new research treatments before they are widely available. Participants also receive regular and careful medical attention from a research team that includes doctors and other health professionals. However, clinical trials may also involve risks of varying degrees, such as unpleasant, serious, or even life-threatening side effects from the treatment being studied.12

Your health care provider can help you decide whether participating in a clinical trial is right for you. For more information, visit NIH Clinical Research Trials and You.

References

References

  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: https://chem.sis.nlm.nih.gov/chemidplus/rn/S900006910. Last accessed onNovember 30, 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 30, 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 30, 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 30, 2017.
  5. Adamson CS. Protease-mediated maturation of HIV: inhibitors of protease and the maturation process. Mol Biol Int. 2012;2012:604261. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3410323/. Last accessed on November 30, 2017.
  6. Sundquist WI, Kräusslich HG. HIV-1 assembly, budding, and maturation. Cold Spring Harb Perspect Med. 2012 Jul;2(7):a006924. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385941/. Last accessed on.
  7. Brown KC, Paul S, Kashuba AD. Drug interactions with new and investigational antiretrovirals. Clin Pharmacokinet. 2009;48(4):211-41. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2857544/. Last accessed onNovember 30, 2017.
  8. 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 30, 2017.
  9. U.S. Food and Drug Administration. Guidance for Industry: Role of HIV Resistance Testing in Antiretroviral Drug Development, October 2007. Page 19. Available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071173.pdf. Last accessed on November 30, 2017.
  10. 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 30, 2017.
  11. 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 30, 2017.
  12. National Institutes of Health (NIH). NIH Clinical Research Trials and You. Available at: https://www.nih.gov/health-information/nih-clinical-research-trials-you. Last accessed on November 30, 2017.
  13. 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 November 30, 2017.
  14. 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 30, 2017.
  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 November 30, 2017.
  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 November 30, 2017.
  17. 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 30, 2017.
  18. 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 30, 2017.

Last Reviewed: December 6, 2017