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Investigational

MPC-4326  Audio icon

Other Names: bevirimat, bevirimat dimeglumine, BVM, PA-457
Drug Class: Maturation Inhibitors
Molecular Formula: C36 H56 O6
Registry Number: 174022-42-5 (CAS)
Chemical Name: (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-(4-hydroxy-3,3-dimethyl-4-oxo-butanoyl)oxy-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-1,2,3,4,5,6,7,7a,9,10,11,11b,12,13,13a,13b-hexadecahydrocyclopenta[a]chrysene-3a-carboxylic acid
Chemical Class: Natural Products, Unspecified Origin; Terpenoids
Company: Myrexis, Inc.
Phase of Development: Phase II (discontinued)
Chemical Image:
Click image to enlarge
bevirimat
bevirimat
Molecular Weight: 584.8324
(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 Myrexis, Inc. press release,3 and Molecular Biology International journal article4)
Patent Version Content

NOTE: The development of MPC-4326 for HIV treatment has been discontinued.


The study of MPC-4326 as a maturation inhibitor HIV medicine was discontinued in 2010. The company developing the drug announced that this decision was made for strategic business reasons and that the company is focusing its resources on cancer drug development.3 Two journal articles noted that, in Phase II clinical trials, MPC-4326 was found to be ineffective in some participants who had HIV with specific naturally occurring polymorphisms. (Polymorphisms are naturally occurring genetic variations [mutations] in HIV that are not caused by antiretroviral drug use.)4,5

 


Pharmacology


Mechanism of Action: Maturation inhibitor. MPC-4326, a betulinic acid derivative, inhibits HIV-1 proteolytic maturation and production of infectious particles by specifically blocking protease–mediated capsid-spacer peptide 1 (CA-SP1) cleavage in Gag. The MPC-4326 binding pocket is located near the CA-SP1 junction within immature virus particles.4,5

Half-life (T½): The MPC-4326 terminal elimination half-life ranged from 56 to 70 hours in a multiple-dose study in healthy participants. In a multiple-dose study in HIV-infected participants, the mean elimination half-life was 62.7 hours.6

Metabolism/Elimination: MPC-4326 is metabolized primarily via hepatic glucuronidation by UGT1A3 and does not interact with cytochrome P450 (CYP) enzymes or P-glycoprotein (P-gp).6,7 Animal studies indicate that MPC-4326 is eliminated primarily by a hepatobiliary route; renal excretion is minimal.8

Resistance: Intrinsic resistance and non-response to MPC-4326 have been associated with naturally occurring HIV-1 polymorphisms located at SP1 residues 6, 7, and 8 (positions 369, 370, and 371 on Gag), also referred to as the QVT (glutamine-valine-threonine) motif. These polymorphisms have a high prevalence, especially in non-clade B HIV-1 isolates.4,5,9

In addition, in vitro drug resistance selection experiments with MPC-4326 have indicated that certain mutations in the QVT motif can be acquired under MPC-4326 pressure. MPC-4326 may also select for several mutations occurring in the vicinity of the CA-SP1 cleavage site. Furthermore, the presence of existing HIV-1 protease inhibitor mutations may significantly impact the resistance profile of MPC-4326.4,10
 


Dosing in Clinical Trials


Study Identifiers: Study 204; NCT0096718711
Phase: II
Study Purpose: Study to evaluate the safety and efficacy of two different doses of MPC-4326 (50-mg tablet formulation) administered as monotherapy for 14 days. Thereafter, investigators continued to evaluate MPC-4326 administered as part of an optimized background regimen for up to 72 weeks.
Study Population: HIV-infected, treatment-naive or –experienced adults
Dosing: MPC-4326 (formulated as 50-mg bevirimat dimeglumine tablets) 200 mg versus 300 mg, administered as monotherapy twice daily over 14 days. Participants who achieved ≥0.5 log10 viral load reduction by Day 15 had the option to continue MPC-4326 in combination with an optimized background regimen for up to 72 weeks.11-14
(See references cited above for information on study results)

Study Identifiers: Study 206; NCT0109707015
Phase: II
Study Purpose: Study to evaluate the pharmacokinetics and safety of a 100-mg tablet formulation of MPC-4326 administered at three different doses for 15 days.
Study Population: HIV-infected, treatment-experienced adults
Dosing: MPC-4326 (formulated as 100-mg bevirimat dimeglumine tablets) for 15 days at doses of 200 mg twice daily, 300 mg once daily, or 400 mg once daily, with each of the doses in combination with participant’s own antiretroviral therapy regimen.15,16
(See references cited above for information on study results)

A previous Phase II study investigated an orally administered liquid formulation of MPC-4326 in treatment-experienced participants.17 In addition, a Phase IIb safety and efficacy study on MPC-4326 was terminated. The terminated study was evaluating MPC-4326 given in combination with an optimized background regimen in HIV-infected individuals failing their current antiretroviral therapy.18  
 


Adverse Events


In Study 204, the most common adverse events that occurred over 14 days of treatment with twice-daily MPC-4326 monotherapy were headache, diarrhea, and nausea. No study discontinuations, serious adverse events, or grade IV events were reported. One grade III event of constipation occurred.12,13

In Study 206, the most common adverse events that occurred over 15 days of treatment with once- or twice-daily MPC-4326 in combination with antiretroviral therapy were diarrhea, abdominal cramping, headache, and nausea. No serious adverse events related to the study drug were reported.16
 
 


Drug Interactions


MPC-4326 is a substrate of UDP-glucuronosyltransferases (UGTs) and has exhibited weak to moderate inhibition of UGT enzymes 1A1, 1A3, 1A4, 1A8, 1A10, and 2B7. MPC-4326 is metabolized primarily by UGT1A3 and does not interact with the CYP enzyme system or with P-gp.6,7

Co-administration with ritonavir has been shown to decrease MPC-4326 exposures. No pharmacokinetic interactions have been noted when atazanavir is coadministered with MPC-4326.6
 
 


References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/174022-42-5. Last accessed on April 29, 2015.
  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 April 29, 2015.
  3. Myrexis, Inc.: Press Release, dated June 8, 2010. Myriad Pharmaceuticals Announces Intent to Focus on Oncology Portfolio. Available at: http://www.myrexis.com/files/documents/Press%20Releases/2010/2010.06.08%20-%20Myriad%20Pharmaceuticals%20Announces%20Intent%20to%20Focus%20on%20Oncology%20Portfolio.pdf. Last accessed on April 29, 2015.
  4. Adamson CS. Protease-Mediated Maturation of HIV: Inhibitors of Protease and the Maturation Process. Mol Biol Int. 2012;2012:604261. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3410323/. Last accessed on April 29, 2015.
  5. Waki K, Durell SR, Soheilian F, Nagashima K, Butler SL, Freed EO. Structural and Functional Insights into the HIV-1 Maturation Inhibitor Binding Pocket. PLoS Pathog. 2012;8(11):e1002997. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3493477/. Last accessed on April 29, 2015.
  6. Brown KC, Paul S, Kashuba AD. Drug Interactions with New and Investigational Antiretrovirals. Clin Pharmacokinet. 2009;48(4):211-41. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2857544/. Last accessed on April 29, 2015.
  7. Smith PF, Ogundele A, Forrest A, et al. Phase I and II Study of the Safety, Virologic Effect, and Pharmacokinetics/Pharmacodynamics of Single-Dose 3-O-(3',3'-Dimethylsuccinyl)Betulinic Acid (Bevirimat) against Human Immunodeficiency Virus Infection. Antimicrob Agents Chemother. 2007 Oct;51(10):3574-81. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2043264/. Last accessed on April 29, 2015.
  8. Martin DE, Salzwedel K, Allaway GP. Bevirimat: a novel maturation inhibitor for the treatment of HIV-1 infection. Antivir Chem Chemother. 2008;19(3):107-13. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19024627. Last accessed on April 29, 2015.
  9. McCallister S, Lalezari J, Richmond G, et al. HIV-1 Gag polymorphisms determine treatment response to bevirimat (PA-457). Abstract presented at: 17th International HIV Drug Resistance Workshop: Basic Principles and Clinical Implications; June 10-14, 2008; Sitges, Spain. Abstract 8. Available at: http://www.euresist.org/c/document_library/get_file?uuid=abfbc26e-aa26-4fda-a35f-1add3453c481&groupId=85965. Last accessed on April 29, 2015.
  10. Fun A, van Maarseveen NM, Pokorná J, et al. HIV-1 protease inhibitor mutations affect the development of HIV-1 resistance to the maturation inhibitor bevirimat. Retrovirology. 2011 Aug 24;8:70. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3184055/. Last accessed on April 29, 2015.
  11. Myrexis Inc. A Phase II Multicenter, Open-label, Randomized, Parallel Group, Study of Bevirimat in HIV-1 Positive Patients to Evaluate the Safety, Efficacy, and Pharmacokinetics of MPC-4326 Administered as Monotherapy for 14 Days and as Part of an Optimized Background Regimen for up to 72 Weeks. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on August 25, 2009. NLM Identifier: NCT00967187. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00967187. Last accessed on April 29, 2015.
  12. Bloch M, Bodsworth N, Fidler M, et al. Efficacy, Safety and Pharmacokinetics of MPC-4326 (Bevirimat Dimeglumine) 200mg bid and 300mg bid Monotherapy Administered for 14 days in Subjects with HIV-1 Infection. Abstract presented at: 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 12-15, 2009; San Francisco, CA. Abstract H-1230. Available at: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=30cfb0e3-06f8-42ba-b4fb-47507d251418&cKey=fc21de4f-4479-4a63-8db7-a7015967dcf3&mKey=14ebfe7e-6f65-4d97-8cb6-f64f4347c38a. Last accessed on April 29, 2015.
  13. Bloch M, Bodsworth N, Mather G, et al. Efficacy, Safety and Pharmacokinetics of MPC-4326 (bevirimat dimeglumine) 200mg BID and 300mg BID Monotherapy Administered for 14 days in Subjects with HIV-1 Infection. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 12-15, 2009; San Francisco, CA. Levin: Bevirimat Antiviral Activity & Safety, 14-Day Monotherapy Study; Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2009. Available at: http://www.natap.org/2009/ICCAC/ICCAC_43.htm. Last accessed on April 29, 2015.
  14. Myriad Pharmaceuticals, Inc. Form 10-K (Annual Report), filed September 28, 2009. Available at: http://www.myrexis.com/files/documents/SEC%20Filings/Annual/2009.09.28%20-%2010-K%20Annual%20Report/10-K%20Annual%20Report%20Sep%2028,%202009.pdf. Last accessed on April 29, 2015.
  15. Myrexis Inc. A Phase II Multicenter, Open-label, Randomized, Parrallel Group Study to Assess the Pharmacokinetics of Bevirimat (BVM) 100 mg Tablets Administered to HIV-1 Positive Patients for 15 Days. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 23, 2010. NLM Identifier: NCT01097070. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01097070. Last accessed on April 29, 2015.
  16. Lalezari J, Richmond G, Thompson M, et al. Pharmacokinetics and Safety of a Novel 100 mg Tablet Formulation of MPC-4326 in Subjects with HIV-1 Infection. Abstract presented at: 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 12-15, 2009; San Francisco, CA. Abstract A1-1309. Available at: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=f494b9aa-551c-47d1-b35e-61f5114d1096&cKey=15bb791c-6e2d-4454-bf57-19159a4b16bc&mKey=%7b14EBFE7E-6F65-4D97-8CB6-F64F4347C38A%7d. Last accessed on April 29, 2015.
  17. Lalezari J, McCallister S, Gigliotti M, et al. A Phase 2 Safety and Efficacy Study of Bevirimat (BVM) in Heavily Treatment Experienced HIV+ Patients Identifies the Target Phase 3 Study Profile. Abstract presented at: 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)/Infectious Diseases Society of America (IDSA) 46th Annual Meeting; October 25-28, 2008; Washington, DC. Abstract H-891. Available at: http://www.abstractsonline.com/viewer/viewAbstract.asp?CKey=%7b5D837F53-ABC7-43C8-8A24-6588038EE046%7d&MKey=%7b26DFAE32-3D6D-446F-9AE5-B759FE42C683%7d&AKey=%7bB156596F-4F2B-4B7B-9988-53EF0A523ACC%7d&SKey=%7bF10DBD93-8EE7-4612-A818-04BD4BDDB220%7d. Last accessed on April 29, 2015.
  18. Myrexis Inc. A Phase 2b Multicenter, Randomized, Open Label, Comparative Trial of MPC-4326 in Combination With a Two to Three Drug Optimized Background Regimen Versus an Optimized, Three to Four Drug Antiretroviral Regimen for the Treatment of Triple Class Antiretroviral Experienced, HIV-1 Infected Subjects Failing Current Therapy. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on December 2, 2009. NLM Identifier: NCT01026727. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01026727. Last accessed on April 29, 2015.
     
 


Last Reviewed: April 29, 2015

Last Updated: April 29, 2015


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