Drugs

Cenicriviroc

Other Names: CVC, TAK-652, TBR-652, cenicriviroc mesylate Drug Class: CCR5 Antagonist
Molecular Formula: C41 H52 N4 O4 S
Registry Number: 497223-25-3 (CAS) Chemical Name: (5E)-8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(S)-(3-propylimidazol-4-yl)methylsulfinyl]phenyl]-3,4-dihydro-2H-1-benzazocine-5-carboxamide Chemical Class: Benzazepines Organization: Allergan, Takeda; Tobira Therapeutics Phase of Development: Cenicriviroc is in Phase IIb development as a treatment for HIV.

Chemical Image:

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cenicriviroc

cenicriviroc

Molecular Weight: 696.9518

(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 Allergan press release,3 ClinicalTrials.gov,4 and Antimicrobial agents and chemotherapy article5)

Pharmacology


Mechanism of Action: HIV-1 CCR5 antagonist. Cenicriviroc is a small-molecule CCR5 co-receptor antagonist that prevents viral entry by binding to a domain of CCR5 and subsequently inhibiting the interaction between HIV-1 gp120 and CCR5.5,6 Cenicriviroc is also a CCR2 antagonist.7

Cenicriviroc has been studied for the treatment of both HIV infection and HIV-associated neurocognitive disease (HAND).4,8 It is also being studied for inflammatory and fibrotic conditions, including non-alcoholic steatohepatitis (NASH) and primary sclerosing cholangitis (PSC).3

Half-life (T½): Cenicriviroc has a long plasma half-life of 30 to 40 hours and requires only once-daily dosing.9

Metabolism/Elimination: In animals (rats, dogs, and monkeys), CYP3A4 and CYP2C8 were the primary enzymes responsible for the oxidative metabolism of cenicriviroc. Cenicriviroc did not inhibit CYP-mediated activity and did not induce CYP3A4 in human hepatocytes. In animals, cenicriviroc was primarily eliminated via the hepatobiliary route as unchanged drug in feces. Only minor amounts of metabolites were detected in feces.10

Resistance: In an in vitro passage study, an R5 HIV-1 isolate exhibiting high levels of resistance to cenicriviroc was selected after 67 weeks. An analysis of viral amino acid changes found that complete resistance to cenicriviroc developed only after several amino acid changes in both the V3 region and other Env regions.11

A Phase I/II 10-day monotherapy dose-escalating study (NCT01092104) examined cenicriviroc in treatment-experienced, CCR5-antagonist-naive participants with HIV. A shift in viral tropism was only detected in 1 participant, who was found to have a tropism shift from CCR5 to CXCR4 co-receptor at baseline and was excluded from efficacy analysis.7,12

In a 48-week Phase IIb study (NCT01338883), 143 treatment-naive participants with HIV received either cenicriviroc (100 mg or 200 mg) once daily or efavirenz once daily, each in combination with emtricitabine/tenofovir DF (Truvada). In this study, virologic failure (VF) occurred in 10 out of 115 cenicriviroc-treated participants and in 1 out of 28 efavirenz-treated participants. NRTI resistance mutations (M184I and/or V) emerged in 5 cenicriviroc-treated participants that had VF; 4 of the 5 participants, however, had suboptimal cenicriviroc plasma concentrations. The NRTI mutations accounted for 75% of the VFs with cenicriviroc 100 mg and for 33% of the VFs with cenicriviroc 200 mg. None of the efavirenz-treated participants with VF had emergent NRTI mutations. One participant with VF who was in the 200-mg cenicriviroc group experienced a tropism switch from R5 to dual/mixed-tropic virus.9,13,14


Select Clinical Trials


Study Identifiers: TBR-652-2-202 (Study 202); NCT01338883
Sponsor: Tobira Therapeutics, Inc.
Phase: IIb
Status: This study has been completed.
Study Purpose: Study 202 was a dose-finding study that compared the safety and efficacy of cenicriviroc with the safety and efficacy of efavirenz over 48 weeks.
Study Population:
  • Participants were treatment-naive adults with R5-tropic HIV.
  • Participants had HIV RNA ≥1,000 copies/mL and CD4 counts ≥200 cells/mm3.
Dosing: Participants were randomized to 1 of the following 3 groups:
  • Arm A: cenicriviroc 100 mg (2 tablets, 50 mg each) + cenicriviroc matching placebo (2 placebo tablets) + efavirenz matching placebo + Truvada
  • Arm B: cenicriviroc 200 mg (4 tablets, 50 mg each) + efavirenz matching placebo + Truvada
  • Arm C: cenicriviroc matching placebo (4 placebo tablets) + efavirenz 600 mg + Truvada

All active and placebo doses were administered orally. Cenicriviroc (active or placebo) was taken once daily following breakfast, while efavirenz (active or placebo) was taken once daily at bedtime.4,9,13-17

Selected Study Results:

Study Identifier: NCT02128828
Sponsor: University of Hawaii
Phase: II
Status: This study has been completed.
Study Purpose: The purpose of this open-label pilot study was to evaluate cenicriviroc’s ability to improve cognitive function in participants with HIV.
Study Population:

  • Participants were adults with HIV who were receiving ART at study entry and who had been receiving ART for at least 1 year prior to screening.
  • Participants had HIV RNA <50 copies/mL at screening and for at least 1 year prior to screening.
  • Participants had mild to moderate cognitive impairment or were cognitively unimpaired.

Dosing: All participants received cenicriviroc once daily in addition to their current ART regimens for 24 weeks. The dose of cenicriviroc was dependent on a participant’s current ART regimen.8,18

Selected Study Results:

The company that was previously studying cenicriviroc developed an optimized cenicriviroc formulation with an improved stability and absorption profile over previous tablet formulations of cenicriviroc.19,20 Furthermore, based on results from Study 202, Phase III clinical trials were at one point being planned to investigate a fixed-dose combination (FDC) tablet containing cenicriviroc plus lamivudine (3TC) in treatment-naive adults with R5-tropic HIV.21 However, study of the FDC tablet has yet to occur.22


Adverse Events


Study 202 (NCT01338883)

In this Phase IIb study, safety data was evaluated in 143 participants (n = 58 cenicriviroc 100 mg; n = 57 cenicriviroc 200 mg; n = 28 efavirenz). Eighty-eight percent of participants receiving cenicriviroc 100 mg, 84% of participants receiving cenicriviroc 200 mg, and 96% of participants receiving efavirenz experienced at least 1 adverse event (AE), most of which were mild to moderate. The following percentages of participants had a treatment-related AE: 50% in the 100-mg cenicriviroc group, 44% in the 200-mg cenicriviroc group, and 71% in the efavirenz group. The most frequent treatment-related AEs associated with cenicriviroc were nausea (12%), headache (10%), diarrhea (7%), and abnormal dreams (7%). Grade 2 or higher treatment-related AEs occurring in at least 5% of participants within a given treatment group were less frequent among cenicriviroc participants than efavirenz participants. Study discontinuations due to an AE occurred in significantly fewer cenicriviroc participants than efavirenz participants. Serious adverse events (SAEs) occurred in 1 participant in each group, accounting for 2%, 2%, and 4% of participants in the cenicriviroc 100 mg, cenicriviroc 200 mg, and efavirenz groups, respectively.9,13,14

The majority of laboratory abnormalities were Grade 1 or 2. Total and LDL cholesterol levels decreased significantly in participants receiving cenicriviroc, but increased in participants receiving efavirenz. Elevated CPK (Grade 3 or 4) was seen in a greater percentage of participants in the 200-mg cenicriviroc group (16%) than in the 100-mg cenicriviroc group (5%) and efavirenz group (7%). All ALT and AST elevations were Grade 1 or 2, with the exception of 1 transient, asymptomatic Grade 3 AST elevation that occurred in a participant receiving cenicriviroc 100 mg.9,13,14

NCT02128828

In this Phase II study, cenicriviroc’s ability to improve cognitive function was evaluated in 17 participants with HIV. The most commonly reported AEs were congestion (17%), fever (23%), cough (41%), fatigue (35%), headache (29%), and diarrhea (17%), all of which were Grade 1 or 2. One Grade 3 event, asymptomatic lipase elevation, occurred; however, it is not known whether it was related to cenicriviroc treatment.8,18


Drug Interactions


Cenicriviroc does not inhibit CYP-mediated activity and does not induce CYP3A4 in human hepatocytes.10

Cenicriviroc plasma exposure was significantly increased when cenicriviroc (50 mg once daily) was coadministered with the following PIs: ritonavir (100 mg once daily), darunavir/ritonavir (800/100 mg once daily), or atazanavir/ritonavir (300/100 mg once daily).23

When cenicriviroc (200 mg once daily) was coadministered with efavirenz (600 mg once daily), cenicriviroc plasma exposure was significantly decreased when compared to cenicriviroc administered alone. Doubling the cenicriviroc dosage to 400 mg was shown to offset these effects. Cenicriviroc 400 mg did not alter efavirenz exposure.24

In a drug interaction study of dolutegravir (50 mg once daily) coadministered with cenicriviroc (150 mg once daily), results suggested that dolutegravir dose adjustments would not be necessary when coadministered with cenicriviroc. However, because dolutegravir reduced cenicriviroc exposure by 23% to 29%, this interaction will require further investigation.25


References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: https://chem.sis.nlm.nih.gov/chemidplus/rn/497223-25-3. Last accessed on October 31, 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 October 31, 2017.
  3. Allergan: Press Release, dated September 20, 2016. Allergan to acquire Tobira Therapeutics expanding global GI R&D pipeline and taking a leading R&D position in NASH. Available at: https://www.allergan.com/news/news/thomson-reuters/allergan-to-acquire-tobira-therapeutics-expanding. Last accessed on October 31, 2017.
  4. Tobira Therapeutics, Inc. A Phase 2b randomized, double-blind, double-dummy trial of 100 or 200 mg once-daily doses of cenicriviroc (CVC, TBR 652) or once-daily EFV, each with open-label FTC/TDF, in HIV 1-infected, antiretroviral treatment-naive, adult patients with only CCR5-tropic virus. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 18, 2011. NLM Identifier: NCT01338883. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01338883. Last accessed on October 31, 2017.
  5. Baba M, Takashima K, Miyake H, et al. TAK-652 inhibits CCR5-mediated human immunodeficiency virus type 1 infection in vitro and has favorable pharmacokinetics in humans. Antimicrob Agents Chemother. 2005 Nov;49(11):4584-91. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1280155/. Last accessed on October 31, 2017.
  6. Briz V, Poveda E, Soriano V. HIV entry inhibitors: mechanisms of action and resistance pathways. J Antimicrob Chemother. 2006 Apr;57(4):619-27. Available at: https://academic.oup.com/jac/article/57/4/619/669426/HIV-entry-inhibitors-mechanisms-of-action-and. Last accessed on October 31, 2017.
  7. Marier JF, Trinh M, Pheng LH, Palleja SM, Martin DE. Pharmacokinetics and pharmacodynamics of TBR-652, a novel CCR5 antagonist, in HIV-1-infected, antiretroviral treatment-experienced, CCR5 antagonist-naive patients. Antimicrob Agents Chemother. 2011 Jun;55(6):2768-74. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101382/. Last accessed on October 31, 2017.
  8. University of Hawaii. Randomized, placebo-controlled, double-blind, pilot study of CCR5/CCR2 inhibitor cenicriviroc (CVC) for HIV associated neurocognitive disorder (HAND). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 4, 2013. NLM Identifier: NCT02128828. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02128828. Last accessed on October 31, 2017.
  9. Feinberg J, Thompson M, Cade J, et al. Final Week 48 analysis of cenicriviroc (CVC) compared to efavirenz (EFV), in combination with emtricitabine/tenofovir (FTC/TDF), in treatment-naive HIV-1-infected adults with CCR5-tropic virus (study 652-2-202; NCT01338883). European AIDS Conference; October 16-19, 2013; Brussels, Belgium. Levin: Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2013. Available at: http://www.natap.org/2013/EACS/EACS_10.htm. Last accessed on October 31, 2017.
  10. Martin DE, Kawase M, Asahi S, et al. Cenicriviroc (CVC, TBR-652) absorption, distribution, metabolism, and excretion (ADME) profile in rats, dogs, monkeys, and humans. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 27-March 2, 2011; Boston, MA. Poster N-101. Available from Tobira Therapeutics at: http://www.d1004496.site.infoquest.com/pdfs/CROI_2011_Poster_N-101.pdf. Last accessed on September 4, 2014.
  11. Baba M, Miyake H, Wang X, Okamoto M, Takashima K. Isolation and characterization of human immunodeficiency virus type 1 resistant to the small-molecule CCR5 antagonist TAK-652. Antimicrob Agents Chemother. 2007 Feb;51(2):707-15. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1797735/. Last accessed on October 31, 2017.
  12. Tobira Therapeutics, Inc. A proof of concept, multiple dose-escalating study to evaluate the antiviral activity, safety, and pharmacokinetics of the CCR5 antagonist TBR 652 in HIV 1-infected, antiretroviral treatment-experienced, CCR5 antagonist-naive patients. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 22, 2010. NLM Identifier: NCT01092104. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01092104. Last accessed on October 31, 2017.
  13. Feinberg J, Thompson M, Cade J, et al. Final Week 48 analysis of cenicriviroc (CVC) compared to efavirenz (EFV), in combination with emtricitabine/tenofovir (FTC/TDF), in treatment-naive HIV-1-infected adults with CCR5-tropic virus. Abstract presented at: European AIDS Conference; October 16-19, 2013; Brussels, Belgium. Abstract PS4/1. Available at: http://www.professionalabstracts.com/eacs2013/planner/index.php?go=abstract&action=abstract_iplanner&print=0&lprID=142&highlight=cenicriviroc&PSID=AOLYUNDFJHCSEFPDLAAC. Last accessed on October 31, 2017.
  14. Thompson M, Saag M, DeJesus E, et al. A 48-week randomized phase 2b study evaluating cenicriviroc versus efavirenz in treatment-naive HIV-infected adults with C-C chemokine receptor type 5-tropic virus. AIDS. 2016 Mar 27; 30(6): 869-78. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794136/pdf/aids-30-869.pdf. Last accessed on October 31, 2017.
  15. Martin D, Beliveau M, Marier JF, Driz R, Palleja S. Pharmacokinetics (PK) of cenicriviroc (CVC) following 100 or 200 mg once-daily dosing with open-label tenofovir / emtricitabine (TDF/FTC) in HIV-1–infected subjects enrolled in a Phase 2b study. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 5-8, 2012; Seattle, WA. Poster 600. Available from Tobira Therapeutics at: http://files.shareholder.com/downloads/AMDA-2VQ912/0x0x770957/d8d885f8-61fa-4138-9459-3401fc0adfa0/770957.pdf. Last accessed on October 31, 2017.
  16. Abdel-Hameed E, Rouster SD, Sherman KE. Assessment of hepatic antifibrotic effect of cenicriviroc in patients with HIV. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 22–25, 2016; Boston, MA. Abstract 552. Available at: http://www.croiconference.org/sessions/assessment-hepatic-antifibrotic-effect-cenicriviroc-patients-hiv. Last accessed on October 31, 2017.
  17. Utay NS, Somasunderam A, Nigalye M, Chang W, Seyedkazemi S, Lefebvre E. Cenicriviroc decreases sCD14 and LBP levels without affecting gut permeability. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 22–25, 2016; Boston, MA. Abstract 239. Available at: http://www.croiconference.org/sessions/cenicriviroc-decreases-scd14-and-lbp-levels-without-affecting-gut-permeability. Last accessed on October 31, 2017.
  18. Ndhlovu LC, D’Antoni ML, Paul R, et al. Cencriviroc improves neurocognition and reduces monocyte activation in treated HIV. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 13–16, 2017; Seattle, WA. Abstract 381. Available at: http://www.croiconference.org/sites/default/files/posters-2017/381_DAntoni.pdf. Last accessed on October 31, 2017.
  19. Menning MM, Dalziel SM. Fumaric acid microenvironment tablet formulation and process development for crystalline cenicriviroc mesylate, a BCS IV compound. Mol Pharm. 2013 Nov 4;10(11):4005-15. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23941629. Last accessed on October 31, 2017.
  20. Tobira Therapeutics: Press Release, dated October 4, 2013. Tobira Therapeutics announces publication of cenicriviroc formulation improvement providing platform for single tablet and fixed-dose combinations. Available at: http://files.shareholder.com/downloads/AMDA-2VQ912/2836889662x0x770944/AA7FC9DB-0793-42C6-9F0E-214F651075C9/770944.pdf. Last accessed on October 31, 2017.
  21. Tobira Therapeutics: Press Release, dated October 17, 2013. Tobira Therapeutics presents positive 48-week data from Phase 2b trial of cenicriviroc in treatment-naive HIV infection at the 14th European AIDS Conference. Available at: http://files.shareholder.com/downloads/AMDA-2VQ912/2836889662x0x770942/A350DD2A-7061-40A6-BDD1-8B6E4986A158/770942.pdf. Last accessed on October 31, 2017.
  22. Clayden P, Collins S, Frick M, et al. HIV i-BASE/Treatment Action Group. 2015 pipeline report. July 2015. Available at: http://www.pipelinereport.org/sites/default/files/201509/2015%20Pipeline%20Report%20Full.pdf. Last accessed on October 31, 2017.
  23. Lefebvre E, Enejosa J, Chang W, et al. Pharmacokinetics of cenicriviroc when administered with and without ritonavir, darunavir/ritonavir or atazanavir/ritonavir. Abstract presented at: International Workshop on Clinical Pharmacology of HIV Therapy; April 22-24, 2013; Amsterdam, Netherlands. Abstract O_09A. Available at: http://regist2.virology-education.com/abstractbook/2013_3.pdf. Last accessed on October 31, 2017.
  24. Lefebvre E, Enejosa J, Chang W, et al. Pharmacokinetic interactions between cenicriviroc and efavirenz. Abstract presented at: International Workshop on Clinical Pharmacology of HIV Therapy; April 22-24, 2013; Amsterdam, Netherlands. Abstract O_09B. Available at: http://regist2.virology-education.com/abstractbook/2013_3.pdf. Last accessed on October 31, 2017.
  25. Lefebvre E, Enejosa J, Chang W, et al. Pharmacokinetic interactions between cenicriviroc and dolutegravir. Abstract presented at: European AIDS Conference; October 16-19, 2013; Brussels, Belgium. Abstract PE10/8. Available at: http://www.professionalabstracts.com/eacs2013/planner/index.php?go=abstract&action=abstract_iplanner&print=0&lprID=1916&highlight=cenicriviroc&PSID=ZMTQAQIREARAYQKSQYIQ. Last accessed on October 31, 2017.


Last Reviewed: October 31, 2017