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Investigational

Cenicriviroc  Audio icon

Other Names: CVC, TAK-652, TBR-652, cenicriviroc mesylate
Drug Class: Entry Inhibitor
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
Company: Takeda; Tobira Therapeutics
Phase of Development: IIb
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Chemical Image:
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cenicriviroc
cenicriviroc
Molecular Weight: 696.9518
(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 and ClinicalTrials.gov3)
Patent Version Content

Pharmacology


Mechanism of Action: HIV-1 entry inhibitor. 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 CCR5.4,5 Cenicriviroc is also a CCR2 antagonist.6

Cenicriviroc has been studied for the treatment of HIV infection and is being studied for the treatment of HIV-associated neurocognitive disease (HAND).3,7 It is also being studied for inflammatory and fibrotic conditions, including non-alcoholic steatohepatitis (NASH) and primary sclerosing cholangitis (PSC).8

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

Metabolism/Elimination: Oxidative metabolism was primarily via CYP3A4 and CYP2C8 in rats, dogs, and monkeys. Cenicriviroc had no inhibitory effects on CYP-mediated activities and no inductive effects on CYP3A4 in human hepatocytes. In animals, elimination of cenicriviroc was primarily as unchanged drug (minor amounts of metabolites) into feces via the hepatobilliary route.10

Resistance: In a study of a cenicriviroc-resistant clinical isolate, several amino acid changes in not only the V3 region but also in other Env regions were required for R5 HIV-1 to develop complete resistance to cenicriviroc.11

In a Phase I/II 10-day monotherapy dose-escalating study (NCT01092104), which included treatment-experienced, CCR5-antagonist-naive, HIV-infected patients, shifts in viral tropism were not detected (except 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).6,12

In a 48-week Phase IIb study (NCT01338883), 143 HIV-infected, treatment-naive participants received either once-daily cenicriviroc (100 mg or 200 mg) or once-daily efavirenz, 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 100-mg cenicriviroc VFs and for 33% of the 200-mg cenicriviroc VFs. None of the efavirenz-treated VF participants had emergent NRTI mutations. One participant with VF who was in the 200-mg cenicriviroc group experienced a tropism switch from CCR5 to dual/mixed-tropic virus.9,13,14

 


Clinical Trials


Study Identifiers: TBR-652-2-202 (Study 202); NCT01338883
Sponsor: Tobira Therapeutics, Inc.
Phase: IIb
Study Purpose: Study 202 was a dose-finding study comparing the safety and efficacy of cenicriviroc with the safety and efficacy of efavirenz over 48 weeks.
Study Population: Participants were HIV-infected, treatment-naive adults with CCR5-tropic virus, HIV RNA ≥1000 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.8,9,13-17
Selected Study Results

 

The company studying cenicriviroc has reported the development of an optimized cenicriviroc formulation with an improved stability and absorption profile over previous tablet formulations of cenicriviroc.18,19 Furthermore, based on results from Study 202, Phase III clinical trials are being planned that will investigate the use of a fixed-dose combination (FDC) tablet containing cenicriviroc plus lamivudine (3TC) in HIV-infected, treatment-naive adults with CCR5-tropic virus.20

In addition, cenicriviroc is being studied in a Phase II trial (NCT02128828) as treatment for HAND in HIV-infected adults with cognitive impairment.7


Adverse Events


In Study 202 (NCT01338883), 88% 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), the majority of which were mild to moderate in severity. The following percentages of participants experienced a treatment-related AE overall: 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 occurring in at least 5% of cenicriviroc-treated participants were nausea (12%), headache (10%), diarrhea (7%), and abnormal dreams (7%). Grade 2 or higher AEs occurring in at least 5% of participants within a given treatment group were experienced by 9% of participants in each of the 100-mg and 200-mg cenicriviroc groups and in 36% of participants in the efavirnez group. There were no significant differences between groups in the number of Grade 3 or higher AEs reported. Study discontinuations due to an AE occurred in significantly fewer cenicriviroc-treated participants than efavirenz-treated participants. Serious AEs occurred in 1 participant in each treatment 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, except for 1 transient, asymptomatic Grade 3 AST elevation occurring in a participant receiving cenicriviroc 100 mg.9,13,14


Drug Interactions


Cenicriviroc has no inhibitory effects on CYP-mediated activities and no inductive effects on 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).21

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 have any effect on efavirenz exposure.22

In a drug interaction study of dolutegraivr (50 mg once daily) coadministered with cenicriviroc (150 mg once daily), results suggested that no dolutegravir dose adjustment will be necessary when these drugs are coadministered; however, because dolutegravir was shown to reduce cenicriviroc exposure by 23% to 29%, this interaction will require further investigation.23


References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/497223-25-3. Last accessed on September 29, 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 29, 2016.
  3. 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-Naïve, 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: http://www.clinicaltrials.gov/ct2/show/NCT01338883. Last accessed on September 29, 2016.
  4. 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: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1280155/. Last accessed on September 29, 2016.
  5. 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: http://jac.oxfordjournals.org/content/57/4/619.long. Last accessed on September 29, 2016.
  6. 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-Naïve Patients. Antimicrob Agents Chemother. 2011 Jun;55(6):2768-74. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101382/. Last accessed on September 29, 2016.
  7. 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: http://www.clinicaltrials.gov/ct2/show/NCT02128828. Last accessed on September 29, 2016.
  8. Tobira Therapeutics website. Cenicriviroc. Available at: http://www.tobiratx.com/pipeline/cenicriviroc/. Last accessed on September 29, 2016.
  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-Naïve HIV-1-Infected Adults with CCR5-Tropic Virus (Study 652-2-202; NCT01338883). 14th 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 September 29, 2016.
  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: 18th 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: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1797735/. Last accessed on September 29, 2016.
  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-Naïve 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 September 29, 2016.
  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-naïve HIV-1-infected Adults with CCR5-Tropic Virus. Abstract presented at: 14th 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 September 29, 2016.
  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: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794136/pdf/aids-30-869.pdf. Last accessed on September 29, 2016.
  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: 19th Conference on Retroviruses and Opportunistic Infections (CROI); March 5-8, 2012; Seattle, WA. Poster 600. Available from Tobira Therapeutics at: http://www.tobiratherapeutics.com/file.cfm/7/docs/pr_3_7_12_TOBIRA_CVC_CROI_PK_Poster.pdf. Last accessed on September 30, 2015.
  16. Abdel-Hameed E, Rouster SD, Sherman KE. Assessment of Hepatic Antifibrotic Effect of Cenicriviroc in Patients With HIV. Abstract presented at: 23rd 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 September 29, 2016.
  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: 23rd 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 September 29, 2016.
  18. 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: http://www.ncbi.nlm.nih.gov/pubmed/23941629. Last accessed on September 29, 2016.
  19. 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 September 29, 2016.
  20. Tobira Therapeutics: Press Release, dated October 17, 2013. Tobira Therapeutics Presents Positive 48-Week Data from Phase 2b Trial of Cenicriviroc in Treatment-Naïve 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 September 29, 2016.
  21. 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: 14th 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 September 29, 2016.
  22. Lefebvre E, Enejosa J, Chang W, et al. Pharmacokinetic interactions between cenicriviroc and efavirenz. Abstract presented at: 14th 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 September 29, 2016.
  23. Lefebvre E, Enejosa J, Chang W, et al. Pharmacokinetic Interactions between Cenicriviroc and Dolutegravir. Abstract presented at: 14th 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 September 29, 2016.


Last Reviewed: September 29, 2016

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