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Elvucitabine

Other Names: ACH-126443, ELV, L-F-D4C, beta-L-Fd4C, l(−)Fd4C
Drug Class: Nucleoside Reverse Transcriptase Inhibitors
Molecular Formula: C9 H10 F N3 O3
Registry Number: 181785-84-2 (CAS)
Chemical Name: 4-amino-5-fluoro-1-[(2S,5R)-5-(hydroxymethyl)-2,5-dihydrofuran-2-yl]pyrimidin-2-one
Chemical Class: Pyrimidine Nucleosides
Company: Achillion Pharmaceuticals
Phase of Development: Elvucitabine is in Phase II development. The company developing elvucitabine previously reported that it is out-licensing elvucitabine and looking to work with partner companies to focus elvucitabine’s development in regions outside the United States. Through a partnership, elvucitabine is being developed in China, Hong Kong, and Taiwan.
Patent Version Content

Pharmacology


Mechanism of Action: Nucleoside reverse transcriptase inhibitor. Elvucitabine, an L-cytosine nucleoside analog, is intracellularly phosphorylated to its active 5′-triphosphate metabolite, which has an intracellular half-life of at least 20 hours.5,6 Elvucitabine triphosphate inhibits the activity of HIV reverse transcriptase by competing with natural substrates and by causing DNA chain termination after incorporation into viral DNA.7,8 Elvucitabine has also demonstrated in vitro and in vivo activity against HBV.9,10

Half-life (T½): In a 21-day study of elvucitabine (5 mg or 10 mg daily or 20 mg every 48 hours) administered in combination with lopinavir/ritonavir in adults with HIV infection, the half-life of elvucitabine was approximately 100 hours.6

Metabolism/Elimination: Elvucitabine is not metabolized by CYP enzymes. Elvucitabine is eliminated renally, primarily unchanged in the urine.6

Resistance: In vitro selection experiments have isolated virus that is resistant to elvucitabine and is associated with mutations at codon 184 (M to I or V).11 Additionally, elvucitabine has been shown to have less in vitro activity against HIV with the K65R mutation than against wild-type (wt) virus.12

Elvucitabine—at doses of 50 mg and 100 mg daily— has demonstrated potent anti-HIV activity in adults with multidrug-resistant HIV, including lamivudine-resistant virus (associated with the M184V mutation).13 A Phase II study (NCT00312039) of a lower elvucitabine dose (10 mg) has been conducted in a similar patient population, one that harbors the M184V mutation. Interim results from a 48-week open-label extension phase of this study were presented in a company press release and indicated a substantial viral load reduction in 8 out of 14 participants receiving elvucitabine.14,15

In a Phase II study (NCT00350272) of treatment-naive adults with HIV receiving either elvucitabine 10 mg daily or lamivudine 300 mg daily, each combined with efavirenz and tenofovir DF, a total of 5 virologic failures occurred in the elvucitabine arm versus 7 in the lamivudine arm through 96 weeks. At Week 96, there was no documented resistance to elvucitabine.16,17


Select Clinical Trials


Study Identifiers: (1) ACH443-015; NCT00350272 and (2) ACH443-904; NCT00675844
Sponsor: Achillion Pharmaceuticals
Phase: II
Status: These studies have been completed.
Study Purpose: ACH443-015 was designed to evaluate the safety and efficacy of elvucitabine when compared with lamivudine. ACH443-904 was a 48-week open-label extension study for participants who had successfully completed either 96 weeks of elvucitabine treatment in ACH443-015 or 48 weeks of elvucitabine treatment in ACH443-018.
Study Population:
  • Participants were treatment-naive adults with HIV who were clinically stable and who had no AIDS-defining events in the 3 months prior to screening.
  • Participants had HIV RNA ≥5,000 copies/mL and CD4 counts ≥200 cells/mm3 and <500 cells/mm3.
  • Participants had HIV that was sensitive to elvucitabine, lamivudine, emtricitabine, efavirenz, and tenofovir DF, as demonstrated by the absence of specific mutations on genotypic testing.

Dosing: During the main study (ACH443-015), participants received elvucitabine 10 mg once daily or lamivudine 300 mg once daily, each in combination with efavirenz and tenofovir DF. Treatments were administered over 12 weeks (primary endpoint analysis) and for up to a total of 96 weeks (secondary endpoint analysis).

During the open-label extension (ACH443-904), participants continued to receive elvucitabine 10 mg in combination with ART for an additional 48 weeks.5,16-18

Selected Study Results:
  • CROI, 2010: Elvucitabine vs lamivudine with tenofovir and efavirenz in antiretroviral-treatment-naïve HIV-1 infected patients: 96 week final results

Study Identifiers: (1) ACH443-014A; NCT00312039, (2) ACH443-018; NCT00380159, and (3) ACH443-904; NCT00675844
Sponsor: Achillion Pharmaceuticals
Phase: II
Status: These studies have been completed.
Study Purpose: The purpose of ACH443-014A was to evaluate the safety and efficacy of elvucitabine as compared with lamivudine in participants with the M184V HIV resistance mutation. ACH443-018 and ACH443-904 were open-label extension studies allowing for participants who completed ACH443-014A to continue receiving elvucitabine.
Study Population:

  • Participants were treatment-experienced adults with HIV who were clinically stable and who had documented M184V HIV mutation.
  • Participants were on a stable lamivudine- or emtricitabine-containing ARV regimen for at least 4 weeks prior to randomization and were experiencing treatment failure on their current regimen.
  • Participants had HIV RNA between 2,000 and 150,000 copies/mL and had CD4 counts >100 cells/mm3.

Dosing: During the main study (ACH443-014A), participants received elvucitabine 10 mg once daily or lamivudine 300 mg once daily, each in combination with existing background ART, administered over 14 days.

During the initial 48-week extension (ACH443-018), participants continued on elvucitabine 10 mg and background regimens were optimized. During the second extension (ACH443-904), participants continued to receive elvucitabine 10 mg in combination with ART for an additional 48 weeks.14,15,18,19

Selected Study Results:


Adverse Events


In the Phase II ACH443-015 trial (NCT00350272), drug-related adverse events (AEs) associated with elvucitabine and occurring in 5% or more of participants were nausea, dizziness, fatigue, diarrhea, vomiting, dyspepsia, and asthenia. The incidence, type, and severity of AEs were similar between the elvucitabine and lamivudine treatment groups. One participant discontinued elvucitabine because of severe neutropenia, which was considered to be probably related with elvucitabine. Twenty-five serious adverse events (SAEs) occurred (13 in the elvucitabine group; 12 in the lamivudine group), none of which were considered to be related to the study drug.5,16,17


Drug Interactions


Elvucitabine is neither an inducer nor an inhibitor of CYP enzymes.6

When ritonavir 300 mg was coadministered with elvucitabine 20 mg in a single-dose drug interaction study, ritonavir significantly reduced the bioavailability of elvucitabine.20


References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: https://chem.nlm.nih.gov/chemidplus/rn/181785-84-2. Last accessed on January 17, 2018.
  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 January 17, 2018.
  3. Achillion Pharmaceuticals. Achillion Pharmaceuticals 2009 annual report. Available at: http://files.shareholder.com/downloads/ACHN/3406700524x0x368900/1A85086D-BD5F-4384-B5F9-960A5E379C48/ACHL_09AR_4.26.10.pdf. Last accessed on January 17, 2018.
  4. Achillion Pharmaceuticals. Annual report 2015. Available at: http://ir.achillion.com/common/download/download.cfm?companyid=ACHN&fileid=886891&filekey=15492205-1075-42CF-B4D3-7D81C2EF4B1E&filename=ACHN_2015_AR.pdf. Last accessed on January 17, 2018.
  5. DeJesus E, Saple D, Morales-Ramirez J, et al. Elvucitabine vs lamivudine with tenofovir and efavirenz in antiretroviral-treatment-naïve HIV-1 infected patients: 96 week final results. Poster presented at: 17th Conference on Retroviruses and Opportunistic Infections (CROI); February 16-19, 2010; San Francisco, CA. Paper 511. Available at: http://www.retroconference.org/2010/PDFs/511.pdf. Last accessed on May 22, 2013.
  6. Colucci P, Pottage JC, Robison H, et al. Multiple-dose pharmacokinetic behavior of elvucitabine, a nucleoside reverse transcriptase inhibitor, administered over 21 days with lopinavir-ritonavir in human immunodeficiency virus type 1-infected subjects. Antimicrob Agents Chemother. 2009 Feb;53(2):662-9. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2630663/. Last accessed on January 17, 2018.
  7. Dutschman GE, Bridges EG, Liu SH, et al. Metabolism of 2',3'-dideoxy-2',3'-didehydro-beta-L(-)-5-fluorocytidine and its activity in combination with clinically approved anti-human immunodeficiency virus beta-D(+) nucleoside analogs in vitro. Antimicrob Agents Chemother. 1998 Jul;42(7):1799-804. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC105686/. Last accessed on January 17, 2018.
  8. Esposito F, Corona A, Tramontano E. HIV-1 reverse transcriptase still remains a new drug target: structure, function, classical inhibitors, and new inhibitors with innovative mechanisms of actions. Mol Biol Int. 2012;Volume 2012:Article ID 586401. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3388302/. Last accessed on January 17, 2018.
  9. Zhu YL, Dutschman DE, Liu SH, Bridges EG, Cheng YC. Anti-hepatitis B virus activity and metabolism of 2',3'-dideoxy-2',3'-didehydro-beta-L(-)-5-fluorocytidine. Antimicrob Agents Chemother. 1998 Jul;42(7):1805-10. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC105687/. Last accessed on January 17, 2018.
  10. DeJesus E, Saple D, Morales-Ramirez J, et al. Elvucitabine Phase II 48 week interim results show safety and efficacy profiles similar to lamivudine in treatment naive HIV-1 infected patients with a unique pharmacokinetic profile. 48th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)/46th Infectious Diseases Society of America (IDSA) Meeting; October 25-28. 2008; Washington DC. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2008. Available at: http://www.natap.org/2008/ICAAC/ICAAC_22.htm. Last accessed on January 17, 2018. [Archived at WebCite]
  11. Hammond JL, Parikh UM, Koontz DL, et al. In vitro selection and analysis of human immunodeficiency virus type 1 resistant to derivatives of beta-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine. Antimicrob Agents Chemother. 2005 Sep;49(9):3930-2. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1195387/. Last accessed on January 17, 2018.
  12. Parikh UM, Koontz DL, Chu CK, Schinazi RF, Mellors JW. In vitro activity of structurally diverse nucleoside analogs against human immunodeficiency virus type 1 with the K65R Mutation in reverse transcriptase. Antimicrob Agents Chemother. 2005 Mar;49(3):1139-44. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC549267/. Last accessed on January 17, 2018.
  13. Dunkle LM, Gathe JC, Pedevillano DE, Robison HG, Rice WG, Pottage JC. Elvucitabine: potent antiviral activity demonstrated in multidrug-resistant HIV infection. Abstract presented at: 12th International HIV Drug Resistance Workshop: Basic Principles & Clinical Implications; June 10-14, 2003; Los Cabos, Mexico. Abstract 2. Available at: https://www.intmedpress.com/serveFile.cfm?sUID=759f6f9d-a638-47c3-be71-7d7aaa2efb7d. Last accessed on January 17, 2018.
  14. Achillion Pharmaceuticals. A 14 day randomized, double blind, study of once daily elvucitabine versus lamivudine in subjects with a documented M184V mutation. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 5, 2006. NLM Identifier: NCT00312039. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00312039. Last accessed on January 17, 2018.
  15. Achillion Pharmaceuticals: Press Release, dated January 31, 2008. New data for Achillion's elvucitabine demonstrate drug's safety, efficacy and suitability for combination therapy in HIV-infected patients. Available at: http://ir.achillion.com/releasedetail.cfm?releaseid=291181. Last accessed on January 17, 2018. [Archived at WebCite]
  16. Mascolini M. Elvucitabine versus 3TC in first-line regimens for 96 weeks - see slides from poster below. Conference Reports for National AIDS Treatment Advocacy Project (NATAP): 17th Conference on Retroviruses and Opportunistic Infections (CROI); February 16-19, 2010; San Francisco, CA. Available at: http://www.natap.org/2010/CROI/croi_60.htm. Last accessed on January 17, 2018. [Archived at WebCite]
  17. Achillion Pharmaceuticals. A randomized, blinded, 12-week comparison of elvucitabine/efavirenz/tenofovir versus lamivudine/efavirenz/tenofovir in HIV-1 infected, treatment naive subjects. There is a 36 week, open label, extension phase for eligible subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 6, 2006. NLM Identifier: NCT00350272. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00350272. Last accessed on January 17, 2018.
  18. Achillion Pharmaceuticals. An open label treatment protocol to provide continued elvucitabine treatment for 48-weeks in subjects who have completed 96-weeks of elvucitabine therapy in protocol ACH443-015 or 48 weeks of therapy in protocol ACH443-018. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 8, 2008. NLM Identifier: NCT00675844. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00675844. Last accessed on January 17, 2018.
  19. Achillion Pharmaceuticals. An open-label,48 week extension study of elvucitabine administered In combination with background antiretroviral agents in subjects who have completed 14 days of treatment in protocol ACH443-014A. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 21, 2006. NLM Identifier: NCT00380159. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00380159. Last accessed on January 17, 2018.
  20. Colucci P, Pottage JC, Robison H, Turgeon J, Ducharme MP. Effect of a single dose of ritonavir on the pharmacokinetic behavior of elvucitabine, a nucleoside reverse transcriptase inhibitor, administered in healthy volunteers. Antimicrob Agents Chemother. 2009 Feb;53(2):646-50. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2630647/. Last accessed on January 17, 2018.


Last Reviewed: January 17, 2018