Drugs

Censavudine

Other Names: 4'-Ed4T, 4'-ethynyl-d4T, 4'-ethynylstavudine, BMS-986001, OBP-601, festinavir Drug Class: Nucleoside Reverse Transcriptase Inhibitors
Molecular Formula: C12 H12 N2 O4
Registry Number: 634907-30-5 (CAS) Chemical Name: 1-[(2R,5R)-5-ethynyl-5-(hydroxymethyl)-2H-furan-2-yl]-5-methyl-pyrimidine-2,4-dione Chemical Class: Pyrimidine Nucleosides Organization: Oncolys BioPharma Phase of Development: IIb

Chemical Image:

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censavudine

censavudine

Molecular Weight: 248.2368

(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 and Oncolys BioPharma website3)

Pharmacology


Mechanism of Action: Nucleoside reverse transcriptase inhibitor. Censavudine (4′-Ed4T), a thymidine analog, is phosphorylated by host cellular kinases to its active triphosphate metabolite (4′-Ed4T triphosphate or 4′-Ed4TTP). 4′-Ed4TTP has an intracellular half-life of approximately 8.0 to 9.7 hours.4 4′-Ed4TTP inhibits the activity of HIV-1 reverse transcriptase by competing with natural substrates and causing DNA chain termination after incorporating itself into viral DNA.5,6 In vitro, censavudine exhibits more potent activity against HIV-2 than against HIV-1.7,8

Half-life (T½): In a single oral-dose escalation study of censavudine administered to healthy participants under fed conditions (10 to 900 mg) and fasting conditions (100 and 300 mg), the apparent half-life of censavudine ranged from 2.3 to 3.7 hours.9

Metabolism/Elimination: In a single oral-dose escalation study of censavudine administered to healthy participants under fed conditions (10 to 900 mg) and fasting conditions (100 and 300 mg), approximately 60% to 95% of a censavudine dose was excreted unchanged in urine.9

Resistance: In vitro experiments have shown that HIV-1 containing K65R, the Q151M complex (without M184), or L74V are susceptible (and in some cases hypersusceptible) to censavudine. Thymidine analogue mutation pattern 1 (TAM1) pathway virus, however, demonstrate reduced susceptibility to censavudine and exhibit increasing fold changes with increasing numbers of mutations. Compared to wild-type (wt) virus, TAM2 pathway virus exhibit a 6- to 8-fold reduced susceptibility to censavudine, regardless of the number of thymidine analogue mutations (TAMs). Decreased censavudine activity has also occurred with virus containing either the T69 insertion complex or the Q151M complex with M184V. The M184V single substitution, which has been selected by censavudine in vitro, was shown to induce a 2.3-fold decrease in susceptibility to censavudine.10,11

Censavudine has demonstrated potent in vitro activity against HIV-2, including HIV-2 mutants containing the K65R and Q151M reverse transcriptase substitutions. The M184V mutation in HIV-2, however, resulted in a 15-fold resistance to censavudine relative to the wild-type HIV-2 strain.7

In a Phase IIa dose-escalation study (EudraCT number 2008-004810-29) of censavudine monotherapy (100 to 600 mg) in treatment-experienced adults, no NRTI-associated resistance mutations were selected after 10 days of treatment.11-13 Three participants had a decreased response to censavudine on Day 11, but did not have NRTI-associated mutations at baseline or on Day 11. Three other participants who had TAMs responded well to censavudine treatment.13

A Phase IIb study (NCT01489046) evaluated censavudine (100 to 400 mg) versus tenofovir DF, each administered with efavirenz and lamivudine in treatment-naive adults. Week 48 analysis showed that a higher percentage of participants developed treatment-emergent NNRTI and NRTI mutations in the censavudine groups (regardless of dose) than in the tenofovir DF group.14,15


Clinical Trials


Study Identifier: EudraCT 2008-004810-29
Funding Organizations: Oncolys Pharma and Bristol-Myers Squibb
Phase: IIa
Status: This study has been completed.
Study Purpose: The purpose of this dose-escalation study was to evaluate the antiviral activity, safety, and pharmacokinetics of censavudine over 10 days.
Study Population:
  • Participants were treatment-experienced adults with HIV who were off ART for at least 3 months before screening.
  • Participants had HIV RNA ≥5,000 copies/mL and CD4 counts ≥250 cells/mm3.

Dosing: Censavudine was administered as monotherapy. Four groups of participants were sequentially assigned to receive either censavudine (100, 200, 300, or 600 mg) or placebo once daily.12,13,16

Selected Study Results:

 

Study Identifiers: AI467003; NCT01489046
Sponsor: Bristol-Myers Squibb
Phase: IIb
Status: This study has been terminated.
Study Purpose: The purpose of this dose-response study was to identify a safe and effective dose of censavudine when combined with efavirenz and lamivudine.
Study Population:

  • Participants were treatment-naive adults with HIV.
  • Participants had HIV RNA >5,000 copies/mL and CD4 counts >200 cells/mm3.
Dosing: Censavudine was administered orally and once daily. Participants were randomized to 1 of the following 4 groups:
  • Censavudine 100 mg + efavirenz + lamivudine
  • Censavudine 200 mg + efavirenz + lamivudine
  • Censavudine 400 mg + efavirenz + lamivudine
  • Tenofovir DF 300 mg + efavirenz + lamivudine

Participants were blinded to the censavudine dose and received matching placebo tablets.14,15,17,18

Selected Study Results:


Adverse Events


EudraCT 2008-004810-29:
In this Phase IIa 10-day dose-escalation study of censavudine monotherapy, 22 out of 24 censavudine-treated participants experienced adverse events (AEs), which were mostly mild and unrelated or unlikely related to the study drug. AEs did not appear to be dose related. There were no study discontinuations due to an AE and no Grade 4 AEs. When compared to participants receiving placebo, a greater proportion of participants receiving censavudine reported Grade 2 and 3 AEs. Two censavudine-unrelated serious adverse events (SAEs) occurred in the 600-mg dose group. The most common AEs in the censavudine groups (occurring in more than 10% of participants) were abdominal pain, lymphadenopathy, nausea, headache, and fatigue.13

AI467003 (NCT01489046):
In this Phase IIb study, 297 total participants were treated with censavudine 100 mg (n = 65), 200 mg (n = 67), 400 mg (n = 66), or tenofovir DF (n = 99) through 48 weeks. Two censavudine-related SAEs (atypical drug eruption; thrombocytopenia) and 2 tenofovir DF-related SAEs (drug induced liver injury; depression and lipodystrophy) led to study discontinuation. One non-study drug-related death occurred. No Grade 2 to 4 AE trends were identified. Grade 2 to 4 laboratory abnormalities were transient and most did not result in study discontinuation.14

In a separate evaluation of bone and metabolic safety data through 48 weeks, bone mineral density (BMD) decline was found to be smaller in the censavudine groups than in the tenofovir DF group. A small and similar proportion of participants in each group had at least 10% or 20% loss of limb fat from baseline. There was a trend towards accumulation of central and peripheral fat across the censavudine groups, with the highest accumulation in the 400-mg dose group. No significant changes in mitochondrial DNA (mtDNA) copy number were seen in any treatment group. When compared with participants in the tenofovir DF arm, participants in the censavudine arms showed a trend for a greater increase in total cholesterol. The increases in total cholesterol in the censavudine arms were not dose-related.18


Drug Interactions


Censavudine drug interactions are currently unknown.


References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: https://chem.sis.nlm.nih.gov/chemidplus/rn/634907-30-5. Last accessed on December 27, 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 December 27, 2017.
  3. Oncolys BioPharma website. OBP-601 (censavudine). Available at: http://www.oncolys.com/en/pipeline/obp-601.html. Last accessed on December 27, 2017. [Archived at WebCite]
  4. Wang X, Tanaka H, Baba M, Cheng YC. Retention of metabolites of 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine, a novel anti-human immunodeficiency virus type 1 thymidine analog, in cells. Antimicrob Agents Chemother. 2009 Aug; 53(8):3317-24. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715651/. Last accessed on December 27, 2017.
  5. Yang G, Wang J, Cheng Y, et al. Mechanism of inhibition of human immunodeficiency virus type 1 reverse transcriptase by a stavudine analogue, 4'-ethynyl stavudine triphosphate. Antimicrob Agents Chemother. 2008 Jun;52(6):2035-42. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2415781/. Last accessed on December 27, 2017.
  6. Paintsil E, Dutschman GE, Hu R, et al. Intracellular metabolism and persistence of the anti-human immunodeficiency virus activity of 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine, a novel thymidine analog. Antimicrob Agents Chemother. 2007 Nov;51(11):3870-9. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2151449/. Last accessed on December 27, 2017.
  7. Smith RA, Raugi DN, Wu VH, et al. The nucleoside analog BMS-986001 shows greater in vitro activity against HIV-2 than against HIV-1. Antimicrob Agents Chemother. 2015 Dec;59(12):7437-46. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4649195/. Last accessed on December 27, 2017.
  8. Smith RA, Raugi DN, Parker K, et al. BMS-986001: a promising candidate for HIV-2 treatment. Abstract presented at: 24th International HIV Drug Resistance Workshop; February 21-22, 2015; Seattle, WA. Abstract 61. Available at: https://www.informedhorizons.com/resistance2015/pdf/RW2015_Book.pdf. Last accessed on November 22, 2016.
  9. Paintsil E, Matsuda T, Ross J, Schofield J, Cheng YC, Urata Y. A Single-dose Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of OBP-601, a Novel NRTI, in Healthy Subjects. 16th Conference on Retroviruses and Opportunistic Infections (CROI); February 8-11, 2009; Montreal, Canada. Levin: Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2009. Available at: http://www.natap.org/2009/CROI/croi_85.htm. Last accessed on December 27, 2017. [Archived at WebCite]
  10. Li Z, Terry B, Olds W, et al. The in vitro cross-resistance profile of the NRTI BMS-986001 against known NRTI resistance mutations. Abstract presented at: International Workshop on HIV & Hepatitis Virus Drug Resistance and Curative Strategies; June 5-9, 2012; Sitges, Spain. Abstract 2. Available at: https://www.intmedpress.com/serveFile.cfm?sUID=8ed08ff3-8b0b-4cda-b481-30a670282653. Last accessed on December 27, 2017.
  11. Li Z, Terry B, Olds W, et al. In vitro cross-resistance profile of nucleoside reverse transcriptase inhibitor (NRTI) BMS-986001 against known NRTI resistance mutations. Antimicrob Agents Chemother. 2013 Nov;57(11):5500-8. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3811251/. Last accessed on December 27, 2017.
  12. Hwang C, Zhu L, Chan H, et al. Antiviral activity, exposure-response, and resistance analyses of monotherapy with the novel HIV NRTI BMS-986001 in ART-experienced subjects. Abstract presented at: 13th International Workshop on Clinical Pharmacology of HIV Therapy; March 16-18, 2012; Barcelona, Spain. Abstract O_06. Available at: http://regist2.virology-education.com/abstractbook/2012_3.pdf. Last accessed on December 27, 2017. [Archived at WebCite]
  13. Cotte L, Dellamonica P, Raffi F, et al. Randomized placebo-controlled study of the safety, tolerability, antiviral activity, and pharmacokinetics of 10-day monotherapy with BMS-986001, a novel HIV NRTI, in treatment-experienced HIV-1-infected subjects. J Acquir Immune Defic Syndr. 2013 Jul 1;63(3):346-54. Available at: http://www.natap.org/2013/HIV/Randomized_Placebo_Controlled_Study_of_the_Safety,.13.pdf. Last accessed on December 27, 2017. [Archived at WebCite]
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  15. Bristol-Myers Squibb. A Phase IIb randomized, controlled, partially blinded clinical trial to investigate safety, efficacy and dose-response of BMS-986001 in treatment-naive HIV-1-infected subjects, followed by an open-label period on the recommended dose. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on December 7, 2011. NLM Identifier: NCT01489046. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01489046. Last accessed on December 27, 2017.
  16. Cotte L, Dellamonica P, Raffi F, et al. A Phase-Ib/IIa dose-escalation study of OBP-601 (4’-ethynyl-d4T, festinavir) in treatment-experienced, HIV-1-infected patients. Abstract presented at: 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 12-15, 2010; Boston, MA. Abstract H-933. Available at: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=d89fb4da-4268-4d6b-88ee-4f4ebcd548de&cKey=74572456-29b9-410f-8a57-972c2b0676c3&mKey=%7b93AEED6A-54D4-4EF6-99BD-A9B3CE9FACD9%7d. Last accessed on December 27, 2017. [Archived at WebCite]
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Last Reviewed: December 27, 2017