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Investigational

BMS-986001  Audio icon

Other Names: 4'-Ed4T, 4'-ethynyl-d4T, festinavir, OBP-601
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
Company: Oncolys BioPharma; Bristol-Myers Squibb
Phase of Development: IIb
Chemical Image:
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BMS-986001
BMS-986001
Molecular Weight: 248.2368
(Compound details obtained from ChemIDplus Advanced1, NIAID Therapeutics Database2, and Bristol-Myers Squibb website3)
Patent Version Content

Pharmacology


Mechanism of Action: Nucleoside reverse transcriptase inhibitor. BMS-986001 (4′-Ed4T), a thymidine analog, is phosphorylated by host cellular kinases to its active triphosphate metabolite (4′-Ed4T triphosphate or 4′-Ed4TTP), with 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

: Apparent half-life ranged from 2.3 to 3.7 hours in a single oral-dose escalation study of healthy subjects in the fed (10 to 900 mg) and fasting states (100 and 300 mg).7

Metabolism/Elimination: Approximately 60% to 95% of the oral BMS-986001 dose was excreted unchanged in urine in a single oral-dose escalation study of healthy subjects in the fed (10 to 900 mg) and fasting states (100 and 300 mg).7

Resistance: In vitro experiments have shown that virus containing the K65R, Q151M (without M184), and possibly L74V mutations demonstrates hypersusceptibility to BMS-986001. Meanwhile, thymidine analogue mutation pattern 1 (TAM1) pathway virus has reduced susceptibility, exhibiting increasing fold changes with increasing numbers of mutations. Compared to wild-type (wt) virus, TAM2 pathway virus exhibited a 6- to 8-fold reduced susceptibility to BMS-986001, regardless of the number of thymidine analogue mutations (TAMs).8

In a dose-escalation study of 100 to 600 mg of BMS-986001 monotherapy in treatment-experienced adults, no NRTI-associated resistance mutations were selected after 10 days of monotherapy.9


Dosing in Clinical Trials


In a single oral-dose escalation study of healthy subjects in the fed (10 to 900 mg) and fasting states (100 and 300 mg), there was no statistically significant effect of food on the pharmacokinetics of BMS-986001.7

BMS-986001 is administered once daily and orally.10,11

Phase Ib/IIa 10-day dose-escalation study (treatment-experienced, currently off treatment):

  • BMS-986001 100 to 600 mg, monotherapy.9,10
Phase IIb dose-response study (treatment-naive):

  • BMS-986001 100- to 400-mg capsules versus tenofovir DF 300 mg, each in combination with efavirenz and lamivudine.11


Adverse Events


At high exposures, the major preclinical toxicities with BMS-986001 have been hematological. A nonclinical renal and bone toxicity study of BMS-986001 in which BMS-986001 was administered orally for 6 months in rats (50-300 mg/kg/day) and monkeys (50-200 mg/kg/day) found no evidence of BMS-986001-related changes in renal function, biomarkers of renal toxicity, serum phosphate, calcium, or biomarkers of bone formation or resorption.12

The in vitro cytotoxicity of BMS-986001 has been compared with four other NRTIs (tenofovir DF, zidovudine, stavudine, and abacavir) in cell cultures of human renal proximal tubule epithelium, muscle, preadipocytes, and differentiated adipocyctes. Based on in vitro cytotoxicity parameters that were measured (total cell protein and ATP content, cell mitochondrial ATP8 DNA content, and lactate concentration in the media), BMS-986001 did not significantly reduce mtDNA and was not cytotoxic in any of the cell culture systems tested. When compared to the four other NRTIs, BMS-986001 was the least cytotoxic, with zidovudine and stavudine being the most cytotoxic.13

In a 10-day dose-escalation study of 100 to 600 mg of BMS-986001 monotherapy, 27 out of 32 enrolled subjects reported 99 adverse events, of which 62 were considered unrelated to the study drug. Two BMS-986001-unrelated grade 4 adverse events occurred in the 600-mg dose group. No clear pattern of adverse events emerged from this trial.10


Drug Interactions


BMS-986001 drug interactions are currently unknown.


References


1. United States National Library of Medicine. ChemIDplus Advanced.

2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development.

3. Bristol-Myers Squibb: Press Releases. Bristol-Myers Squibb and Oncolys BioPharma Enter Global Licensing Agreement for Investigational HIV Compound. Accessed May 10, 2013.

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.

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.

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.

7. Matsuda T, Paintsil E, Ross JS, Schofield J, Cheng YC, Urata Y. A Single Dose Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of OBP-601 (Festinavir, a Novel NRTI) in Healthy Subjects. Poster presented at: 16th Conference on Retroviruses and Opportunistic Infections (CROI); February 8-11, 2009; Montreal, Canada. Poster 568.

8. 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.

9. 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.

10. 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.

11. 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. Last Accessed: May 10, 2013.

12. Guha M, Pilcher G, Moehlenkamp J, et al. Absence of renal and bone toxicity in non-clinical studies of BMS-986001, a nucleoside reverse transcriptase inhibitor (NRTI) of human immunodeficiency virus (HIV). Abstract presented at: 19th International AIDS Conference; July 22-27, 2012; Washington DC. Abstract TUPE041.

13. Wang F, Flint O. The HIV NRTI BMS-986001 does not degrade mitochondrial DNA in long term primary cultures of cells isolated from human kidney, muscle and subcutaneous fat. Abstract presented at: 19th International AIDS Conference; July 22-27, 2012; Washington DC. Abstract TUPE042.


Last Reviewed: May 17, 2013

Last Updated: May 17, 2013


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