Mechanism of Action: Nucleoside reverse transcriptase inhibitor. OBP-601 (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
Half-life (T½): Apparent half-life ranged from 2.3 to 3.7 hours in a single oral-dose escalation study of healthy subjects in the fed state (10 to 900 mg) and fasting state (100 and 300 mg).7
Metabolism/Elimination: Approximately 60% to 95% of an oral OBP-601 dose was excreted unchanged in urine in a single oral-dose escalation study of healthy subjects in the fed state (10 to 900 mg) and fasting state (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 OBP-601. Meanwhile, thymidine analogue mutation pattern 1 (TAM1) pathway virus has reduced susceptibility, exhibiting increasing fold changes with increasing numbers of mutations. Decreased susceptibility was also associated with virus containing the T69 insertion complex and with a Q151M virus that also contained M184V. Compared to wild-type (wt) virus, TAM2 pathway virus exhibited a 6- to 8-fold reduced susceptibility to OBP-601, regardless of the number of thymidine analogue mutations (TAMs).8,9
In a dose-escalation study of 100 to 600 mg of OBP-601 monotherapy in treatment-experienced adults, no NRTI-associated resistance mutations were selected after 10 days of monotherapy.9,10 Three participants had a decreased response to OBP-601 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 OBP-601 treatment.11
Dosing in Clinical Trials
Food does not significantly affect the pharmacokinetics of OBP-601.7
: 2008-004810-29 (EUDRACT Number)11
: Dose-escalation study to evaluate the antiviral activity, safety, and pharmacokinetics of OBP-601 over 10 days
: HIV-infected, treatment-experienced adults (off antiretroviral [ARV] therapy for at least 3 months)
: OBP-601 was administered as monotherapy. Four groups of participants were sequentially assigned to receive either OBP-601 (100, 200, 300, and 600 mg) or placebo once daily.10-12
(See references cited above for information on study results.)
: Dose-response study to identify a safe and effective dose(s) of OBP-601 when combined with efavirenz and lamivudine; tenofovir DF combined with efavirenz and lamivudine used as a comparison
: HIV-infected, treatment-naive adults
: OBP-601 was administered orally and once daily. Participants were randomized to one of the following four groups:
- OBP-601 100 mg plus OBP-601 matching placebo plus efavirenz and lamivudine
- OBP-601 200 mg plus OBP-601 matching placebo plus efavirenz and lamivudine
- OBP-601 400 mg plus efavirenz and lamivudine
- Tenofovir DF 300 mg plus efavirenz and lamivudine.13
* This study has been terminated.13
At high exposures, the major preclinical toxicities with OBP-601 have been hematological. A nonclinical renal and bone toxicity study of OBP-601 in which OBP-601 was administered orally for 6 months in rats (50 to 300 mg/kg/day) and monkeys (50 to 200 mg/kg/day) found no evidence of OBP-601-related changes in renal function, biomarkers of renal toxicity, serum phosphate, calcium, or biomarkers of bone formation or resorption.14
The in vitro cytotoxicity of OBP-601 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), OBP-601 did not significantly reduce mitochondrial DNA and was not cytotoxic in any of the cell culture systems tested. When compared to the four other NRTIs, OBP-601 was the least cytotoxic, with zidovudine and stavudine being the most cytotoxic.15
In a 10-day dose-escalation study of 100 to 600 mg of OBP-601 monotherapy, 22 out of 24 OBP-601-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. No study discontinuations due to an AE and no Grade 4 AEs occurred. When compared to participants receiving placebo, a greater proportion of participants receiving OBP-601 reported Grade 2 and 3 AEs. Two OBP-601-unrelated serious AEs occurred in the 600-mg dose group. The most common AEs in the OBP-601 groups (occurring in more than 10% of participants) were abdominal pain, lymphadenopathy, nausea, headache, and fatigue.11
OBP-601 drug interactions are currently unknown.
- United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/634907-30-5. Last accessed on October 1, 2014.
- 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 October 1, 2014.
- Clayden P, Collins S, Daniels C, et al. HIV i-BASE/Treatment Action Group. 2014 Pipeline Report. Benzacar A, ed. July 2014. Available at: http://www.pipelinereport.org/sites/g/files/g575521/f/201407/2014%20Pipeline%20Report%20Full_0.pdf. Last accessed on October 1, 2014.
- 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: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715651/. Last accessed on October 1, 2014.
- 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: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2415781/. Last accessed on October 1, 2014.
- 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: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2151449/. Last accessed on October 1, 2014.
- 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 October 1, 2014.
- 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: http://www.intmedpress.com/serveFile.cfm?sUID=8ed08ff3-8b0b-4cda-b481-30a670282653. Last accessed on October 1, 2014.
- 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: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3811251/. Last accessed on October 1, 2014.
- 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 October 1, 2014.
- 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 October 1, 2014.
- 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 October 1, 2014.
- 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: http://www.clinicaltrials.gov/ct2/show/NCT01489046. Last Accessed on October 1, 2014.
- 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. Available at: http://pag.aids2012.org/abstracts.aspx?aid=16832. Last accessed on October 1, 2014.
- 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. Available at: http://pag.aids2012.org/abstracts.aspx?aid=17957. Last accessed on October 1, 2014.
Last Reviewed: October 1, 2014
Last Updated: October 1, 2014