A Clinical Overview of BMS-663068

May 20, 2013

Other Names: Prodrug of BMS-626529
Drug Class: Entry and Fusion Inhibitors
Registry Number: S900005840 (ChemID)
Company: Bristol-Myers Squibb
Phase of Development: II
Molecular Weight: 704.6303
(Compound details obtained from ChemIDplus Advanced1 and NIAID Therapeutics Database2)


Mechanism of Action: HIV-1 entry inhibitor. BMS-663068 is a methyl phosphate prodrug of the small molecule inhibitor BMS-626529.3,4 BMS-626529 prevents viral entry by binding to the viral envelope gp120 and interfering with virus attachment to the host CD4 receptor.5

: BMS-626529, multiple-ascending-dose study: 3.2 to 4.5 hours (immediate-release formulation); 7 to 14 hours (extended-release formulation [with or without ritonavir]).6

Metabolism/Elimination: BMS-626529 is metabolized via esterase-mediated hydrolysis and cytochrome P450 (CYP)-mediated oxidation.7 In a single-dose study, urinary recovery of BMS-626529 was less than 4%.6

Resistance: Monotherapy with BMS-663068 does not appear to select for BMS-626529 resistance.8 The gp120 substitutions M426L and S375M are associated with low susceptibility to BMS-626529.9

No in vitro cross resistance between BMS-626529 and other entry inhibitors (ibalizumab, enfuvirtide) has been observed. Some maraviroc-resistant envelopes exhibited decreased susceptibility to BMS-626529; however, susceptibility to BMS-626529 was shown to be independent from maraviroc resistance.10

In vitro activity of BMS-626529 has generally not been associated with tropism or subtype (with the exception of subtype AE and possibly group O).11 BMS-663068 is unlikely to promote resistance via generation of CD4-independent virus.10


BMS-663068 is administered orally.5

Phase IIa (clade B, treatment-naive or -experienced):

  • Various doses and dosing schedules with total daily BMS-663068 doses ranging from 1200 mg to 2400 mg (with and without ritonavir).3,12

Phase IIb (treatment-experienced):

  • BMS-663068 (400 or 800 mg twice daily; or 600 or 1200 mg once daily) versus atazanavir 300 mg plus ritonavir 100 mg, each in combination with raltegravir and tenofovir DF.13

Adverse Events

The most common adverse events associated with BMS-663068 (various doses up to 1200 mg twice daily) in a Phase IIa trial were headache and rash. All doses were generally well tolerated, with no deaths, serious adverse events, or study discontinuations due to adverse events. There were no clinically relevant effects on electrocardiogram (ECG), laboratory values, vital signs, or physical exams.5

Drug Interactions

BMS-663068 and BMS-626529 are neither inducers nor inhibitors of major CYP enzymes. Dose adjustments are not necessary when BMS-663068 is co-administered with tenofovir DF.7


  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. Nettles RE, Schürmann D, Zhu L, et al. Pharmacodynamics, safety, and pharmacokinetics of BMS-663068, an oral HIV-1 attachment inhibitor in HIV-1-infected subjects. J Infect Dis. 2012 Oct 1;206(7):1002-11.
  4. Nowicka-Sans B, Gong Y-F, Ho H-T, et al. Antiviral Activity of a New Small Molecule HIV-1 Attachment Inhibitor, BMS-626529, the Parent of BMS-663068. Paper presented at: 18th Conference on Retroviruses and Opportunistic Infections (CROI); February 27-March 2, 2011; Boston, MA. Paper 518.
  5. Nettles R, Schurmann D, Zhu L, et al. Pharmacodynamics, Safety, and Pharmacokinetics of BMS-663068: A Potentially First-in-class Oral HIV Attachment Inhibitor. Paper presented at: 18th Conference on Retroviruses and Opportunistic Infections (CROI); February 27-March 2, 2011; Boston, MA. Paper 49.
  6. Mascolini M. Levels of Novel HIV Attachment Inhibitor With or Without Ritonavir. Conference Reports for National AIDS Treatment Advocacy Project (NATAP): 12th International Workshop on Clinical Pharmacology of HIV Therapy; April 13-15, 2011; Miami, FL. Accessed March 20, 2013.
  7. Zhu L, Hwang C, Shah V, et al. No clinically significant drug interaction when BMS-663068, a novel HIV-1 attachment inhibitor, is coadministered with tenofovir disoproxil fumarate. Abstract presented at: 13th International Workshop on Clinical Pharmacology of HIV Therapy; March 16-18, 2012; Barcelona, Spain. Abstract P_13.
  8. Ray N, Wind-Rotolo M, Healy M, et al. Lack of Resistance Development to the HIV-1 Attachment Inhibitor BMS-626529 during Short-term Mono-therapy with Its Pro-drug BMS-663068. Paper presented at: 19th Conference on Retroviruses and Opportunistic Infections (CROI); March 5-8, 2012; Seattle, WA. Paper 725.
  9. Zhou N, Ray N, Healy M, et al. Genotypic and phenotypic correlates of virological response to the attachment inhibitor BMS-626529 in a short-term monotherapy study with its prodrug BMS-663068. Abstract presented at: International Workshop on HIV & Hepatitis Virus Drug Resistance and Curative Strategies; June 5-9, 2012; Sitges, Spain. Abstract 6.
  10. Li Z, Zhou N, Sun Y, et al. Activity of the HIV-1 attachment inhibitor BMS-626529 against HIV-1 envelopes resistant to other entry inhibitors. Abstract presented at: 19th International AIDS Conference; July 22-27, 2012; Washington DC. Abstract TUPE015.
  11. Nowicka-Sans B, Gong YF, McAuliffe B, et al. In vitro antiviral characteristics of HIV-1 attachment inhibitor BMS-626529, the active component of the prodrug BMS-663068. Antimicrob Agents Chemother. 2012 Jul;56(7):3498-507.
  12. Bristol-Myers Squibb. Randomized, Open Label, Multiple-Dose Study to Evaluate the Pharmacodynamics, Safety and Pharmacokinetics of BMS-663068 in HIV-1 Infected Subjects. In: Bethesda (MD): National Library of Medicine (US). Registered on November 6, 2009. NLM Identifier: NCT01009814. Last Accessed: March 20, 2013.
  13. Bristol-Myers Squibb. A Phase IIb Randomized, Controlled, Partially-Blinded Trial to Investigate Safety, Efficacy and Dose-Response of BMS-663068 in Treatment-experienced HIV-1 Subjects, Followed by an Open-Label Period on the Recommended Dose. In: Bethesda (MD): National Library of Medicine (US). Registered on June 23, 2011. NLM Identifier: NCT01384734. Last Accessed: March 20, 2013.

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