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ICAAC 2014: NRTI BMS-986001 Safe and Effective, but Associated with Resistance

BMS-986001, an experimental HIV nucleoside reverse transcriptase inhibitor, was shown to be as effective as tenofovir with less bone loss, but more people who took it developed resistance, researchers reported at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy this week in Washington, DC. Bristol-Myers Squibb has announced it will end its development of the drug.

Modern nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) are generally safe and effective components of combination antiretroviral therapy, but the most widely used NRTI -- tenofovir disoproxil fumarate (Viread, also in the Atripla, Complera, and Stribild coformulations) -- can cause kidney problems and bone loss in some people.

Samir Gupta from Indiana University School of Medicine and colleagues conducted a Phase 2b trial (AI467003) comparing the safety and efficacy of BMS-986001, a novel thymidine analog NRTI, versus tenofovir. This antiretroviral subclass is potent against HIV, but the older drugs zidovudine (AZT, Retrovir) and stavudine (d4T, Zerit) are associated with side effects including mitochondrial toxicity, body fat loss (lipoatrophy), and peripheral neuropathy.

This multinational study included 301 participants starting HIV treatment for the first time in North and South America, Spain, South Africa, Australia, and Thailand. Two-thirds were men, half were black, about 20% were Asian, about 14% were white, and the median age was 31 years. The median CD4 T-cell count was just over 300 cells/mm³ and the median baseline HIV viral load was approximately 4.4 log. People with a history or current evidence of resistance to any of the study drugs were excluded.

Participants were randomly assigned to receive BMS-986001 at doses of 100, 200, or 400 mg or tenofovir at 300 mg, both once-daily, in combination with lamivudine (300 mg) and the NNRTI efavirenz (Sustiva).

Results

• After 24 weeks of treatment, 81% to 94% of BMS-986001 recipients, depending on dose, reached undetectable viral load (< 50 copies/mL), compared with 89% of tenofovir recipients -- not a statistically significant difference.
• After 48 weeks, the proportions with undetectable viral load were 75% to 89% in the BMS-986001 arms vs 82% in the tenofovir arm.
• CD4 cell gains were similar across all treatment arms.
• A greater proportion of people in the BMS-986001 arm developed resistance to study drugs: 14% with 100 mg BMS-986001 and 6% with 200 or 400 mg BMS-986001 vs just 1% with tenofovir.
• BMS-986001 was generally safe and well -tolerated through 48 weeks.
• Serious adverse events were reported by 8% to 12% of BMS-986001 recipients and 9% of tenofovir recipients.
• There were 2 serious adverse events leading to early drug discontinuation in the BMS-986001 arms (all doses combined) and 2 in the tenofovir arm.
• Laboratory abnormalities were mostly transient and did not lead to drug discontinuation.
• Limb fat and trunk fat increased more in the BMS-986001 arms -- especially 400 mg -- than in the tenofovir arm.

"Through Week 24/48, higher doses of BMS-986001 demonstrated comparable efficacy to [tenofovir] when combined with [efavirenz + lamivudine] in treatment-naive, HIV-1-infected subjects," the researchers conclude. However, they added, a "higher percentage of subjects developed resistance to study drug(s) in the BMS-986001 arms regardless of dose."

A related poster presentation by Grace McComsey from Case Western Reserve University and colleagues reported that BMS-986001 was associated with less bone loss at the hip and lumbar spine after starting treatment compared with tenofovir. There was a trend toward more central and abdominal fat accumulation in the BMS-986001 arms, again especially at the highest dose. However, there were "no meaningful changes" in mitochondrial DNA, an indicator of mitochondrial toxicity.

Despite the promising safety and efficacy of BMS-986001 in these studies, the higher risk of developing drug resistance is a concern. Gupta reported that Bristol-Myers Squibb decided to terminate its agreement with Oncolys BioPharma to co-develop the drug, and it is not yet known whether Oncolys will move forward with it.

9/12/14

References

SK Gupta, J Lombaard, J Echevarria, et al. HIV NRTI BMS-986001 in Antiretroviral-Naive Subjects: Week 24/48 Analyses. 54th Interscience Conference on Antimicrobial Agents and Chemotherapy(ICAAC 2014), September 5-9, in Washington, DC. Abstract H-642.

GA McComsey, SK Gupta, C Orrell, et al. HIV NRTI BMS-986001 in Antiretroviral-Naive Subjects: Evaluation of Bone and Metabolic Safety Data Through Week 48. 54th Interscience Conference on Antimicrobial Agents and Chemotherapy(ICAAC 2014), September 5-9, in Washington, DC. Abstract H-1644.