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HIV Attachment Inhibitor BMS-663068 Looks Good in Early Studies

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Bristol-Myers Squibb's novel attachment inhibitor pro-drug BMS-663068, which binds to HIV's gp120 envelope protein, potently suppressed viral load and was generally well-tolerated in a week-long monotherapy study, according to a report in the August 14, 2012, advance online edition of the Journal of Infectious Diseases. A related study showed that the active form of the drug worked against virus resistant to other entry inhibitors.

BMS-663068, a pro-drug of the small-molecule attachment inhibitor BMS-626529, prevents attachment of gp120 to the CD4 receptor on T-cells, which is required for HIV to infect these cells. Because it targets a different step of the viral lifecycle than existing antiretroviral agents, it offers promise for individuals with highly drug-resistant virus.

In this open-label study, Richard Nettles from Bristol-Myers Squibb Research and Development and colleagues randomly allocated 50 HIV positive participants to receive 1 of 5 different doses of BMS-663068 for 8 days:

  • 600 mg BMS-663068 + 100 mg ritonavir booster every 12 hours;
  • 1200 mg BMS-663068 + 100 mg ritonavir every 12 hours;
  • 1200 mg BMS-663068 + 100 mg ritonavir each night at bedtime;
  • 1200 mg BMS-663068 + 100 mg ritonavir each morning;
  • 1200 mg BMS-663068 without ritonavir every 12 hours.

About 70% of participants were antiretroviral-naive, the rest treatment-experienced. All had HIV RNA > 5000 copies/mLat study entry, with a median of about 25,000 copies/mL. The median CD4 count was about 430 cells/mm3. Viral load and CD4 counts were monitored at the beginning and end of the dosing period, and again at days 15 and 50.

Results

  • After a small viral load increase on treatment days 2 and 3, viral load then dropped through day 15, returning to baseline by day 50.
  • Maximum median decreases in plasma HIV RNA load from baseline ranged from 1.21 log copies/mL in the unboosted arm, to 1.73 log copies/mL in the boosted every-12-hour arm.
  • 18 people achieved viral load below 400 copies/mL.
  • Antiviral activity was similar in treatment-naive and treatment-experienced participants.
  • Antiviral activitydid not differ significantly in the 1200 mg once-daily arms based on time of dosing.
  • After excluding 4 participants with reduced susceptibility to BMS-626529 who were randomly assigned to the unboosted arm, ritonavir boosting did not significantly increase anti-HIV activity.
  • Overall, plasma concentrations of the active compound BMS-626529 were not associated with antiviral response.
  • However, low baseline inhibitory concentrations, as well as minimum and average steady-state BMS-626529 plasma concentrations, were linked with antiviral response after adjusting for baseline inhibitory quotient (which takes into account protein-binding).
  • CD4 cell counts increased in all arms, with gains ranging from 23 to 130 cells/mm3.
  • BMS-663068 was generally well-tolerated, with adverse events being mild-to-moderate.
  • The most commonly reported side effects were headache, skin rash, and urinary urgency.

Based on these findings, the study authors concluded, "Administration of BMS-663068 for 8 days with or without ritonavir resulted in substantial declines in plasma HIV-1 RNA levels and was generally well-tolerated."

"These data, together with the favorable pharmacokinetic profile and generally good tolerability observed in this study, support further clinical development of BMS-663068 in combination antiretroviral therapy," they added.

Speculating about the reason for the initial rise in viral load, they suggested that blocking HIV attachment to and entry into cells might allow virus to instead briefly build up in the bloodstream.

In a related laboratory study presented at the recent XIX International AIDS Conference (AIDS 2012), Bristol-Myers Squibb researchers looked at mechanism of resistance to BMS-626529 and cross-resistance with the entry inhibitors maraviroc (Selzentry), enfuvirtide (T-20; Fuzeon) and the experimental monoclonal antibody ibalizumab (TMB-355/TNX-355).

The investigators found that enfuvirtide-resistant and ibalizumab-resistant HIV envelopes remained susceptible to BMS-626529. Some maraviroc-resistant virus was also resistant to BMS-626529, though apparently due to a different mechanism. Conversely, BMS-626529-resistant HIV remained susceptible to all the entry inhibitors.

Furthermore, HIV isolates that do not require the CD4 receptor for cell entry were also susceptible to BMS-626529, and the virus did not escape the attachment inhibitor by becoming CD4-independent. Prior in vitro studies showed that BMS-626529 inhibits both CCR5-tropic and CXCR4-tropic HIV.

"Clinical use of the pro-drug BMS-663068 is unlikely to promote resistance via generation of CD4-independent virus," the researchers concluded. "No cross-resistance between the attachment inhibitor BMS-626529 and other HIV entry inhibitors was observed, which could allow for its use sequentially or concurrently with different classes of entry inhibitors."

A Phase 2b trial of BMS-663068 in combination antiretroviral regimens is currently underway and recruiting treatment-experienced participants (NCT01384734).

9/4/12

References

RE Nettles, D Schürmann, L Zhu, et al. Pharmacodynamics, Safety, and Pharmacokinetics of BMS-663068, an Oral HIV-1 Attachment Inhibitor in HIV-1-Infected Subjects. Journal of Infectious Diseases. August 14, 2012 (Epub ahead of print).

Z Li, N Zhou, Y Sun, et al. Activity of the HIV-1 attachment inhibitor BMS-626529 against HIV-1 envelopes resistant to other entry inhibitors. XIX International AIDS Conference (AIDS 2012). Abstract TUPE015.