HIV Attachment Inhibitor BMS-663068 Looks Good in Early Studies


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:

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.


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).



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.