Treatment with BMS-663068, an experimental HIV-1 attachment inhibitor, achieves substantial reductions in viral load and has only mild side-effects, results of an eight-day study published in the online edition of the Journal of Infectious Diseases show.
The study involved 48 HIV-positive people, all of whom had a viral load above 5000 copies/ml. These participants were randomised to receive one of five doses of BMS-663068, with or without a 100mg ritonavir booster.
“Short-term dosing of BMS-663068 with or without ritonavir, resulted in substantial declines in plasma HIV-1 RNA levels in both antiretroviral-naïve and antiretroviral-experienced subjects,” comment the authors. All the investigational regimens achieved a drop of viral load of at least 1 log10.
BMS-663068 is a prodrug of the attachment inhibitor BMS-626529. It binds to gp120, a glycoprotein in HIV, preventing the attachment of HIV to CD4 cells. Studies conducted in HIV-negative volunteers showed that BMS-663068 was rapidly converted into the active drug, BMS-626529, with good absorption. The use of a ritonavir booster was shown to enhance exposure to BMS-626529.
Investigators wanted to find out more about the anti-HIV activity, pharmacokinetics and safety of BMS-663068 in HIV-positive people. They therefore designed an eight-day monotherapy study.
Healthy HIV-positive adults were randomised to receive one of five doses of BMS-663068, each of which was taken with food:
- 600mg BMS-663068 plus 100mg ritonavir every twelve hours.
- 1200mg BMS-663068 plus 100mg ritonavir at bedtime.
- 1200mg BMS-663068 plus 100mg ritonavir every twelve hours.
- 1200mg BMS-663068 plus 100mg ritonavir every morning.
- 1200mg BMS-663068 without a ritonavir booster every twelve hours.
The participants were admitted to a clinical facility where they remained for eleven days. They returned for further evaluation on day 15 and again on day 50.
Viral load was monitored before entry to the study, between days 1 and 11, and again on days 15 and 50. CD4 cell count was measured on days 1, 8, 15 and 50. Blood samples were regularly monitored to assess the participants’ susceptibility to the therapy (IC50). Maximum, minimum and steady-state concentrations of the therapy were assessed at regular intervals.
Approximately 70% of participants had never taken HIV therapy before. Median baseline viral load was 25,000 copies/ml, and the median CD4 cell count was 432 cells/mm3.
Overall, there was an increase in viral load during days two and three of therapy. “The etiology for these observations is unknown but is possibly associated with the unique mechanism of action of an attachment inhibitor that binds to the gp120 molecule and does not allow the virus to bind to host cells, thereby resulting in an initial increase of circulating HIV-1 virons detectable in plasma,” suggest the authors.
However, viral load then fell up to day 15 in all treatment groups. It had returned to baseline values by day 50.
The median fall in viral load ranged between 1.21 log10 for the participants taking unboosted BMS-663068 to 1.73 log10 among the participants treated with 1200mg BMS-663068 twice daily with ritonavir.
The authors believe that the poorer virological response in people taking the unboosted drug was because four individuals had reduced susceptibility to BMS-663068. When these participants were excluded from analysis, no significant differences in anti-HIV activity were observed between this and the other treatment arms. Nor did the efficacy of the treatment differ between treatment-naive and treatment-experienced patients.
“Drug susceptibility at baseline has previously been shown to be an important determinant of viral response with this class of drug,” note the researchers.
A viral load below 400 copies/ml was achieved by 18 participants. None of the people with reduced drug susceptibility achieved a viral load below this level.
By day eight, there had been increases in CD4 cell count in all the study arms (between 23 and 130 cells/mm3). However, the investigators were unclear as to the clinical significance of these changes.
Pharmacokinetic analysis showed that use of a ritonavir booster led to only modest increases in drug exposure, which did not translate to improved virological control. “These findings support the further investigation of lower doses of BMS-663068 given without ritonavir in subjects with susceptible virus at baseline,” write the authors.
The treatment appeared to be safe. Two-thirds of patients developed treatment-related side-effects. But these were all mild or moderate. The most frequent were headache, rash and an urgent need to urinate.
“This proof-of-concept study demonstrates the potent antiviral activity of the novel attachment inhibitor prodrug BMS-663068,” conclude the authors. “These data, together with the favourable pharmacokinetic profile and generally good tolerability observed in this study, support the further clinical development of BMS-663068 in combination antiretroviral therapy. A phase IIb study of BMS-663068 in treatment-experienced subjects (NCT01384734) is currently ongoing.”
Nettles RE et al. Pharmacodynamics, safety, and pharmacokinetics of BMS-663068 an oral HIV-1 attachment inhibitor in HIV-1 infected subjects. J Infect Dis, online edition. DOI: 10.1093/infdis/jis432, 2012.