 | HIV
and Hepatitis.com
Coverage of
the 13th Annual Conference on Retroviruses and Opportunistic Infections February 5 - 8, 2006, Denver, CO |
Schering Revives
Study of Experimental
CCR5 Entry Inhibitor
Vicriviroc in
Treatment-naďve
HIV Patients
The CCR5 entry inhibitors have shown promise in the treatment of HIV infection, but there also have been unexpected and serious setbacks that at least temporarily has shaken confidence in this new anti-HIV drug class. The first surprise came in September 2005 when GlaxoSmithKline halted all studies of its investigational CCR5 antagonist aplaviroc due to concerns about hepatotoxicity. Also citing liver toxicity concerns, Pfizer temporarily halted a Phase 3 study of the experimental CCR5 drug maraviroc in November 2005, but in January 2006 the drug’s Data and Safety Monitoring Board recommended continuation of the maraviroc Phase 3 development program. Schering had terminated the Phase 2 vicriviroc study in October 2005 when treatment-naďve patients receiving the drug in combination with zidovudine/lamivudine (Combivir) experienced virologic breakthrough compared to those who received the control regimen of Combivir and efavirenz (Sustiva). In his presentation at the 13th CROI, Wayne L. Greaves, MD, Senior Director of Global Clinical Development, Schering-Plough Research Institute said the Phase 2 study of 92 treatment-naďve patients showed vicriviroc was well-tolerated and demonstrated no evidence of liver toxicity. A clear dose response to treatment at two weeks as measured by the decline of viral load was observed, proving a strong predictor of sustained virologic response throughout the study. Shifts in tropism (R5 virus shift to dual mixed) were infrequent in this trial and observed in all treatment groups including placebo, with subsequent optimal HAART resulting in viral suppression. Finally, said Dr. Greaves, the optimal dose and background regimen for use with vicriviroc in this patient population requires further study. “These results have proven instructive to the further development of vicriviroc and will inform our plans for designing additional studies. While the optimal dose of vicriviroc and its role in antiretroviral regimens require further evaluation, vicriviroc was shown to be well tolerated by patients in this trial with no marked safety concerns – specifically, no liver toxicity,” said Greaves. “Further, separate drug interaction studies with commonly used protease inhibitors showed no need for dose adjustment for vicriviroc, which bodes well for studying vicriviroc in various protease inhibitor-containing treatment regimens in our future trials.” Treatment-Naďve Study and Results In
this trial,
CCR5-tropic
patients with
HIV from 22
sites throughout
Europe and The endpoints of this 48-week trial included mean change in log10 HIV RNA (the amount of virus in the blood) from baseline at two weeks, the proportion of patients with greater than 1 log decrease, the proportion of patients with HIV RNA less than 50 and less than 400 copies per milliliter, and the mean change in CD4 count from baseline. Mean duration of patient follow-up was 31.8 weeks (1-53.8 week range). Primary analysis at two weeks showed a mean decrease in HIV RNA of 0.93 log10 in the 25 mg arm, 1.18 in the 50 mg arm, 1.34 in the 75 mg arm, and 0.07 in the placebo arm (p<0.001 for each vicriviroc arm vs. placebo). The proportion of patients who experienced virologic breakthrough (RNA greater than or equal to 50 copies/mL) was 4 percent (1/24) in the placebo group, 56 percent (13/23) in the 25 mg group, 41 percent (9/22) in the 50 mg group, and 17 percent (4/23) in the 75 mg group (p<0.001, pooled vs. control). Mean change in CD4 count from baseline at week two was an increase of 24 cells/µL in the 25 mg group, 85 cells/µL in the 50 mg group, 90 cells/µL in the 75 mg group, and 3 cells/µL in the placebo group (p<0.001 for 50 and 75 mg vicriviroc arms vs. placebo). Drug Interaction Studies The results of drug interaction studies with vicriviroc and ritonavir-boosted protease inhibitors was the subject of another presentation by Schering-Plough researchers. Vicriviroc was studied in combination with ritonavir-boosted atazanavir (Reyataz), fosamprenavir (Lexiva), indinavir (Crixivan), nelfinavir (Viracept), and saquinavir (Invirase). There were no significant changes in vicriviroc plasma concentrations when combined with the protease inhibitor combinations. Regardless of whether a protease inhibitor affected other CYP450 enzymes or p-Gp, no change in effect on vicriviroc exposure was observed with the additional protease inhibitor vs. that observed with ritonavir (Norvir) alone. All three-agent combinations were well tolerated. Therefore, vicriviroc may be studied further for use in ritonavir-boosted protease inhibitor-containing regimens without dose adjustment or therapeutic drug monitoring. Ongoing Development Program Schering-Plough continues its development of vicriviroc with an ongoing and fully enrolled Phase II study in US treatment-experienced patients that is being conducted by the NIH-sponsored Adult AIDS Clinical Trials Group (ACTG). In a press announcement on the Phase 2 study, the company said its first priority is “patient safety” and that the Company “will not commence patient screening into their Phase III program until all available data have been carefully evaluated.” 02/14/06 Source Reference
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