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Racivir - New HIV Drug
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Sept 17 2008
http://www.pharmasset.com
Racivir is an oral, once-daily cytidine nucleoside analog that we are developing as an HIV therapy for use in combination with other approved HIV drugs. We have completed a Phase 2 clinical trial, Study 201, to assess the safety, tolerability and antiviral effect of a 600 mg dose of Racivir head-to-head against lamivudine in HIV-infected, treatment-experienced patients with the M184V mutation who have been on lamivudine therapy. The goal of this study was to evaluate the benefit of Racivir in patients carrying the M184V mutation by replacing lamivudine with Racivir in existing therapies.
Study 201 was a randomized, double-blind, placebo-controlled, multicenter study of 54 patients who were randomized into two groups: one group receiving Racivir instead of lamivudine in their existing therapies, and the other group continuing on a current lamivudine-containing therapy without any change. The study entry criteria included patients who were failing a HAART regimen. The study had a blinded treatment period of up to 28 days, followed by an open label treatment period of up to 20 weeks. Patients are subsequently being followed for an additional four weeks after the conclusion of the study treatment periods. The goal of this study was to evaluate the benefit of Racivir in patients carrying the M184V mutation by replacing lamivudine with Racivir in existing therapies.
In this study, 42 subjects were randomized to receive either Racivir (n=26) in place of lamivudine or to continue with lamivudine (n=16) in a double-blind manner for 28 days. HIV viral loads and genotypes were determined at baseline (mean viral load = 4.1 log) and throughout the study. After the blinded treatment period, subjects were allowed to continue Racivir in an open label manner with or without optimized background therapy for an additional 20 weeks, based on their primary care physiciansf advice. After 28 days of blinded treatment, the mean viral load rose by 0.13 log (a 34.9% increase) in the lamivudine group and dropped by 0.4 log (60.2% reduction) in the Racivir group (p=0.02). A subset analysis of the Racivir-treated group revealed that the change in viral load was largely due to a positive antiviral response in subjects who had an HIV mutation pattern that included M184V and less than 3 thymidine analog mutations with or without NNRTI or PI mutations. In this subset of patients (n=14), replacing lamivudine with Racivir in their existing therapies caused a mean drop in viral load of 0.7 log (80% reduction, p=0.004) in the second week of treatment, with 28% of these patients achieving an undetectable level of virus (less than 400 copies per milliliter) and 64% of these patients achieving at least a 0.5 log (68%) drop in viral load. No serious adverse events attributed to therapy were noted in either group over the 28 days.
In summary, Racivir demonstrated antiviral activity in patients harboring HIV with the M184V mutation and less than three thymidine analog mutations. These patients have genotypes consistent with first-line therapy failure and may be candidates for second line treatment regimens that contain Racivir. Future studies will be designed to explore this potential use of Racivir in a combination therapy for second-line therapy.
We have conducted a Phase 1 clinical trial with Racivir as a single agent and a Phase 1 clinical trial, Study 101, with Racivir in combination with two FDA-approved therapies for the treatment of HIV infection. Racivir was shown to be generally well-tolerated in both studies. In Study 101, Racivir was tested at 200, 400 and 600 mg doses against lamivudine once daily for 14 days in combination with stavudine and efavirenz in 32 HIV-infected, treatment-naive individuals. In this study, mean viral loads of 4.7 log to 4.85 log were reduced by approximately 99% on average by day 14 at all dose levels and in the lamivudine control arm. In this study, replacing lamivudine with Racivir did not affect the efficacy of stavudine and efavirenz. The purpose of the Phase 1 study was to assess the safety of Racivir and was not designed to provide statistical evidence of efficacy. Therefore, a "p" value measuring the statistical significance of this viral load reduction was not calculated.
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