www.hivandhepatitis.com

Early Data on BMS-790052 HCV NS5A Inhibitor Published

Bristol-Myers Squibb's experimental HCV NS5A inhibitor, BMS-790052, demonstrated potent antiviral activity, was well-tolerated, and pharmacokinetic parameters support once-daily dosing, according to a small 14-day proof-of-concept study described in the August 11, 2011, advance online edition of Hepatology.

Data from this and later trials of BMS-790052 alone or in combination have already been presented at medical conferences, but this is among the first published reports.

Richard Nettles from Bristol-Myers Squibband colleagues evaluated the antiviral activity, resistance profile, pharmacokinetics (PK), safety, and tolerability of BMS-790052 in a double-blind, placebo-controlled, multiple ascending dose study.

BMS-790052 inhibits the hepatitis C virus (HCV) NS5Areplication complex. The precise function of the NS5A element is not clear, but it appears to play a key role in viral replication, including promoting the activity of the adjacent NS5B polymerase (which copies viral genetic material) and modulating cell signaling pathways.

This pilot study included 30 previously untreated patients with hard-to-treat genotype 1 chronic hepatitis C. About 80% were men and most were white. Individuals with cirrhosis and HIV or hepatitis B coinfection were excluded.

Participants were randomly assigned to receive BMS-790052 monotherapy at doses of 1, 10, 30, 60, or 100 mg once-daily or 30 mg twice-daily, or else placebo, for 14 days.

Results

• The average change in HCV RNA from baseline to day 7 ranged from 2.1 to 3.3 log IU/mL in the different BMS-790052 dose groups, while the placebo group showed no decrease.
• Average maximum viral load declines from baseline ranged from 2.8 to 4.1 log IU/mL.
• Patients with HCV genotype 1b experienced more marked and sustained viral load reduction than those with genotype 1a (4 of 7 vs 0 of 17, respectively, with undetectable HCV RNA).
• Most patients experienced viral rebound on or before day 7 of treatment with BMS-790052 monotherapy, suggesting emergence of drug resistance.
• Viral rebound was associated with mutations that were previously associated with resistance in a laboratory replicon model system.
• The pharmacokinetic profile of BMS-790052 supported once-daily dosing.
• Median peak plasma concentration occurred 1-2 hours after administration and mean terminal half-life was 12-15 hours.
• A steady state concentration was achieved after 3-4 days of daily dosing.
• BMS-790052was generally well-tolerated at all dose levels.
• There were no deaths, serious adverse events, or treatment discontinuations due to adverse events.
• Adverse events occurred with a similar frequency in the BMS-790052 and placebo groups.
• No clinically relevant changes in vital signs, laboratory values, or electrocardiogram readings were observed.

"BMS-7590052 is the first NS5A replication complex inhibitor with multiple dose proof-of-concept in clinic," the study authors concluded. "At doses of 1-100 mg daily, BMS-790052 was well-tolerated, had a PK profile supportive of once-daily dosing, and produced a rapid and substantial decrease in HCV RNA levels in patients chronically infected with HCV genotype 1."

"The early suppression of HCV replication with BMS-790052 monotherapy is comparable with, and in some cases exceeds, that observed for other DAA [direct-acting antiviral] agents," they added in their discussion. "[P]reliminary data suggest that the combination of BMS-790052 with [pegylated interferon + ribavirin] therapy or other DAA agents will be effective at markedly reducing viral rebound."

"These results confirm the importance of inhibiting NS5A-mediated HCV replication and the potential of BMS-790052 as part of combination therapy in the treatment of HCV," they concluded. "Additional clinical trials are ongoing to further confirm the safety and efficacy of BMS-790052 in patients with chronic HCV infection."

An interim analysis from one such study presented at the EASL 2011 conference in April showed that about 90% of treatment-naive genotype 1 chronic hepatitis C patients treated with BMS-790052 plus pegylated interferon/ribavirin achieved sustained response 12 weeks after completion of therapy.

Another study described at the same meeting found that 90% of prior null responder genotype 1 patients achieved 24-week sustained virological response using a quadruple combination of BMS-790052, BMS-650032, and pegylated interferon/ribavirin; more impressive, nearly 40% did so using only the 2 oral DAA drugs.

Investigator affiliations: Bristol-Myers Squibb, Research and Development, Hopewell, NJ, Wallingford, CT, and Princeton, NJ; Orlando Clinical Research Center, Orlando, FL; PAREXEL, Baltimore, MD; Advanced Clinical Research Institute, Anaheim, CA; Fundacion de Investigacion de Diego, Santurce, Puerto Rico; West Coast Clinical Trials, Cypress, CA; Elite Research Institute Miami, FL; Alamo Medical Research, San Antonio, TX.

9/13/11

Reference

RE Nettles, M Gao, M Bifano, et al. Multipleascending dose study of BMS-790052, an NS5A replication complex inhibitor, in patients infected with hepatitis C virus genotype 1. Hepatology (abstract). August 11, 2011 (Epub ahead of print).