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EASL 2012: GS-7977 with Interferon/Ribavirin Cures Most Treatment-Naive Hepatitis C Patients in 12 Weeks

Adding GS-7977 to pegylated interferon and ribavirin for 12 weeks led to a sustained response rate of 90% for previously untreated chronic hepatitis C patients with difficult-to-treat genotype 1, researchers reported at the 47th International Liver Congress (EASL 2012) last week in Barcelona.

Last year's approval of the first direct-acting antiviral agents has changed the face of hepatitis C treatment. The first such drugs still must be taken with pegylated interferon and ribavirin, but they increase cure rates and offer the potential for shorter treatment.

GS-7977 (formerly PSI-7977) is a uridine nucleotide HCV NS5B polymerase inhibitor that has demonstrated good efficacy in early studies when combined with standard therapy or other direct-acting antivirals, though most people relapsed when they used GS-7977 plus ribavirin alone.

After favorable results from the PROTON trial showed that most patients achieved a cure with 12 weeks of GS-7977 plus pegylated interferon/ribavirin followed by another 12 weeks on pegylated interferon/ribavirin alone, the phase 2b ATOMIC trial was designed to test whether a similar outcomes could be obtained with GS-7977 and only 12 weeks of pegylated interferon/ribavirin.

Kris Kowdley from Virginia Mason Medical Center in Seattle and investigators at several other U.S. sites enrolled 332 treatment-naive hepatitis C patients without cirrhosis but with difficult-to-treat HCV genotypes. All but 16 had HCV genotype 1, about 70% of them with subtype 1a (the rest had genotypes 4 or 6).

Two-thirds of participants were men, about 85% were white, and the average age was about 50 years. Approximately 25% had the favorable IL28B CC gene pattern associated with good response to interferon.

Participants were randomly assigned to receive 400 mg once-daily GS-7977 plus once-weekly pegylated interferon and daily ribavirin for 12 or 24 weeks, or else triple therapy for 12 weeks followed by either GS-7977 alone or GS-7797 plus ribavirin for an additional 12 weeks (24 total weeks on treatment).

Results

• Overall, viral suppression was rapid during the first 2 weeks on treatment, regardless of IL28B status.
• After 4 weeks on therapy, rapid virological response rates (< LOD 15 IU/mL) were 94% in the 12-week triple therapy arm, 98% in 24-week triple therapy arm, and 97% in patients who received 12-week triple therapy with 12 weeks of follow-on treatment.
• At the end of treatment, the corresponding response rates were 98%, 99%, and 99%, respectively.
• No patients experienced viral breakthrough while on therapy.
• 4 weeks after completion of treatment, 94% of people in the 12-week triple therapy arm and 92% in the other 2 groups achieved sustained virological response (SVR4).
• Looking just at participants in the first arm who received 12 weeks of triple therapy, 90% achieved 12-week sustained response (SVR12), generally regarded as a cure (follow-up is continuing for patients treated for 24 weeks).
• 4 people who relapsed after finishing treatment in this arm had their virus sequenced, and none showed evidence of the S282T resistance mutation.
• GS-7977 triple therapy was generally well-tolerated.
• The most common side effects were those associated with interferon including fatigue and headache.
• Fever and chills were more than twice as common among people who received the shortest combination regimen.
• Skin rash and anemia were more common in the 2 groups treated for 24 weeks.
• Although 10% of patients in the 12-week triple therapy arm experienced severe adverse events compared with 5% and 4% in the other 2 arms, none were attributed to GS7977 and no 2 patients experienced the same serious events.

"GS-7977 400mg once daily in combination with [pegylated interferon/ribavirin] for 12 weeks is potent, safe and highly effective for the treatment of HCV genotype 1," the researchers concluded, adding that "12 weeks of GS-7977 in combination with [pegylated interferon/ribavirin] appears to be as effective as 24 weeks of therapy."

During the question period following his presentation, Kowdley noted that 8 of the 11 genotype 4 patients in the study and all 5 of the genotype 6 patients achieved SVR4.

Asked about his presentation's provocative subtitle referencing "an end to response-guided therapy," Kowdley suggested that a drug with a low barrier to resistance such as GS-7977 might allow a "paradigm shift" toward standardized shorter treatment.

4/27/12

Reference

KV Kowdley, E Lawitz, I Crespo, et al. 97% RVR for PSI-7977 + PEG/RBV x 12 Week Regimen in HCV GT1: An End to Response-guided Therapy? 47th International Liver Congress (EASL 2012).Barcelona, April 18-22, 2012. Abstract 1.