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AASLD 2015: Sofosbuvir/ Velpatasvir + GS-9857 for 8 Weeks Cures Most Genotype 1 or 3 Hepatitis C Patients

An 8-week triple combination of Gilead Sciences' sofosbuvir, velpatasvir, and GS-9857 showed a high sustained response rate in a Phase 2 study of difficult-to-treat hepatitis C patients including treatment-experienced people with HCV genotype 3 and liver cirrhosis, according to results presented at the 2015 AASLD Liver Meetingtaking place this week in San Francisco. A 6-week regimen appeared inadequate, however, and more than 8 weeks may be needed for people who previously used direct-acting antivirals.

Interferon-free direct-acting antiviral (DAA) therapy has revolutionized treatment for chronic hepatitis C, but there is still room to optimize therapy for difficult-to-treat patients, enabling them to take advantage of shorter-duration ribavirin-sparing regimens like those currently available for easier-to-treat people. Ideally such a regimen would be pangenotypic, meaning it could be routinely prescribed without the need for genotype testing.

Edward Gane of Auckland Clinical Studies in New Zealand presented final results from a Phase 2 trial (NCT02202980) evaluating a 3-drug regimen consisting of the HCV NS5B polymerase inhibitor sofosbuvir, the pangenotypic NS5A inhibitor velpatasvir (formerly GS-5816), and the pan-genotypic NS3/4A protease inhibitor GS-9857. Combining drugs that attack HCV at 3 different steps of its lifecycle may improve efficacy and enable shorter treatment.

This study included 157 participants divided into 7 cohorts with various characteristics predicting good or poor treatment response. All were treated with the triple regimen for 4, 6, or 8 weeks. Sofosbuvir and velpatasvir were taken as a once-daily fixed-dose coformulation (400/100 mg); GS-9857 (100 mg) was also taken once-daily.

The easiest-to-treat group -- previously untreated HCV genotype 1 patients without cirrhosis -- were randomly assigned to receive the combo for 4 or 6 weeks. Treatment-naive genotype 1 patients with cirrhosis and people with prior DAA failure (with or without cirrhosis) were all treated for 6 weeks.

Gane presented results for these first 3 cohorts at the EASL International Liver Congress earlier this year. Response rates ranged from 67% to 93% in the 6-week arms, but fell to a dismal 27% in the 4-week arm.

At the AASLD meeting Gane presented findings for the final 4 cohorts of harder-to-treat patients:

• Genotype 1 pegylated interferon/ribavirin-experienced with cirrhosis (n=17);
• Genotype 1 protease inhibitor-experienced with or without cirrhosis (n=28);
• Genotype 3 treatment-naive with cirrhosis (n=18);
• Genotype 3 pegylated interferon/ribavirin-experienced with cirrhosis (n=19).

Both genotype 1 cohorts were treated for 8 weeks. The genotype 3 treatment-naive and treatment-experienced groups received 6 and 8 weeks of therapy, respectively.

In these 4 cohorts a majority of participants were men (56% to 82%), most were white (67% to 95%), and mean ages ranged from 52 to 58 years.  A third had the favorable IL28B CC gene pattern. In the protease inhibitor-experienced cohort 39% had cirrhosis.

Results

• All participants in all 4 cohorts completed treatment with no discontinuations.
• The sustained virological response rate at 12 weeks-post-treatment (SVR12) for genotype 1 treatment-experienced patients with cirrhosis was 100%.
• The overall SVR12 rate in the genotype 1 protease inhibitor-experienced cohort was 89%; in this group cirrhotics uncharacteristically responded better than people without cirrhosis (94% vs 82%), but the numbers were small.
• The 3 genotype 1 patients without SVR12 all relapsed.
• Turning to the genotype 3 cohorts, the SVR12 rate was 83% in the treatment-naive cirrhotic cohort treated for 6 weeks, with 2 relapses and 1 withdrawal of consent.
• In the treatment-experienced cirrhotic cohort treated for 8 weeks, 100% achieved SVR12.
• Looking more closely at the 5 participants who relapsed, there was no consistent pattern of drug resistance-associated variants (RAVs) at baseline or at the time of relapse.
• At baseline 3 people had NS3 RAVs (R155K x 2, I170T, V36M, T54S and Q168K), while 2 had NS5A RAVs (M28V and L31M); at relapse 2 had NS3 RAVs and 2 had NS5A RAVs -- 1 relapser had no RAVs at either baseline or relapse.
• The presence of NS3 RAVs at baseline appeared to have more influence on treatment response (88% with RAVs vs 96% without) than baseline NS5A RAVs (90% vs 95%, respectively).
• Treatment with the triple regimen was generally safe and well-tolerated.
• Only 3 of the 82 participants in these 4 cohorts experienced serious adverse events and no one discontinued treatment for this reason.
• The most common side-effects were headache, fatigue, nausea, and diarrhea.

Sofosbuvir/velpatasvir for 8 weeks "resulted in high SVR12 rates in difficult-to-cure, treatment-experienced populations," the researchers concluded. "Baseline RAVs reduced SVR rates among PI-experienced patients" and "treatment-emergent RAVs were uncommon."

The 8-week triple regimen was "very robust" and "looks highly efficacious" for people with previous pegylated interferon/ribavirin failure, including cirrhotics, Gane said. But for DAA-experienced people, "I think you have to go beyond 8 weeks," and future data will tell whether that needs to be 10 or 12 weeks.

11/16/15

Reference

EJ Gane, RH Hyland, Y Yang et al. Sofosbuvir/GS-5816+GS-9857 for 6 or 8 weeks in genotype 1 or 3 HCV-infected patients. AASLD Liver Meeting 2015. San Francisco, November 13-17, 2015. Abstract 38.