New Triple DAA Combo in the pipeline

A new 3-drug regimen of sofosbuvir, velpatasvir, and voxilaprevir, taken without ribavirin for 8 weeks, produced sustained virological response in 96% of previously untreated patients with all hepatitis C virus (HCV) genotypes, while a 12-week course cured 99% of treatment-experienced patients, researchers reported at the recent IDWeek meeting in New Orleans. Response rates dropped off, however, when treatment was shortened to 6 weeks.

The advent of direct-acting antiviral agents (DAAs) used in interferon-free regimens has revolutionized treatment for chronic hepatitis C, but there is still room for shorter, simpler therapy and better options for difficult-to-treat patients. Pangenotypic regimens active against all HCV genotypes could potentially be used worldwide without the need for genotypic testing.

Gilead Sciences is testing a new 3-drug regimen combining agents from 3 different classes: the previously approved HCV polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the investigational protease inhibitor voxilaprevir (formerly GS-9857).

Gilead already sells 2 highly effective 2-drug coformulations, sofosbuvir/ledipasvir (Harvoni) and sofosbuvir/velpatasvir (Epclusa), the latter of which is pangenotypic. It does not yet have an FDA-approved HCV protease inhibitor, although other companies do (Janssen's simeprevir [Olysio], AbbVie's paritaprevir [in Viekira and Technivie coformulations], and Merck's grazoprevir [in Zepatier coformulation]). In early studies voxilaprevir appeared to have an improved resistance profile compared to other protease inhibitors.

At IDWeek Ronald Nahass from ID Care, Inc. presented findings from a post-hoc integrated analysis of the safety and efficacy of sofosbuvir/velpatasvir plus voxilaprevir in a pair of Phase 2 clinical trials.

The integrated analysis included a total of 325 participants. Around two-thirds were men, most were white, and the average age was approximately 56 years. Study GS-US-367-1168 enrolled people with HCV genotype 1, while GS-US-367-1169 enrolled patients with genotypes 2-6. 

Taken together, about 60% of participants had genotype 1, 10% had genotype 2, 23% had hard-to-treat genotype 3, 5% had genotype 4, none had genotype 5, and 3 people had genotype 6. Nearly half had liver cirrhosis. About 40% were treatment-experienced, including 27% who had previously used NS5A inhibitors, 52% who had used other DAAs, and 21% who had used pegylated interferon plus ribavirin.

Regimens were assigned on the basis of genotype, prior treatment history, and presence of cirrhosis:

• 67 easier-to-treat participants -- treatment-naive genotype 1-6 patients without cirrhosis -- received sofosbuvir/velpatasvir plus voxilaprevir for 6 weeks.
• 99 treatment-naive genotype 1 patients with or without cirrhosis received sofosbuvir/velpatasvir plus voxilaprevir for 8 weeks.
• 31 treatment-naive genotype 1 cirrhotic patients received sofosbuvir/velpatasvir plus voxilaprevir with ribavirin for 8 weeks.
• 128 treatment-experienced genotype 1-6 patients with or without cirrhosis received sofosbuvir/velpatasvir plus voxilaprevir for 12 weeks.

The primary endpoint was sustained virological response, or continued undetectable HCV RNA at 12 weeks after completing treatment (SVR12). Results from the treatment-experienced group were previously presented at this year's EASL International Liver Congress.

Results

• The 6-week regimen was least effective, with an overall SVR12 rate of 79%.
• However, all 21 genotype 3 patients (100%) were cured, compared to 71% of people with genotype 1 and 64% with genotypes 2, 4, or 6.
• The 8-week regimen without ribavirin produced an overall SVR12 rate of 96%, with similar rates across all genotypes (92%-97%).
• The 8-week regimen with ribavirin cured 81% of genotype 1 patients (the only ones treated with this combination).
• The 12-week regimen produced an overall cure rate of 99%, again similar across all genotypes (97%-100%).
• The 8- and 12-week regimens without ribavirin cured 94% and 98% of patients with cirrhosis, respectively, and 100% of non-cirrhotics.
• SVR12 rates were high for hard-to-treat genotype 3 patients with or without cirrhosis (94% and 100%, respectively), even using the short 6-week regimen.
• 47% of treatment-naive participants had pre-existing resistance-associated variants, and their overall cure rate was the same as that of patients without baseline RAVs (96%).
• Treatment-experienced patients had high SVR12 rates with or without a prior history of NS5A use (100% and 99%, respectively).
• Treatment with sofosbuvir/velpatasvir plus voxilaprevir was generally safe and well-tolerated, with only 1 serious adverse event and 4 discontinuations due to adverse events.
• The most common adverse events were headache, fatigue, nausea, and diarrhea, generally mild or moderate.
• Side effects and laboratory abnormalities were more common in the group that received ribavirin, including 6 cases of anemia (vs none in the ribavirin-free arms).

"Treatment with sofosbuvir/velpatasvir plus voxilaprevir administered once daily for 8 weeks was generally safe, well tolerated, and highly effective in treatment-naive HCV genotype 1-6 patients with and without cirrhosis," the researchers concluded. "6 week treatment duration was associated with higher relapse rate for genotypes 1, 2, 4, and 6. Sofosbuvir/velpatasvir plus voxilaprevir for 12 weeks resulted in 99% SVR12 rate in treatment-experienced patients with HCV genotypes 1-6."

Sofosbuvir/velpatasvir plus voxilaprevir have been combined in a once-daily single-tablet regimen and evaluated in the Phase 3 POLARIS trials. Gilead recently reported in a press release that the coformulation taken for 8 or 12 weeks produced SVR12 rates of 95% to 97% for DAA-naive and DAA-experienced patients with HCV genotypes 1-6, with or without cirrhosis. The company indicated that it plans to request Food and Drug Administration approval of the new coformulation by the end of the year.

11/7/16

Sources

R Nahass, E Lawitz, IM Jacobson, et al. Sofosbuvir/Velpatasvir Plus Voxilaprevir for 6, 8, or 12 Weeks in Genotype 1-6 HCV-Infected Patients: An Integrated Analysis of Safety and Efficacy from Two Phase 2 Studies. IDWeek. New Orleans, October 26-30, 2016. Abstract 1785.

Gilead Sciences. Gilead Announces SVR12 Rates From Four Phase 3 Studies of a Once-Daily, Fixed-Dose Combination of Sofosbuvir, Velpatasvir and Voxilaprevir in Treatment-Naive and Treatment-Experienced Genotype 1-6 Chronic HCV-Infected Patients. Press release. October 20, 2016.