Gilead рассчитывает до конца года получить официальное разрешение на использование новой комбинации от гепатита С

A new 3-drug regimen of sofosbuvir, ledipasvir, 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.