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AASLD 2016: 8-Week Triple Combo Cures Most Patients with Genotype 1-6 Hepatitis C

A 3-drug regimen of sofosbuvir, velpatasvir, and voxilaprevir taken for 8 weeks demonstrated an overall sustained virological response rate of 95% for previously untreated patients with all hepatitis C virus (HCV) genotypes, while a 12-week regimen cured 96%-97% of people who experienced prior treatment failure on direct-acting antivirals (DAAs), according to a set of Phase 3 studies presented last week at the AASLD Liver Meeting in Boston.

The 8-week triple regimen failed to match a 12-week dual regimen of sofosbuvir and velpatasvir for treatment-naive patients due to a number of relapses among people with HCV genotype 1a. But the shorter regimen did cure 96%-99% of the most difficult-to-treat genotype 3 patients with cirrhosis.

The advent of direct-acting antivirals used in interferon-free regimens has made treatment for chronic hepatitis C shorter, more convenient, and much more effective, but there is still room for better options for hard-to-treat patient groups. There is also an unmet need for pangenotypic regimens that are active against all HCV genotypes and could be used anywhere in the world without the need for genotypic testing.

Targeting multiple steps of the viral lifecycle makes for more effective therapy. Gilead Sciences is evaluating a new triple regimen combining pangenotypic agents from 3 different classes in a once-daily coformulation: the previously approved HCV nucleotide polymerase inhibitor sofosbuvir (sold alone as Sovaldi), the NS5A inhibitor velpatasvir, and the investigational HCV protease inhibitor voxilaprevir (formerly GS-9857).

Gilead already sells 2 highly effective dual coformulations, sofosbuvir/ledipasvir (Harvoni) and sofosbuvir/velpatasvir (Epclusa), the latter of which is pangenotypic. However, it does not yet have an approved HCV protease inhibitor.

Treatment-Naive, All Genotypes

Ira Jacobson from Mount Sinai Beth Israel hospital presented late-breaking findings from the Phase 3 POLARIS-2 study (NCT02607800), a head-to-head trial comparing 8 weeks of sofosbuvir/velpatasvir/voxilaprevir against 12 weeks of sofosbuvir/velpatasvir, both without ribavirin, for people with all HCV genotypes.

This analysis included 941 participants enrolled at 117 sites in the U.S., Canada, France, Germany, U.K., Australia, and New Zealand. About half were men, 80% were white, and the mean age was approximately 53 years.

About 35% had HCV genotype 1a, 13% had 1b, 13% had genotype 2, about 19% had genotype 3, 13% had genotype 4, about 2% had genotype 5, and about 4% had genotype 6. About a quarter had received interferon-based therapy, but they had not previously used DAAs. The mean baseline viral load was approximately 6.1 log IU/mL. About 19% had compensated cirrhosis, however genotype 3 patients with cirrhosis were excluded from this study and enrolled POLARIS-3 (described below).

In this open-label study participants with genotypes 1-4 were randomly assigned to receive the triple regimen for 8 weeks or the dual regimen for 12 weeks; all genotype 5 or 6 patients got the 3-drug regimen. The primary study endpoint was sustained virological response, or continued undetectable HCV RNA at 12 weeks after completing treatment (SVR12).

Results

• 95% of patients receiving sofosbuvir/velpatasvir/voxilaprevir for 8 weeks and 98% receiving sofosbuvir/velpatasvir for 12 weeks achieved SVR12.
• This did not meet pre-specified criteria, indicating that the shorter triple regimen was not shown to be non-inferior to the longer dual regimen.
• SVR12 rates for the triple regimen were 92% for genotype 1a, 97% for 1b, 97% for genotype 2, 99% for genotype 3, 92% for genotype 4, 94% for genotype 5, and 100% for genotype 6; all genotypes had SVR12 rates in the 97%-100% range using the dual regimen.
• The lower response rate for sofosbuvir/velpatasvir/voxilaprevir was driven by 14 relapses among patients with genotype 1a; in contrast, all other genotypes had only 0-2 relapses.
• SVR12 rates for people without cirrhosis were 96% for the triple regimen and 98% for the dual regimen; among cirrhotics cure rates were 91% and 99%, respectively, indicating that the disadvantage of shorter therapy was more pronounced in this group.
• 97% of people with resistance-associated substitutions and 98% of those without RASs at baseline achieved SVR12; everyone with baseline NS5B RASs was cured.
• Treatment was generally safe and well-tolerated with no serious drug-related adverse events and just 2 discontinuations due to adverse events, both in the dual therapy arm.
• The most common adverse events were headache, fatigue, diarrhea, and nausea.
• Gastrointestinal side effects were about twice as common with the regimen containing voxilaprevir (18% vs 7% for diarrhea; 16% vs 9% for nausea), but were mostly mild.

This direct comparison of 2 combinations was able to tease out a higher relapse rate for genotype 1a that was not apparent in Phase 2 studies. This study, the researchers said, "demonstrates the value of large controlled trials to compare highly effective regimens."

Genotype 3

Graham Foster from Queen Mary University in London reported findings from POLARIS-3 (NCT02639338), which specifically looked at one of the hardest-to-treat patients groups, those with HCV genotype 3 and compensated cirrhosis; about a third were also previously treated with interferon.Current recommended regimens for interferon-experienced genotype 3 cirrhotics require longer duration or addition of ribavirin -- or both -- which adds to the cost and side effects of treatment.

This analysis included 219 participants from the same countries. About 70% were men, 90% were white, and the average age was approximately 54 years. At baseline the mean HCV viral load was about 6.2 log IU/mL. The mean FibroScan fibrosis score was 22.5 (14 or 15 is the usual cutoff for stage F4 or cirrhosis) and they had a low platelet count (mean 145,000/mcL) indicating impaired liver function.

Results

• SVR12 rates were 96% in both the 8-week sofosbuvir/velpatasvir/voxilaprevir arm and the 12-week sofosbuvir/velpatasvir arm.
• There were 2 relapses in the triple therapy arm, and 1 on-treatment breakthrough and 1 relapse in the dual therapy arm.
• Among previously untreated patients, SVR12 rates were 96% for the triple regimen and 99% for the dual regimen.
• Among treatment-experienced patients response rates were 97% and 91%, respectively.
• In both arms SVR12 rates were 95% for people with no baseline resistance-associated substitutions, while all those with any type of RASs -- including the Y93H mutation -- were cured.
• There were no treatment-emergent RASs in the sofosbuvir/velpatasvir/voxilaprevir arm, but both virological failures in the sofosbuvir/velpatasvir group developed the Y93H mutation.
• Treatment was again well-tolerated with no serious drug-related adverse events and only 1 discontinuation due to an adverse event in the dual regimen arm. Nausea (21% vs 9%) and diarrhea (15% vs 5%) were again more common among people taking voxilaprevir.

In this study treatment-naive patients were well-served by 12 weeks of dual therapy, Foster said, but treatment-experienced people did better on triple therapy even though the duration was shorter.

DAA-Experienced Patients

POLARIS-1 AND POLARIS-4 evaluated sofosbuvir/velpatasvir/voxilaprevir as "salvage therapy" for patients who were not previously cured with prior DAA regimens.

Stephan Zeuzem from JW Goethe University Medical Center presented results from POLARIS-4 (NCT02639247), which enrolled 333 patients with all HCV genotypes who had previously been treated with DAAs, but had not used an NS5A inhibitor or an older HCV protease inhibitor plus pegylated interferon/ribavirin.

Again most were white men with an average age of 57 years. About 30% had HCV genotype 1a, about 13% had 1b, about 19% had genotype 3, 32% had genotype 3, and about 5% had genotype 4; no one had genotypes 5 or 6. Nearly half had cirrhosis and the mean baseline viral load was 6.3 log IU/mL. The majority (69%) had previously used sofosbuvir and a quarter had used an NS5B inhibitor plus an HCV protease inhibitor (including discontinued investigational agents).

Participants with genotypes 1-3 were randomly assigned to receive either sofosbuvir/velpatasvir/voxilaprevir or sofosbuvir/velpatasvir for 12 weeks, while everyone with genotype 4 got the triple regimen.

SVR12 rates were 97% in the triple therapy arm and 90% in the dual therapy arm, showing that the former was statistically superior. There was 1 relapse in the triple therapy arm, and 1 viral breakthrough and 14 relapses in the dual therapy arm. Cure rates for cirrhotic patients were 96% and 86%, respectively (98% vs 94% for non-cirrhotics). People with genotype 1b or 2 had high response rates on both regimens, but those with genotype 1a (98% vs 89%) and 3 (94% vs 85%) did better on the triple compared to the dual regimen.

Of the 22 patients with NS5B resistance-associated substitutions at baseline, all achieved SVR12. The relapser in the triple therapy arm had no treatment-emergent RASs, but 10 of the 15 patients with virological failure in the dual therapy arm developed Y93 mutations.

Again treatment was generally well-tolerated with no serious drug-related adverse events, and diarrhea (20% vs 5%) and nausea (12% vs 8%) were more common with voxilaprevir. But Zeuzem stressed that in nearly 90% of cases diarrhea was grade 1 -- meaning no more that 2 soft stools per day -- and the rest were grade 2.

Zeuzem concluded that sofosbuvir/velpatasvir/voxilaprevir"is a highly effective salvage therapy for non-NS5A-experienced patients."

Finally, turning to individuals who had previously used NS5A inhibitors, Marc Bourlière from Hospital Saint Joseph presented findings from POLARIS-1 (NCT02607735), which compared sofosbuvir/velpatasvir/voxilaprevir for 12 weeks against a placebo.

The study included 415 patients, again mostly white men, with a mean age of 58 years. In the triple therapy arm 38% had genotype 1a, 17% had 1b, 2% had genotype 2, 30% had genotype 3, 8% had genotype 4, and about 3% had genotypes 5 or 6. Only people with genotype 1a (77%) or 1b (20%) were assigned to the placebo arm. 46% in the triple therapy arm and 34% in the placebo arm had cirrhosis, and the mean viral load was 6.3 log IU/mL.

All participants had previously received NS5A inhibitors including ledipasvir (51%), daclatasvir (27%), ombitasvir as part of the AbbVie "3D" regimen (11%), or others (13%).

The SVR12 rate in the triple therapy arm was 96%, while no one in the placebo arm achieved sustained response. There was 1 viral breakthrough in a patient thought to be non-adherent and 6 relapses. Cure rates were 96% for genotype 1a, 100% for 1b, 2, 5, and 6, 95% for genotype 3, and 91% for genotype 4. 99% of non-cirrhotic patients and 93% of those with cirrhosis achieved SVR12; all relapsers had cirrhosis.

People with and without resistance-associated substitutions at baseline had similar response rates (96% and 98%); however, those with only NS5A RASs did a bit worse (94%). None of the relapsers developed treatment-emergent RASs.

Here too, treatment was generally well-tolerated with no serious drug-related adverse events. The frequency of diarrhea in the triple therapy arm (18%) was within the range seen in the other POLARIS trials -- but this side effect was actually more common in the placebo arm (13%) than in the dual therapy arm of the other studies.

"In NS5A-inhibitor experienced patients, treatment with sofosbuvir/velpatasvir/voxilaprevir for 12 weeks resulted in a 96% SVR rate in difficult-to-cure patients with multiple unfavorable characteristics," the researchers concluded.

"We now have near 100% cure rate options for all the patients we come across," Foster said.

Gilead recently indicated that it plans to request U.S. Food and Drug Administration approval of the sofosbuvir/velpatasvir/voxilaprevircoformulation by the end of 2016.

11/17/16

Sources

M Bourlière, SC Gordon, A Ramji, et al. Sofosbuvir/Velpatasvir/Voxilaprevir for 12 Weeks as a Salvage Regimen in NS5A Inhibitor-Experienced Patients with Genotype 1-6 Infection: The Phase 3 POLARIS-1 Study. AASLD Liver Meeting. Boston, November 11-15, 2016. Abstract 194.

IM Jacobson, T Asselah, R Nahass, et al. A Randomized Phase 3 Trial of Sofosbuvir/Velpatasvir/Voxilaprevir for 8 Weeks Compared to Sofosbuvir/Velpatasvir for 12 Weeks in DAA-Naive Genotype 1-6 HCV-Infected Patients: The POLARIS-2 Study. AASLD Liver Meeting. Boston, November 11-15, 2016. Abstract LB-12.

GR Foster, AJ Thompson, PJ Ruane, et al. A Randomized Phase 3 Trial of Sofosbuvir/Velpatasvir/Voxilaprevir for 8 Weeks and Sofosbuvir/Velpatasvir for 12 Weeks for Patients with Genotype 3 HCV Infection and Cirrhosis: The POLARIS-3 Study. AASLD Liver Meeting. Boston, November 11-15, 2016. Abstract 258.

S Zeuzem, SL Flamm, MJ Tong, et al. A Randomized, Controlled, Phase 3 Trial of Sofosbuvir/Velpatasvir/Voxilaprevir or Sofosbuvir/Velpatasvir for 12 Weeks in Direct Acting Antiviral-Experienced Patients with Genotype 1-6 HCV Infection: The POLARIS-4 Study. AASLD Liver Meeting. Boston, November 11-15, 2016. Abstract 109.