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AASLD 2016: Grazoprevir Triple Regimen Demonstrates High Cure Rates, Even for Hard-to-Treat Patients

A new 3-drug coformulation containing Merck's grazoprevir plus the investigational agents MK-3682 and ruzasvir was highly effective for people with hepatitis C virus (HCV) genotypes 1, 2, or 3, with sustained response rates of 86% to 100% depending on treatment duration, according to study results presented this month at the AASLD Liver Meeting in Boston. Related studies showed that the combination is also effective for retreating people who were not cured with a previous course of direct-acting antivirals (DAAs).

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. However, there is still room for better regimens for hard-to-treat patients as well as pangenotypic combinations active against all HCV genotypes; furthermore, additional options are expected to bring down the cost of treatment due to increased competition.

Combining agents that attack multiple steps of the viral lifecycle makes for more effective therapy and may shorten treatment. Merck is evaluating a once-daily fixed-dose coformulation containing its approved HCV protease inhibitor grazoprevir (part of the Zepatier coformulation with elbasvir), the investigational nucleotide NS5B polymerase inhibitor MK-3682, and the next-generation NS5A inhibitor ruzasvir (formerly MK-8408).

The Phase 2 C-CREST trials tested the coformulation -- dubbed "MK3" -- taken with or without ribavirin for 8, 12, or 16 weeks.

Genotypes 1, 2, and 3

Eric Lawitz from the Texas Liver Institute presented results from Part B of C-CREST 1 and 2, which together evaluated the combination in 664 patients with HCV genotypes 1, 2, or 3, mostly from North America and Europe.

About 60% of the study population were men, 90% were white, and the median age was 54 years. About a quarter (27%) had HCV genotype 1 (half with harder-to-treat subtype 1a and half with 1b), 23% had genotype 2, and 51% had genotype 3 -- considered the most difficult to treat with DAAs. All genotype 1 and 2 patients were previously untreated, while 44% of the genotype 3s had been treated with pegylated interferon/ribavirin. Over a third of patients with each genotype had liver cirrhosis (38% overall) and 3% were coinfected with HIV.

People with genotype 1 were assigned to take the MK3 regimen without ribavirin for either 8 or 12 weeks. Genotype 2 and 3 patients were allocated to receive the coformulation without or without ribavirin for 8 or 12 weeks, or without ribavirin for 16 weeks. An additional 25 genotype 3 patients received MK3 plus ribavirin for 16 weeks.

The primary study endpoint was sustained virological response, or continued undetectable HCV RNA at 12 weeks after completing treatment (SVR12).

Results

• In an intention-to-treat analysis including all participants, SVR12 rates were 93% for genotype 1a patients treated with MK3 alone for 8 weeks and 98% for those treated for 12 weeks; cure rates were 98% and 100%, respectively, for those with genotype 1b.
• Among people with genotype 2, cure rates were 86% for MK3 with or without ribavirin taken for 8 weeks, 97% for 12 weeks, and 100% for 16 weeks.
• Among genotype 3 patients, SVR12 rates were 95% for the 8-week regimen, 97% for 12 weeks, and 96% for 16 weeks.
• Cure rates were high and similar for people with or without cirrhosis in all genotype groups; all but 2 cirrhotic patients achieved SVR12 in a per-protocol analysis.
• In the genotype 2 and 3 analysis, SVR12 rates were similar with or without ribavirin -- and in fact the lowest rate (83%) was seen in the genotype 2 group treated with ribavirin for 8 weeks.
• In the genotype 3 analysis, SVR12 rates were similar for treatment-naive and treatment-experienced patients receiving 8, 12, or 16 weeks of therapy.
• There were 3 relapses among genotype 1 patients and 7 among genotype 2 patients treated for 8 weeks, but none among those receiving the 12-week regimen; among genotype 3 patients relapses occurred after 8, 12, or 16 weeks of therapy (4, 3, and 2 cases, respectively).
• Among genotype 1 patients, the presence of resistance-associated variants (RAVs) at baseline did not impair treatment efficacy.
• Among genotype 2 patients with the L31M RAV at baseline, the cure rate fell to 80% when treated for 8 weeks but was 100% when treated for 12 weeks.
• Among genotype 3 patients with the Y93H RAV, cure rates were lower with both 8 and 12 weeks of treatment (50% and 71%, respectively), although the number of these patients was small.
• Treatment was generally safe and well-tolerated, with 2 drug-related serious adverse events (worsening COPD and depression due to ribavirin) and 1 discontinuation due to drug-related adverse events (fatigue and malaise).
• The most common adverse events were headache (22%), fatigue (19%), and nausea (13%).
• There was 1 case of reinfection with a different HCV strain in an individual who had reached SVR8.

Based on these findings, the researchers concluded that MK-3682/grazoprevir/ruzasvir for 8 or 12 weeks was highly effective for HCV genotype 1 patients, while 12 or 16 weeks was effective for genotype 2 patients, and 8, 12, or 16 weeks was effective for genotype 3 patients. Adding ribavirin did not increase SVR12 rates.

Lawitz noted that all genotype 3 treatment-experienced patients with cirrhosis -- the hardest group to treat -- were cured using MK3 without ribavirin for 12 or 16 weeks (the only relapser was on the most intensive 16-week regimen with ribavirin).

He also reported that all but 1 of the 23 HIV/HCV coinfected patients achieved SVR12, but the single reinfected individual was coinfected.

Retreatment with Intensive MK3 Regimens

Edward Gane from Auckland Clinical Studies in New Zealand reported findings from C-CREST Part C, in which people who relapsed after receiving a triple DAA regimen for 8 weeks in C-CREST Part A were retreated with a more intensive regimen of MK3 plus ribavirin for 16 weeks.

This analysis included 1 person each with genotypes 1a and 1b, 14 with genotype 2, and 8 with genotype 3. They were non-cirrhotic and almost all had absent to moderate fibrosis (stage F0-F2). In Part A of the study 14 had used elbasvir and 10 had used ruzasvir as their NS5A inhibitor. At baseline all but 1 had NS3 RAVs, 83% had NS5A RAVs, and 1 person had an NS5B RAV.

SVR12 rates in an intention-to-treat analysis were 100% for genotype 1, 93% for genotype 2, and 100% for genotype 3. There were no relapses, but 1 person in the genotype 2 group discontinued treatment after a single dose due to serious adverse events (vomiting and tachycardia) that were considered to be drug-related.

The researchers concluded that the MK3 coformulation plus ribavirin for 16 weeks was highly effective for patients without cirrhosis who had previously experienced treatment failure on an 8-week triple-DAA regimen, despite a high prevalence of NS3 and NS5A RAVs.

In response to a question, Gane said he was not sure whether 16 weeks of retreatment without ribavirin would be equally effective, and that a study needs to be done. However, he noted that both patients who stopped or reduced their dose of ribavirin due to anemia went on to achieve SVR12.

Finally, David Wyles from the University of California at San Diego presented results from another retreatment study -- C-SURGE -- which looked at 94 people with HCV genotype 1 who had experienced prior treatment failure on sofosbuvir/ledipasvir (Harvoni) or grazoprevir/elbasvir (Zepatier).

Most were white men, the median age was 60 years, and 86% had HCV subtype 1a. Most had high HCV RNA (>800,000 IU/mL), 84% had NS5A RAVs and 65% had NS3 RAVs at baseline (more than half had both), and 42% had compensated cirrhosis.

Participants in this open-label trial were randomly assigned to received MK-3682/grazoprevir/ruzasvir with ribavirin for 16 weeks or alone for 24 weeks. Wyles reported sustained virological response results for the 44 people in the 16-week arm and 30 people in the 24-week arm who had reached 8 weeks of post-treatment follow-up. While SVR8 is not considered a cure, it is a good predictor of SVR12.

All but 1 patient (98%) in the 16-week arm and 100% in the 24-week arm achieved SVR8. The single participant who did not do so withdrew early after receiving 3 doses of therapy. The presence of baseline RAVs had no effect on treatment efficacy.

There were no drug-related serious adverse events or study discontinuations due to adverse events. Fatigue, itching, rash, and anemia were more frequent in the ribavirin-containing arm. No one stopped ribavirin, but 10 people reduced their dose due to side effects.

The researchers concluded that MK3 with or without ribavirin was highly effective for cirrhotic and non-cirrhotic genotype 1 patients who previously failed an NS5A inhibitor-containing direct-acting antiviral regimen.

11/21/16

Sources

E Lawitz, EM Yoshida, M Buti, et al. Safety and Efficacy of the Fixed-Dose Combination Regimen of MK-3682/Grazoprevir/MK-8408 With or Without Ribavirin in Non-cirrhotic or Cirrhotic Patients with Chronic HCV GT1, 2 or 3 Infection (Part B of C-CREST-1 & 2). AASLD Liver Meeting. Boston, November 11-15, 2016. Abstract 110.

L Serfaty, S Pianko, Z Ari, EJ Gane, et al. High Sustained Virologic Response (SVR) Rates in Patients with Chronic HCV GT1, 2 or 3 Infection Following 16 Weeks of MK-3682/Grazoprevir/MK-8408 Plus Ribavirin After Failure of 8 Weeks of Therapy (Part C of C-CREST-1 & 2). AASLD Liver Meeting. Boston, November 11-15, 2016.Abstract 112.

DL Wyles, H Wedemeyer, R Reddy, et al. Safety and Efficacy of the Fixed-Dose Combination Regimen of MK-3682/Grazoprevir/MK-8408 in Cirrhotic or Non-cirrhotic Patients with Chronic HCV GT1 Infection who Previously Failed a Direct-acting Antiviral Regimen (C-SURGE). AASLD Liver Meeting. Boston, November 11-15, 2016.Abstract 193.