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Daclatasvir, Asunaprevir, and Beclabuvir Shows High Cure Rates for People with Genotype 1 Hepatitis C

A twice-daily fixed-dose coformulation of daclatasvir, asunaprevir, and beclabuvir taken for 12 weeks cured 91% of genotype 1 chronic hepatitis C patients without liver cirrhosis, and even higher sustained response rates were obtained for people with cirrhosis when ribavirin was added, according to findings from the Phase 3 UNITY studies published in the May 5 issue of JAMA.

Bristol-Myers Squibb is evaluating a combination pill containing the HCV NS5A inhibitor daclatasvir (BMS-790052), the NS3/4A HCV protease inhibitor asunaprevir (BMS-650032), and the non-nucleoside NS5B polymerase inhibitor beclabuvir (BMS-791325). Daclatasvir is pan-genotypic, or active against multiple HCV genotypes, while asunaprevir and beclabuvir are active against genotypes 1 and 4.

Daclatasvir (Daklinza) is currently approved in Europe, and daclatasvir plus asunaprevir (Sunvepra) is approved in Japan. Daclatasvir is under U.S. Food and Drug Administration review for HCV genotype 3, but the company decided not to seek FDA approval of the dual combination for genotype 1. An effective triple combination could compete with coformulations for genotype 1 produced by Gilead Sciences (Harvoni) and AbbVie (Viekira Pak), though a pan-genotypic combination regimen would address more unmet need.

Previous studies showed that asunaprevir plus daclatasvir was highly effective for HCV subtype 1b, but did not work as well against harder-to-treat subtype 1a. However, adding a third direct-acting antiviral improved cure rates. This 3-drug "TRIO" combination was evaluated in the Phase 3 UNITY-1 and UNITY-2 studies. Results were previously reported in part at the 2014 AASLD Liver Meeting last November.

UNITY-1

As described in the first report, Fred Poordad from the Texas Liver Institute and colleagues presented results from the UNITY-1 study (NCT01979939), which assessed daclatasvir/asunaprevir/beclabuvir without ribavirin for genotype 1 chronic hepatitis C patients without cirrhosis.

This international study, conducted at 66 sites in the U.S., Canada, France, and Australia between December 2013 and August 2014, included 312 previously untreated and 103 treatment-experienced participants. About 60% were men, most were white, and the median age was 55 years. 73% had HCV subtype 1a, about 80% had high baseline HCV viral load, and 74% had unfavorable IL28B variants. In the treatment-experienced group about 40% were prior relapsers and about a quarter were null responders.

All participants in this open-label study received the TRIO coformulation, containing 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg beclabuvir, taken twice-daily for 12 weeks.

Results  

• Overall, 91% of participants achieved sustained virological response, or continued undetectable HCV RNA at 12 weeks post-treatment (SVR12).
• SVR12 rates were similar for treatment-naive and treatment-experienced patients (92% and 89%, respectively).
• Cure rates were higher for people with HCV subtype 1b (98%-100%) compared to those with subtype 1a (85%-90%).
• 34 patients (8%) experienced virological failure, including 5 who still had detectable viral load at the end of treatment, 8 who experienced viral breakthrough while on therapy, and 21 who relapsed after completing treatment.
• Daclatasvir/asunaprevir/beclabuvir was generally safe and well-tolerated.
• There were 7 serious adverse events and 1 death, all considered unrelated to the study drugs, as well as 3 adverse events leading to early treatment discontinuation.
• The most common adverse events were headache, fatigue, diarrhea, and nausea.

"In this open-label, non-randomized, uncontrolled study, a high rate of SVR12 was achieved in treatment-naive and treatment-experienced non-cirrhotic patients with chronic HCV genotype 1 infection who received 12 weeks of treatment with the oral fixed-dose regimen of daclatasvir, asunaprevir, and beclabuvir," the study authors concluded.

UNITY-2

The second report described findings from the UNITY-2 study (NCT01973049). Andrew Muir from Duke Clinical Research Institute and colleagues tested the

daclatasvir/asunaprevir/beclabuvir TRIO coformulation taken with or without ribavirin for genotype 1 hepatitis C patients with compensated cirrhosis.

This trial, conducted at 49 sites in the U.S., Canada, France, and Australia between December 2013 and October 2014, included 112 treatment-naive and 90 treatment-experienced participants. Again, a majority were men, most were white, and the median age was 59 years. Three-quarters had HCV subtype 1a and unfavorable IL28B variants, and most had high baseline viral load. About a third of the treatment-experienced patients were prior null responders. All patients had cirrhosis confirmed by liver biopsies or non-invasive methods; people with decompensated liver disease were not included.

All participants received the daclatasvir/asunaprevir/beclabuvir coformulation twice-daily for 12 weeks. In addition, they were randomly assigned to receive weight-based ribavirin (1000-1200 mg/day) or a matching placebo.

Results

• Using daclatasvir/asunaprevir/beclabuvir alone, the overall SVR12 rates were 93% for treatment-naive and 87% for treatment-experienced patients.
• Among participants who also received ribavirin, cure rates rose to 98% and 93%, respectively, for treatment-naive and treatment-experienced patients.
• Among the 13 people with virological failure, 1 still had detectable HCV at the end of treatment, 2 experienced viral breakthrough on therapy, and 10 relapsed after treatment; 9 of the relapsers did not take ribavirin.
• Sustained response rates were somewhat lower for people with HCV subtype 1a; only 1 patient with subtype 1b, who did not take ribavirin, experienced virological failure.
• Again, treatment was generally safe and well-tolerated.
• There were 3 serious adverse events considered to be treatment-related and 4 discontinuations due to adverse events.
• The most common adverse events were again headache, fatigue, nausea, and diarrhea.
• Most side effects were more common among patients who took ribavirin compared to those who did not, including headache (23% vs 17%), fatigue (28% vs 12%), insomnia (15% vs 6%), and pruritus (15% vs 6%).
• 4 patients experienced treatment-emergent grade 3 or 4 ALT elevations, including 1 in conjunction with bilirubin elevation.
• Anemia occurred more often among ribavirin recipients, but was still uncommon (5% vs 0%).

"In this open-label uncontrolled study, patients with chronic HCV genotype 1 infection and cirrhosis who received a 12-week oral fixed-dose regimen of daclatasvir, asunaprevir, and beclabuvir, with or without ribavirin, achieved high rates of SVR12," the investigators concluded.

The UNITY-2 results confirm findings from others studies indicating that the hardest to treatment hepatitis C patients -- such as prior non-responders with HCV subtype 1a and cirrhosis -- remain challenging to treat and can benefit from either adding ribavirin to direct-acting antivirals or lengthening treatment to 24 weeks.

Ribavirin or Longer Treatment

"Among patients without cirrhosis, rates of SVR have exceeded 90% among patients who are treatment-naive as well as treatment-experienced, even without ribavirin," Hari Conjeevaram from the University of Michigan at Ann Arbor wrote in an accompanying JAMA editorial. "Although similar SVR rates have been reported among patients who are treatment-naive with cirrhosis with 12 weeks’ therapy, the addition of ribavirin or extension of treatment to 24 weeks appears to be warranted with some regimens. The high response rates, especially among patients with cirrhosis, is substantial and important clinically, given that viral eradication has been shown to delay or decrease chance of decompensation of liver disease and also hepatocellular carcinoma."

It remains to be seen in clinical practice whether hard-to-treat patients will benefit more from including ribavirin, with its potential for added side effects, versus longer treatment duration, which typically costs more.

"Despite the progress and the success of viral eradication, numerous questions remain unanswered such as response based on race, still difficult-to-treat situations such as patients with end-stage liver disease or undergoing hemodialysis, access to and affordability of these therapies, improvement in quality of life, and cost-effectiveness," Conjeevaram continued. "It is time to reflect on these challenges and find solutions because the influence of HCV infection on global society is an ongoing challenge."

5/13/15

References

F Poordad, W Sievert, L Mollison, et al. Fixed-Dose Combination Therapy With Daclatasvir, Asunaprevir, and Beclabuvir for Noncirrhotic Patients With HCV Genotype 1 Infection. JAMA 313(17):1728-1735. May 5, 2015.

AJ Muir, F Poordad, J Lalezari, et al. Daclatasvir in Combination With Asunaprevir and Beclabuvir for Hepatitis C Virus Genotype 1 Infection With Compensated Cirrhosis. JAMA 313(17):1736-1744. May 5, 2015.

H Conjeevaram. Continued Progress Against Hepatitis C Infection (Editorial). JAMA 313(17):1716-1717. May 5, 2015.