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DDW 2016: ABT-493 + ABT-530 Cures Most Hepatitis C Patients in SURVEYOR Studies

A coformulation of AbbVie's experimental next-generation direct-acting antiviral agents ABT-493 and ABT-530 was well-tolerated and led to sustained virological response in 97% or more of patients with all hepatitis C virus (HCV) genotypes in a set of studies reported this week at the 2016 Digestive Disease Week meeting in San Diego.

Interferon-free therapy using direct-acting antivirals (DAAs) has revolutionized treatment for chronic hepatitis C, but researchers continue to try to optimize therapy, especially for difficult-to-treat patients such as those with liver cirrhosis or hard-to-treat HCV genotype 3. An ideal regimen would not require ribavirin and would be pangenotypic, or active against multiple HCV genotypes.

The Phase 2b SURVEYOR trials evaluated a pangenotypic combination of the HCV NS3/4A protease inhibitor ABT-493 plus the NS5A inhibitor ABT-530. The studies had multiple parts and included various patient populations based on HCV genotype, prior treatment experience, and presence of liver cirrhosis.

SURVEYOR-1 initially enrolledchronic hepatitis C patients with HCV genotype 1 and no cirrhosis. They were treated with ABT-493 (200 or 300 mg) plus ABT-530 (40 or 120 mg) once-daily for 12 weeks. The second part of the study evaluated a shorter 8-week treatment duration for genotype 1 patients without cirrhosis, and a 12-week duration for cirrhotic genotype 1 patients and non-cirrhotic people with genotypes 4, 5, and 6.

SURVEYOR-2 recruited non-cirrhotic patients with HCV genotype 2 and genotype 3 patients with or without cirrhosis, both treatment-naive or prior non-responders. They were treated with ABT-493 and ABT-530 once-daily for 8 or 12 weeks; one of the 12-week arms included ribavirin.

Prior results from SURVEYOR-1 and SURVEYOR-2 were presented at the AASLD Liver Meeting in November. Researchers at DDW reported pooled results from these studies according to HCV genotype.

Genotypes 1 and 2

Fred Poordad from the Texas Liver Institute presented results for genotype 1 and 2 patients without cirrhosis treated with 300 mg ABT-493 + 120 mg ABT-530 for 8 weeks.

In the group of 34 genotype 1 patients 56% were men, the median age was 54 years, 71% had harder-to-treat subtype HCV 1a, 15% were treatment-experienced, and 12% had advanced fibrosis (stage F3). Of the 54 genotype 2 patients 61% were men, the median age was 57 years, 13% were treatment-experienced, and 6% had stage F3 fibrosis. NS3 or NS5A resistance-associated substitutions were detected in 76% and 58%, respectively, at baseline.

Overall, 97% of genotype 1 patients and 98% of genotype 2 patients achieved sustained virological response, or continued undetectable HCV viral load at 12 weeks post-treatment (SVR12); a genotype 1 patient discontinued early due to a non-drug-related adverse event and a genotype 2 patients was lost to follow-up. In a modified analysis that excluded these non-virological failures, the cure rates were 100% for both genotype groups.

Treatment was generally safe and well-tolerated, with 1 non-drug-related serious adverse event in each genotype group. The most commonly reported adverse events were fatigue and headache, mostly mild. No grade 2 or higher laboratory abnormalities were observed.

The combination of ABT-493 and ABT-530 for 8 weeks led to high SVR12 rates "regardless of baseline viral load, prior treatment history, or HCV subtype," the researchers concluded.

Genotype 3

Andrew Muir from Duke University School of Medicine reported findings for treatment-naive genotype 3 patients without cirrhosis in SURVEYOR-2 who were treated with 300 mg ABT-493 + 120 mg ABT-530 for 8 weeks.

In Part 1 of this study, 97% of patients treated with this regimen for 12 weeks were cured in a modified analysis, setting the stage for testing of the shorter duration.

This analysis included 29 patients. Half were men, the median age was 47 years, 86% had HCV subtype 3a, and a quarter had stage F3 fibrosis. 46% had NS3 or NS5A resistant variants at baseline.

The overall SVR12 rate was 97%. 1 patient withdrew consent after treatment week 6, leaving a cure rate of 100% when excluding this non-virological failure. Again treatment was well-tolerated, with no serious adverse events, grade 3-4 laboratory abnormalities, or discontinuations due to adverse events.

Genotypes 4, 5, and 6

Finally, Edward Gane from Auckland City Hospital in New Zealand presented results from Part 2 of SURVEYOR-1, looking at non-cirrhotic patients with HCV genotypes 4, 5, or 6 who were treated with 300 mg ABT-493 + 120 mg ABT-530 for 12 weeks.

Although HCV genotype 1 is most common in North and South America, Europe, and much of Asia, genotypes 4, 5, and 6 occur more often in low- and middle-income countries with a high burden of hepatitis C. Genotype 4 is the predominant type in the Middle East and parts of Africa, genotype 5 is most common in South Africa, and genotype 6 is found in parts of Asia.

This analysis included 34 patients: 22 with genotype 4, 1 with genotype 5, and 11 with genotype 6. Half were men, a quarter were Asian, the median age was 55 years, 15% were treatment-experienced, and 15% had advanced fibrosis.

The SVR12 rate was 100% for all these less extensively studied genotypes. Treatment was safe and well-tolerated, with no serious adverse events, grade 2 or higher laboratory abnormalities, or discontinuations for this reason.

Based on these findings from SURVEYOR-1 and SURVEYOR-2, Phase 3 studies are now evaluating ABT-493 plus ABT-530 for 8 or 12 weeks in a larger number of patients with all 6 major HCV genotypes, with and without cirrhosis.

5/26/16

References

F Poordad, F Felizarta, S Wang, et al. High SVR Rates With the Combination of ABT-493 + ABT-530 for 8 Weeks in Non-Cirrhotic Patients with HCV Genotype 1 or 2 Infection. Digestive Disease Week (DDW 2016). San Diego. May 22-24, 2016. Abstract 752.

A Muir, S Strasser, S Wang et al. High SVR Rates With ABT-493 + ABT-530 Co-Administered for 8 Weeks in Non-Cirrhotic Patients with HCV Genotype 3 Infection. Digestive Disease Week (DDW 2016). San Diego. May 22-24, 2016. Abstract 753.

E Gane, J Lalezari, A Asatryan, et al. SURVEYOR I: 100% SVR12 and Favorable Safety of ABT-493 + ABT-530 Administered for 12 Weeks in Non-Cirrhotic Patients With Genotypes 4, 5, or 6 Infection. Digestive Disease Week (DDW 2016). San Diego. May 22-24, 2016. Abstract 755.

PY Kwo, F Poordad, AR Porcalla, et al. Safety of ABT-493 and ABT-530 Co-Administered in Patients with HCV Genotype 1 - 6 Infection: Results From the SURVEYOR-I and SURVEYOR-II Studies. Digestive Disease Week (DDW 2016). San Diego. May 22-24, 2016. Abstract Su1416.