AASLD 2014: AbbVie Next-Generation Hepatitis C Drugs Promising in Early Studies

AbbVie's investigational HCV protease inhibitor ABT-493 and NS5A inhibitor ABT-530 demonstrated good antiviral activity in patients with genotype 1 chronic hepatitis C in a 3-day monotherapy study, as well as potent and synergistic activity against multiple HCV genotypes in laboratory replicon studies, according to presentations at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting held recently in Boston.

The advent of direct-acting antivirals (DAAs) that can be used in interferon-free regimens has brought about a revolution in hepatitis C treatment. The recently approved Harvoni (Gilead Sciences' sofosbuvir/ledipasvir) and Viekira Pak (AbbVie's paritaprevir/ombitasvir/ritonavir plus dasabuvir) combinations are highly effective against HCV genotype 1, but there remains a need for therapies that are equally active against other genotypes.

HCV Genotype 1

Eric Lawitz from the University of Texas Health Science Center and colleagues evaluated ABT-493 and ABT-530 as monotherapy for previously untreated HCV genotype 1 patients with or without compensated liver cirrhosis.

This open-label Phase 2 dose-ranging study enrolled a total of 89 participants. About 75% were men, most were white, and the mean age was approximately 55 years. More than 80% had harder-to-treat HCV subtype 1a.

Groups of 8 patients without cirrhosis were allocated to receive ABT-493 at doses of 100, 200, 300, 400, or 700 mg once-daily for 3 days; cirrhotic patients received only the 200 mg dose. Similarly, separate groups of 8 non-cirrhotic patients received ABT-530 at doses of 15, 40, 120, or 400 mg once-daily for 3 days; cirrhotic patients received only the 120 mg dose. After 3 days everyone started the Viekira Pak regimen.

Results

• For ABT-493 monotherapy, mean maximal HCV viral load decreases over 3 days ranged from -3.8 to -4.3 log IU/mL, with no significant differences across dose groups.
• There was also no significant difference in HCV RNA decreases between patients with or without cirrhosis.
• For ABT-530 monotherapy, mean maximal viral load decreases over 3 days ranged from -3.4 to -4.5 log IU/mL (-3.9 to -4.3 log IU/mL using the 40 mg dose).
• All higher doses were associated with significantly larger decreases than the 15 mg dose, however no greater potency was seen at doses over 40 mg.
• Mean maximal viral load decreases were slightly higher among patients without cirrhosis compared to cirrhotics (-4.1-4.5 vs -3.9 among those receiving 40 mg).
• For both drugs, the largest HCV RNA decreases were seen during the first 24 hours, with smaller incremental decreases during days 2 and 3.
• ABT-493 and ABT-530 were both generally safe and well-tolerated.
• 45% of patients receiving ABT-493 and 25% receiving ABT-530 experienced treatment-emergent adverse events, mostly mild.
• The most common adverse events with ABT-493 were headache (22%), abdominal discomfort (6%), diarrhea (6%), fatigue (6%), and rash (6%).
• The most common adverse events with ABT-530 were headache (10%), constipation (5%), and nausea
(5%).
• No clinically significant laboratory abnormalities were attributed to either study drug.

"In this Phase 2, open-label, dose-ranging trial, 3-day monotherapy with ABT-493 or ABT-530 resulted in robust plasma HCV RNA declines from baseline in treatment-naive patients with HCV genotype 1 infection with and without compensated cirrhosis," the researchers concluded.

While a formal comparison between patients with genotypes 1a and 1b was not possible due to the small number of people with 1b, viral load declines "appeared to
be similar," they added.

Other HCV Genotypes

Teresa Ng and colleagues from AbbVie conducted laboratory studies to test ABT-493 and ABT-530 in HCV replicons, or models of the virus expressing the NS4 or NS5A proteins from all 6 major genotypes.

Results

• ABT-493 showed potent and broad antiviral activity against multiple genotypes.
• ABT-493 was highly active against HCV genotype 3a, for which many other protease inhibitors are less effective.
• ABT-493 retained potency against most clinically important protease resistance variants, including genotype 1 R155 and D168 variants.
• ABT-493 demonstrated a high genetic barrier to resistance.
• ABT-530 showed high pangenotypic potency, with similar activity against genotypes 1 through 6.
• ABT-530 retained potency against genotype 1-6 viral variants resistant to other NS5A inhibitors, including genotype 1 Y93 variants.
• ABT-530 also demonstrated a high barrier to resistance.
• The combination of ABT-493 plus ABT-530 showed synergistic antiviral activity in vitro, meaning its potency was greater than the additive potency of the 2 drugs used separately.
• No drug resistance emerged in any of the replicons.

"These results, together with the potent antiviral activity of ABT-530 and ABT-493 observed in 3-day monotherapy studies in HCV genotype 1-infected patients, support the ongoing Phase 2 and future clinical studies of these DAAs in combination for the treatment of patients with chronic HCV infection," the researchers concluded.

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References

E Lawitz, WD O'Riordan, BL Freilich, et al. Potent Antiviral Activity of ABT-493 and ABT-530 With 3-Day Monotherapy in Patients With and Without Compensated Cirrhosis With Hepatitis C Virus (HCV) Genotype 1 Infection. American Association for the Study of Liver Diseases (AASLD) Liver Meeting. Boston, November 7-12, 2014. Abstract 1956.

T Ng, T Pilot-Matias, L Lu, et al.A Next Generation HCV DAA Combination: Potent, Pangenotypic Inhibitors ABT-493 and ABT-530 With High Barriers to Resistance. American Association for the Study of Liver Diseases (AASLD) Liver Meeting. Boston, November 7-12, 2014. Abstract1946.

C-Wei Lin, W Liu, A Asatryan, et al. Pharmacokinetics and Safety of Pan-Genotypic, Direct Acting Protease Inhibitor, ABT-493, and NS5A Inhibitor, ABT-530, Following 3 day Monotherapy in HCV Genotype-1 Infected Subjects with or without Compensated Cirrhosis. American Association for the Study of Liver Diseases (AASLD) Liver Meeting. Boston, November 7-12, 2014. Abstract 1986.