AbbVie next-generation hepatitis C drugs look 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 three-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 Viekirax + Exviera (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.

Glossary

cirrhosis

Severe fibrosis, or scarring of organs. The structure of the organs is altered, and their function diminished. The term cirrhosis is often used in relation to the liver. 

monotherapy

Taking a drug on its own, rather than in combination with other drugs.

antiviral

A drug that acts against a virus or viruses.

dose-ranging trial

A clinical trial where two or more doses of a drug are compared to see which works best and is least harmful, usually done at an early stage of drug development.

log

Short for logarithm, a scale of measurement often used when describing viral load. A one log change is a ten-fold change, such as from 100 to 10. A two-log change is a one hundred-fold change, such as from 1,000 to 10.

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

For ABT-493 monotherapy, the mean maximal HCV viral load decreases over three 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, the mean maximal viral load decreases days ranged from -3.4 to -4.5 log IU/ml, and from -3.9 to -4.3 log IU/m using the selected 40mg dose. All higher doses produced significantly larger decreases than the 15mg dose, but no greater potency was seen at doses over 40mg. Maximal viral load decreases were slightly higher among patients without cirrhosis compared to cirrhotics (-4.1-4.5 vs -3.9 among those receiving 40mg).

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% of those receiving ABT-530 experienced treatment-emergent adverse events, mostly mild.

The most common adverse events with ABT-493 were headache (22%), abdominal discomfort (6%), diarrhoea (6%), fatigue (6%) and rash (6%). The most common side-effects with ABT-530 were headache (10%), constipation (5%) and nausea
(5%). No clinically significant laboratory abnormalities were attributed to either drug.

"In this phase 2, open-label, dose-ranging trial, three-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 HCV subtypes 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 six major genotypes.

ABT-493 showed potent and broad antiviral activity against multiple genotypes. It 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. It also demonstrated a high genetic barrier to resistance.

ABT-530 showed high pangenotypic potency, with similar activity against HCV genotypes 1 through 6. It 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 two drugs used separately. No drug resistance emerged in any of the replicons when the two drugs were used together.

"These results, together with the potent antiviral activity of ABT-530 and ABT-493 observed in three-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.

References

E Lawitz 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, abstract 1956, 2014.

T Ng 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, abstract 1946, 2014.

C-W Lin 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, abstract 1986, 2014.