A combination of two experimental direct-acting antivirals
developed by AbbVie cured 97 to 100% of people without cirrhosis with genotype 1
hepatitis C infection in a mid-stage phase 2 study presented this week at the
2015 AASLD Liver Meeting in San Francisco.
The SURVEYOR-1 study assessed the effectiveness and safety of
two experimental next-generation direct-acting antivirals. ABT-493 is an HCV
NS3/4A protease inhibitor active against all genotypes of hepatitis C. ABT-530
is a NS5A inhibitor also active against all genotypes of HCV. Both agents are
active against common variants that confer resistance to first-generation
agents of their classes. ABT-493 is more potent against genotype 3 than other HCV
protease inhibitors, including products being developed by Merck (grazoprevir)
and Gilead (GS-9451), and ABT-530 has demonstrated higher potency than most
other NS5A inhibitors across all genotypes.
The new experimental combination is not only active across
all genotypes, but does not need ritonavir boosting to maintain adequate levels
of its protease inhibitor component. This minimises the potential for drug-drug
interactions, which are a concern with any ritonavir-containing treatment due
to the agent’s interaction with a wide range of medications metabolised through
the p450 CYP3A4 liver enzyme pathway.
The study compared two doses of ABT-530 (40 or 120mg)
combined with 200mg of ABT-493, both dosed orally once a day, for 12 weeks.
The study recruited 79 previously untreated people or previous
null responders to pegylated interferon and ribavirin, all with genotype 1
infection and no evidence of cirrhosis. Participants were randomly assigned to
the ABT-530 40mg (n = 39) or 120mg arm (n = 40).
Participants were evenly matched in most respects, with an
average age of 53 years, 64% previously untreated and median HCV viral load of
6.6 log10 IU/ml. Those in the 120mg arm were more likely to have F3
fibrosis (32% vs 18%) and somewhat more likely to be male (58% vs 46%) and to
have genotype 1a infection (85% vs 77%).
After 12 weeks of treatment 97% of the 40mg arm and 100% of
the 120mg arm had a sustained virologic response 12 weeks post-treatment,
commonly defined as a cure. One participant experienced a virologic relapse
after completion of treatment in the 40mg arm. This patient showed no evidence of non-adherence nor baseline
resistance mutations that might have contributed to treatment failure, but had
two NS5A resistance mutations conferring high-level resistance to ABT-530 at
relapse. All treatment-experienced patients achieved SVR12.
Treatment was well tolerated in the vast majority of
participants. One grade three severe adverse event was reported in the 40mg arm
(metastatic prostate cancer) but this was not considered to be related to
treatment. Two severe adverse events occurred in the 120mg arm. One case of elevated
blood glucose in a man weighing 115kg was not considered to be related to
treatment, but a case of decreased blood phosphorus was considered study
drug-related, but in all three cases participants achieved SVR 12.
In a subsequent phase of the SURVEYOR-1 study, 34 participants
with genotype 1 received 8 weeks of treatment with ABT-530 (120mg) combined
with 200mg of ABT-493.
Study participants were 56% male, 71% had genotype
1a infection and 15% had F3 stage fibrosis. 88% were previously untreated, 12%
were null responders to previous treatment with pegylated interferon and
ribavirin.
At 12 weeks post-treatment 97% (33/34) achieved a
sustained virological response. One participant discontinued the study
at treatment week 4 due to adenocarcinoma, unrelated to study drugs. No
drug-related serious adverse events were reported. The most frequent adverse
event (> 5 percent of patients) was fatigue.
On the basis of these results AbbVie will test 8 and 12-week regimens
in six phase 3 studies due to start this month, using a 120mg dose of ABT-530
and 200mg of ABT-493.