November 11, 2016
By Will Boggs MD
NEW YORK (Reuters Health) - Polymorphisms in hepatitis C virus (HCV) NS5A are associated with reduced efficacy of the fixed-dose combination of elbasvir and grazoprevir, according to an analysis by the U.S. Food and Drug Administration.
"While we have observed an impact of HCV polymorphisms on treatment efficacy with other HCV direct-acting antivirals (e.g., NS3 Q80K for simeprevir), we did not expect that NS5A polymorphisms would have such a significant impact with this regimen given the generally high SVR12 rates overall in the indicated populations," Dr. Takashi E. Komatsu and Dr. Patrick R. Harrington from the FDA's Center for Drug Evaluation and Research in Silver Spring, Maryland, told Reuters Health in a joint email.
Elbasvir is an inhibitor of HCV NS5A, which is essential for viral RNA replication and virion assembly. Grazoprevir inhibits the HCV NS3/4A protease, which is necessary for the proteolytic cleavage of the HCV polyprotein into mature forms that are essential for viral replication.
Drs. Komatsu and Harrington and colleagues analyzed HCV drug resistance and HCV RNA results reported from selected phase 2 and phase 3 clinical trials of elbasvir and grazoprevir administered with or without ribavirin.
The overall sustained virologic response at 12 weeks (SVR12) was 93% for patients infected with HCV genotype 1a and 96% for patients infected with HCV genotype 1b, according to the report, online October 20 in Gastroenterology.
Virologic failure was universally associated with the detection of resistance-associated substitutions in at least one drug target. Treatment-emergent NS5A substitutions were detected in 81% of genotype 1a-, 88% of genotype 1b- and 100% of genotype 4-infected patients. Treatment-emergent NS3 substitutions were detected in 78%, 25% and 40%, respectively.
M28V was the most common variant in NS5A, and it was associated with a significantly lower SVR12 (86%) among patients infected with genotype 1a. SVR12 rates were even lower (<50%) among patients with the less common Q30H/L/R or L31M polymorphisms.
NS5A polymorphisms in genotype 1b-infected patients were associated with only slightly lower SVR12 rates (94% vs. 99%), whereas SVR12 rates among genotype 4-infected patients were 100% for patients with baseline NS5A polymorphisms.
NS3 polymorphisms, on the other hand, did not appear to affect treatment outcomes.
"Our analyses of HCV genotype 1a-infected patients indicated that an intensified treatment regimen of elbasvir and grazoprevir plus ribavirin for 16 weeks may overcome the impact of NS5A polymorphisms," Dr. Komatsu and Dr. Harrington said. "However, this conclusion relied on only 6 patients who had an NS5A polymorphism. While these patients had NS5A polymorphisms at a key resistance-associated position and all achieved SVR24, more data would have been ideal at the time of FDA review."
"An additional post-marketing study is currently ongoing to characterize more precisely the efficacy of elbasvir and grazoprevir with ribavirin for 16 weeks in a larger group of HCV genotype 1a-infected patients with NS5A polymorphisms," they note.
"In patients with HCV genotype 1a infection, polymorphisms in NS5A at baseline (before treatment) can affect the efficacy of this direct-acting antiviral regimen, and pre-treatment resistance analyses can optimize treatment selection," Dr. Komatsu and Dr. Harrington conclude. "Care providers should consider information in the elbasvir/grazoprevir drug prescribing information and current treatment guidelines to determine the appropriate treatment regimens for their patients."
"We believe that publishing the methods and results of independent FDA analyses such as these is important for public health, as it provides transparency in the FDA analysis and review process, and can help the treatment community understand the rationale behind FDA regulatory decisions that impact how drugs are used in clinical practice," they add.
In this case, the findings ultimately contributed to a decision to recommend pretreatment testing for NS5A resistance-associated polymorphisms for patients with HCV genotype 1a infection in order to guide the optimal use of elbasvir and grazoprevir.
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