Tuesday, December 3, 2013

Olysio (simeprevir) - Resistant Variant (Q80K)

Resistant Variant (Q80K)

Good morning everyone, while we're all waiting this week for news from the FDA on Gilead's sofosbuvir, LabCorp has captured our attention with a press release announcing the company's enhanced version of a drug resistance test used to screen for the Q80K polymorphism; a naturally occurring polymorphism that develops in certain strains of HCV, making the virus less susceptible to Janssen Therapeutics' OLYSIO(TM) (simeprevir), Quest Diagnostics also offers the Hepatitis C Viral RNA NS3 genotype test.

OLYSIO™ (simeprevir) - Q80K polymorphism
Last month, Olysio (simeprevir), the first "second wave direct-acting antiviral" was FDA approved in combination with peginterferon alfa and ribavirin to treat HCV genotype 1, adults, with compensated liver disease, including cirrhosis, who are treatment-naïve or who have failed previous interferon therapy (pegylated or non‑pegylated) with ribavirin. Although, simeprevir appears to be slightly more effective than the standard of care, curing 80 percent of treatment-naïve patients, and easier to take, there are some drawbacks. Before starting simeprevir patients with HCV genotype 1a need to be screened for a genetic mutation called Q80K polymorphism. Alternative therapy should be considered for people with the mutation, according to simeprevir prescribing information.

In the QUEST-1 and QUEST-2 studies, researchers reported in QUEST-1 patients with HCV genotype 1a had almost a 20% less SVR than HCV genotype 1b. As noted, at baseline, the mutation Q80K was found in approximately 1/3 of genotype 1a patients. On the contrary, in QUEST-2 this mutation was infrequent and did not impact significantly the SVR rate.

Johnson & Johnson went on to perform an analysis pooling all subjects from the C205, C206, C208, C216, and HPC3007 trials, and found 48 percent of U.S. patients with a HCV genotype 1a  had the Q80K polymorphism at baseline, compared to only 19 percent of patients in Europe. The mutation is almost nonexistent in those with a genotype 1b infection.

**Notably, no Q80K-related reductions in efficacy were observed during the pivotal trials of the currently approved NS3/4A protease inhibitors, telaprevir and boceprevir.

Excerpt: OLYSIO™ (simeprevir) Receives FDA Approval for Combination Treatment of Chronic Hepatitis C, November 2013

Genotype 1a treatment-naïve patients receiving OLYSIO who had the Q80K polymorphism
In the QUEST-1 and QUEST-2 studies, among genotype 1a treatment-naïve patients receiving OLYSIOTM who had the Q80K polymorphism (a naturally occurring variation in the HCV NS3/4A protease enzyme), 58 percent achieved SVR12 versus 84 percent of patients without the Q80K polymorphism. In the placebo arm, 52 percent of patients with the Q80K polymorphism achieved SVR12. In the PROMISE study, among prior-relapser patients with the Q80K polymorphism who received OLYSIOTM, 47 percent achieved SVR12 versus 78 percent of patients without the polymorphism. In the placebo arm, 30 percent of patients with the Q80K polymorphism achieved SVR12.

Table 2 presents SVR12 data by subgroups from the pooled studies in treatment-naïve subjects (C208 and C216) as well as from the trial in subjects who relapsed after prior interferon-based therapy (HPC3007). In all other subgroup analyses presented in Table 2, SVR12 rates were significantly higher in the simeprevir group compared to the Control group.
*A study of an all-oral combination of simeprevir with Gilead's sofosbuvir has shown that the regimen mitigates the effect Q80K has on simeprevir, Gaston Picchio, hepatitis disease area leader at J&J's Janssen unit, said during the meeting.
As mentioned, given the high frequency of the Q80K polymorphism in the U.S. population and its significant negative impact on rates of SVR12, according to the prescribing information, the FDA is recommending that all Genotype 1a patients be screened for the Q80K polymorphism. Alternative treatment options should be considered for patients found to be infected with this polymorphic variant.

Source - FDA review  package for simeprevir and Johnson & Johnson document released Oct 23.

FDA review package for simeprevir is available at NATAP, no download required to view.

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