J&J/Medivir’s Simeprevir Review Makes For Back-To-Back Hep C Advisory Committees

Like Merck’s boceprevir and Vertex’s telaprevir in 2011, simeprevir and Gilead’s sofosbuvir both have been accepted as priority review candidates for hepatitis C therapy, and will be reviewed by FDA’s Antiviral Drugs Advisory Committee on consecutive days. A positive tone is anticipated at both panel meetings.

Mirroring the events of 2011, when FDA’s Antiviral Drugs Advisory Committee reviewed a pair of experimental drugs for hepatitis C on consecutive days, the panel will be overviewing the NDA for simeprevir (TMC-435), a second-generation protease inhibitor for HCV being co-developed by Johnson & Johnson and Medivir AB. The meeting slated for Oct. 24 in Silver Spring, Md., comes one day before the previously announced panel review of Gilead Sciences Inc.’s sofosbuvir, a nucleoside polymerase inhibitor for HCV.

As with the review of sofosbuvir, the panel to look at the simeprevir filing likely will be a positive one intended mainly to highlight important new therapies, a tact the antiviral committee used in 2011 when reviewing the NDAs for Vertex Pharmaceuticals Inc.’s Incivek (telaprevir) and Merck & Co. Inc.’s Victrelis (boceprevir), a briefing by PrevisionPolicy suggests.

J&J and Medivir filed the simeprevir NDA in April; it was accepted for priority review with a Nov. 28 PDUFA date (Also see "J&J Hoping To Position Simeprevir As Top Next-Gen Protease Inhibitor For HCV" - Pink Sheet, 14 May, 2013.). Gilead’s sofosbuvir also has been accepted for a six-month review, with an action date of Dec. 8 (Also see "Gilead’s Sofosbuvir Heads To FDA Advisory Panel; Novelty Seems Main Issue" - Pink Sheet, 13 Sep, 2013.).

“The antivirals panel is one exception to the general trend at FDA for ad comms to be negative events, especially in the context of priority reviews,” PrevisionPolicy said in an Aug. 26 Regulatory and Policy Research Note. “This division at the agency continues to see public advisory committees as good settings to highlight important treatment advances.”

The NDA proposes an indication for the treatment of chronic hepatitis C genotype 1 infection, in combination with a backbone of oral antiviral ribavirin and weekly injections of pegylated interferon in adult patients with compensated liver disease who are treatment-naïve or who have failed previous interferon-based therapy. Incivek and Victrelis both are approved to treat HCV with the same backbone therapy, but the real competition for simeprevir and other experimental, direct-acting antivirals is to become part of paradigm-changing, all-oral regimens for hepatitis C offering higher cure rates, shorter duration of therapy and better side-effect profiles (Also see "Sweden’s Medivir Prepares For Simeprevir And Profitability" - Pink Sheet, 23 Aug, 2013.).

Simeprevir also is filed in Europe and Japan, with approvals expected in early 2014 and later this year, respectively. While Medivir has laid out a simple rationale for taking market share from Incivek and Victrelis in the current treatment paradigm – simeprevir is taken once-daily, whereas the other two protease inhibitors are dosed three times a day – the bigger opportunity lies in whether J&J/Medivir can produce their own oral DAA regimen or get included in a regimen with other top HCV candidates such as sofosbuvir or Bristol-Myers Squibb Co.’s daclatasvir, an NS5A inhibitor.

“The window of opportunity for simeprevir is closing rapidly,” Credit Suisse analyst Ravi Mehrotra said in an Aug. 22 note on Medivir. Upcoming data from combination trials with the Gilead and Bristol compounds will be key catalysts for simeprevir, he added.

Combo Trial Data Imminent

Before the end of the year, top-line data are expected from a Phase II trial testing simeprevir and daclatasvir, with and without ribavirin, in genotype 1a and 1b treatment-naïve patients and null responders. Another Phase II trial should report out top-line data before year’s end for a combination of simeprevir and sofosbuvir in genotype 1 cirrhotic patients who are treatment-naïve or null responders.

In August, Medivir and J&J announced promising results from another cohort of the combo trial with sofosbuvir, showing that combination therapy produced sustained virological response (SVR) at four weeks in 96% of non-cirrhotic genotype 1 null responders without ribavirin. When ribavirin was added on, an SVR4 rate of 100% was achieved (Also see "News In Brief From Elcelyx, Medivir, Repligen" - Pink Sheet, 9 Sep, 2013.).

The advisory committee should find little to take issue with in simeprevir’s trial data from investigation with the ribavirin/peg-interferon backbone. In the Phase III QUEST-1 and QUEST-II trials, the protease inhibitor produced SVR rates of 80% and 81% after 12 weeks of therapy in treatment-naïve genotype 1 patients, compared with 50% of control arm patients in both study cohorts.

Meanwhile, simprevir produced a safety profile that J&J characterized as similar to that of placebo. The most common side effects seen in the Phase III program were fatigue, itch and headache, while Merck’s boceprevir had issues with anemia and Vertex’s telaprevir with skin rash in those drugs’ respective Phase III programs. Each was approved on time by FDA despite those safety issues.

Going forward, Medivir has said its focus in HCV will be on the nucleoside polymerase inhibitor (or “nuc”) class. Sofosbuvir is the leading nuc in development, with Vertex’s VX-135 the only other nuc in the clinic among the safety-plagued class. On Aug. 15, Medivir discontinued its NS5A inhibitor program, saying its candidates were not significantly differentiated from Bristol’s daclatasvir or other candidates in the class.