Simeprevir Clears FDA, But Tougher Road Lies Ahead

Unlike HCV competitors Incivek and Victrelis, Janssen’s second-generation protease inhibitor Olysio carries a recommendation for screening to weed out patients with a hepatitis C variant associated with poor response – but the strength of its efficacy and safety should still beat out those drugs. The harder part will be gaining share as patients are opting to wait for even better regimens.

Janssen Pharmaceutical Cos.’s Olysio (simeprevir) cleared FDA with the best possible labeling and should stand to unseat the first-generation protease inhibitors for HCV, but it may take a marketing masterpiece to establish the drug in the face of coming competition.

Product labeling includes a recommendation for screening to identify a prevalent subgroup of patients unlikely to respond, but FDA stopped short of a full contraindication.

A second-generation NS3/4A protease inhibitor, Olysio was approved Nov. 22 for treatment of chronic hepatitis C in combination with interferon/ribavirin.

Simeprevir offers a clear advance over Vertex Pharmaceuticals Inc.’s Incivek (telaprevir) and Merck & Co. Inc.’s Victrelis (boceprevir), both approved in 2011 – with greater convenience, safety and efficacy. But those agents are already on the decline as patients and practitioners wait for even better things to come.

Unlike Incivek and Victrelis, Olysio has been associated with poor response in patients with a specific HCV variant and FDA advises against use in those patients.

“Screening patients with HCV genotype 1a infection for the presence of virus with the NS3 Q80K polymorphism at baseline is strongly recommended,” labeling states. It says alternative therapy should be considered for those patients.

Extensive information is included in the clinical pharmacology section and the inferior results are prominently featured in the clinical studies section. FDA’s decision not to include a contraindication is consistent with the advice of its Antiviral Drugs Advisory Committee (Also see "Janssen Persuades Advisory Committee That Simeprevir Doesn’t Need Contraindication" - Pink Sheet, 4 Nov, 2013.).

Labeling carries warnings on both photosensitivity and rash, both concerns discussed at the advisory committee review (Also see "Is It A Rash Or Photosensitivity? FDA May Have To Distinguish Them In Simeprevir Label" - Pink Sheet, 28 Oct, 2013.).

One issue discussed by the committee was how to differentiate between the two dermal reactions and whether outside consultation is warranted. The photosensitivity warning describes the potential reactions in detail, characterized by “an exaggerated sunburn reaction,” that may feature “burning, erythema, exudation, blistering and edema.” Hospitalization has been required. The agency says that discontinuation should be considered and patients monitored until the reaction resolves, but “if a decision is made to continue Olysio in the setting of a photosensitivity reaction, expert consultation is advised.”

Photosensitivity presented most frequently during the first four weeks of treatment but could occur at any time. The same timeframe is given for rash. That warning notes that most of the events were mild or moderate, but there has been severe rash and rash requiring discontinuation. “Patients with mild to moderate rashes should be followed for possible progression of rash, including the development of mucosal signs (e.g., oral lesions, conjunctivitis) or systemic symptoms. If the rash becomes severe, Olysio should be discontinued. Patients should be monitored until the rash has resolved,” labeling states.

Rash has been a problem for Incivek. In addition to labeling at the time of approval, a “black box” warning about severe rash-related adverse events, including death, was added to that product’s labeling at the end of 2012 (Also see "Incivek Black Box Creates Fallout Risk For Vertex, FDA On Rash-related Fatalities" - Pink Sheet, 19 Dec, 2012.).

Simeprevir’s Strengths

The approval was based on three pivotal Phase III studies – QUEST-1 and -2 in treatment-naïve patients and PROMISE in patients who relapsed after prior interferon-based treatment, as well as the Phase IIb ASPIRE study in prior non-responders.

A pooled analysis of the QUEST trials showed that 80% of treatment-naïve patients on Olysio achieved sustained virologic response 12 weeks after the end of treatment (SVR12, considered a cure) compared to 50% of patients on placebo. In the PROMISE trial of prior relapsers, 79% of the simeprevir group achieved SVR12 compared to 37% of the placebo group. In ASPIRE, SVR24 was reached in 65% of prior partial-responders and 53% of prior null responders compared to 9% and 19% of the corresponding placebo groups.

Olysio was studied in combination with pegylated interferon and ribavirin, an aspect that will soon hinder the drug’s performance on the market.

The HCV community is poised for an all-oral regimen that eliminates the problematic interferon component. Such regimens are advancing and Janssen has hoped to position simeprevir in combination with some of the leading candidates, such as Gilead Sciences Inc.’s nucleoside polymerase inhibitor sofosbuvir and Bristol-Myers Squibb Co.’s NS5A inhibitor daclatasvir (Also see "J&J Hoping To Position Simeprevir As Top Next-Gen Protease Inhibitor For HCV" - Pink Sheet, 14 May, 2013.).

But the field is moving fast and competition for an all-oral regimen is fierce (Also see "Merck Seen As Late-Riser In HCV Combo Race, As Some Competitors Fade" - Pink Sheet, 28 Oct, 2013.). The market has already shown that patients are willing to wait for treatment with drugs still in development and that use quickly shifts to the best performing option: Incivek, which quickly overtook Victrelis, is in a downward spiral as the HCV community awaits additional advances (Also see "With Incivek Deflated, Vertex’s HCV Roller Coaster Ride Hinges On Phase II Candidate VX-135" - Pink Sheet, 29 Oct, 2013.).

Janssen will need to make the most of its time on the market with simeprevir. Gilead’s sofosbuvir – widely anticipated to be a top performer in the segment – was reviewed by FDA’s advisory committee the day after simeprevir (with a similarly unanimous endorsement) and is expected to clear FDA ahead of its Dec. 8 user fee deadline. Sofosbuvir was recommended for European approval on Nov. 22 as Sovaldi (Also see "Europe’s CHMP Clears Sofosbuvir, Dolutegravir And Dalamanid" - Pink Sheet, 22 Nov, 2013.).

Janssen has launched a patient support program designed in partnership with the HCV community.