The FDA approves Radicava; is it a breakthrough moment for ALS?

On Friday, May 5th, the FDA approved Mitsubishi Tanabe Pharma’s Radicava (edaravone) for the treatment of amyotrophic lateral sclerosis (ALS), more than a m­­onth in advance of its PDUFA date of June 16, 2017. The drug’s approval is only the second for ALS, coming more than two decades after the first—riluzole (Concordia Healthcare’s Rilutek, generics), which reached market in 1995. Radicava, an IV-administered free radical scavenger, was initially approved in Japan as a post-stroke therapy, and it garnered a label extension to treat ALS in that market in 2015.

Although trial data are mixed, Radicava slowed functional decline in a trial enrolling early-stage ALS patients in Japan. The primary data supporting the drug’s approval in the United States and Japan derive from a positive trial enrolling approximately 130 Japanese ALS patients with a disease duration of less than two years, who had reasonable respiratory function and were generally independent. The primary end point of the study measured the change from baseline in ALS Functional Rating Scale-Revised (ALSFRS-R) at six months versus placebo, which declined by 5.01 points in Radicava-treated patients, a 33% improvement over placebo (mean: -7.5-point decline, p=0.0013); Radicava was administered in six infusion cycles, in total comprising more than 60 infusions of the drug during the six-month period. However, the drug has failed to show efficacy in multiple studies that enrolled patients with more advanced disease. Overall, despite the drug’s open U.S. indication for all ALS patients, clinical data suggest that the optimal balance of benefit and risk/delivery burden may be in newly- or recently-diagnosed ALS patients.

Interviewed ALS experts welcome any/all new drugs, but harbor lingering doubts over Radicava’s clinical impact. Although Radicava will be a welcome addition to the ALS armamentarium, ALS experts, in recent interviews, contended that the therapy appears unlikely to be transformative—at least in the context of available clinical data.  The drug slowed functional decline and improved quality of life in the pivotal trial, but the short duration precluded meaningful assessment of any impact on survival, time to assisted ventilation, or disability. Experts also expressed concern over the mixed results in Phase IIII studies, and the lack of clinical data outside Japan—a population for which diversity in population demographics (e.g., ethnicity) and ALS clinical practice may differ meaningfully from the United States. Some interviewed clinicians raised concerns relating to the logistics and burden of daily infusion required for administration of Radicava, which would require more than 100 infusions per year. Ultimately, experts expect the drug to be effective predominantly for patients in the early stages of ALS, and they expect to prescribe it in that fashion.

Notably, The FDA solicited the NDA for Radicava. According to the Eric Bastings, M.D., Deputy Director of the Division of Neurology Products at the FDA, the agency invited Mitsubishi Tanabe Pharma to file Radicava for regulatory approval after learning of its use for ALS in Japan (FDA, press release 5, May, 2017)—an uncommon event, especially for a development program with mixed data, and which did not include a single trial conducted in the United States. Undoubtedly, the pressing unmet need in this arena factored in to these developments. Indeed, the FDA has recently been aggressive in evaluating and approving drugs for life-threatening rare diseases with strong public awareness and patient advocacy. Last year, the FDA approved Sarepta’s Exondys 51 (eteplirsen) for a subset of patients with Duchenne muscular dystrophy (DMD), amid controversy surrounding its efficacy and cost-effectiveness; this decision was perhaps influenced, to some extent, by a strong push from DMD patient advocacy groups. The ex-U.S. availability of a drug boasting a positive Phase III efficacy signal in ALS, combined with the high awareness/advocacy in the wake of the Ice Bucket Challenge, likely contributed to the FDA’s swift action to request an NDA for Radicava, grant orphan drug designation, and complete a timely review of the program.

Radicava’s cost may be hard to justify. Initial media reports suggest that Radicava’s U.S. price will be approximately $145,000/year before rebates and discounts, based on a per-infusion cost of $1,086—several fold higher than the product’s price in the Japanese market. This price point may be questionable for a drug that appears to provide functional benefit to only a subset of patients (e.g. early stage), for which long-term benefits (i.e., longer than six months) remain uncertain. U.S. payers have been increasingly scrutinizing reimbursement for high-cost orphan drugs, and some ALS patients may face reimbursement hurdles, or a financial burden from out-of-pocket costs. However, a string of recent orphan drug approvals, some with lesser evidence of clinical benefit than Radicava, has likely minimized any “sticker shock” associated with the drug’s price, and riluzole’s low cost (due to generic availability) will permit combination use of the two approved ALS therapies—an approach ALS experts are primed for—rather than force a difficult choice to select one over the other. With additional new brands on the horizon, however, ALS patients may indeed face difficulty in accessing a medication or regimen that optimally balances benefit, risk, and cost.

Radicava’s approval marks the first of a series of key 2017 events in the ALS market. It’s an exciting time in the ALS community; after a 22-year lull, a new drug has been approved and two additional pharmacotherapies are on the near-term horizon. Pivotal clinical data for Cytokinetics’ tirasemtiv, currently being assessed for its efficacy in preserving respiratory function in a Phase III study in the United States, are expected at the end of 2017. In addition, AB Science’s masitinib is undergoing a regulatory review for conditional approval by the EMA on the basis of positive interim data from a randomized placebo-controlled Phase II/III study; a regulatory decision is expected in Q4 2017 (AB Science presentation, March 20, 2017). Full data from the drug’s positive Phase III trial will be presented shortly at the European Network for the Cure of ALS (ENCALS) annual meeting in Ljubljana, Slovenia (18 – 20 May, 2017). While a cure for ALS remains elusive, the clinical landscape in ALS is improving, and the pipeline is percolating; we’ll be here to break down all of the developments during this landmark year.

To learn more about the ALS market, read our Niche & Rare Disease Landscape & Forecast | Amyotrophic Lateral Sclerosis | US/EU5 content.