Catalyst Will Try To Salvage Rare Disease Drug from Failed Phase III Trial
Executive Summary
Despite a Phase III study that found no statistically significant outcomes for its endpoints for Firdapse, Catalyst will seek FDA approval for treating a subgroup of patients who showed improvement
Catalyst Pharmaceuticals Inc. is hoping to find a path forward for its rare disease drug Firdapse (amifampridine phosphate) in certain subtypes of congenital myasthenic syndromes (CMS), having failed to meet primary and secondary endpoints in a Phase III study of a broad cohort of patients with the rare neuromuscular disorders.
Firdapse is currently on the market as a treatment for Lambert-Eaton Myasthenic Syndrome (LEMS) in adults. But Catalyst also has been attempting to develop the 3,4-diaminopyridine phosphate as a symptomatic treatment for related conditions, including CMS, a group of rare inherited neuromuscular disorders which cause problems with nerve transmissions to the muscles, causing weakness, fatigue and diminished motor and sensory functioning. Catalyst notes there is “a spectrum of more than 50 genetic defects, with some of the various mutations having as few as a handful of diagnosed patients,” and there is variable severity and course of disease across the genetic subtypes.
The CMS-001 study was designed to evaluate the efficacy and safety of amifampridine phosphate in patients aged 2 years and above, diagnosed with specific genetic subtypes of CMS. There were 20 patients enrolled, with 16 of them randomized, in a double-blind, placebo-controlled, two-treatment crossover study, which was conducted over a two-year period. Given the rarity of the conditions, the trial took four years to enroll, the firm noted, and it made special efforts to push (and cover) diagnosis.
But Catalyst reported 30 October that across all tested subtypes of CMS, the drug did not achieve statistical significance for subject global impression (SGI), the trial’s primary endpoint, or its secondary endpoint of muscle function measure (MFM).
The variety of genetic mutations making up CMS, as well as the study’s small sample size, may have hindered the achievement of statistically significant results. There were, however, improvements for individual patients in some genetic subgroups – and that’s where the company still sees a viable opportunity. Catalyst is not revealing the subgroups that were in the study, saying only that “more than a handful” of the 20 study participants showed symptom improvement and that it expects to discuss those patients with the FDA by year-end.
“We will present it the FDA and ultimately come to some kind of agreement on what specific genetic subtypes, or CMS classifications, we can agree are potentially approveable and work toward agreement on something that they’re willing to approve,” Catalyst CSO Steven Miller explained in an interview with Scrip.
The company is expressing confidence that, with positive outcomes for a niche group of patients, Firdapse is likely to win approval as a treatment for those patients from FDA.
“Since there are only about 1,000 CMS patients, the FDA has a fair amount of latitude,” Patrick McEnany, chairman and CEO of Catalyst Pharmaceuticals, added. “We think there is an argument to be made mechanistically for CMS subtypes that are presynaptic. Firdapse has already been approved in LEMS, which is a presynaptic form of the neuromuscular disorder, so there are some arguments we can make scientifically that will hold water.”
Complicated History With The FDA
Firdapse was initially designated a breakthrough treatment for LEMS by the FDA, but has had a complicated path. The agency initially met Catalyst’s 2016 new drug application (NDA) with a refusal-to-file (RTF) letter. (Also see "Catalyst Collapses On FDA Firdapse Refusal " - Scrip, 18 Feb, 2016.) Catalyst had to go back to the clinic, completed its LMS-003 study and secure data on the drug’s safety and efficacy, before finally winning approval in November 2018. (Also see "Keeping Track: Intercept Submits OCA For NASH; Zogenix’ Fintepla Returns; US FDA Approves Bavarian Nordic Vaccine" - Pink Sheet, 29 Sep, 2019.)
But nearly a year later, Catalyst is suing the FDA over the approval of a rival version of amifampridine for LEMS. In May, the agency approved Jacobus Pharmaceutical Co.'s amifampridine drug, Rizurgi, to treat pediatric LEMS. Catalyst charged in a June court filing that the tentative approval of Rizurgi for adults with LEMS amounts to endorsement of off-label use, and is in violation of orphan-drug exclusivity rights granted to Firdapse when the FDA approved it for adults with LEMS. (Also see "Catalyst Alleges US FDA 'Facilitating' Off-Label Use With Jacobus' Ruzurgi Approval" - Pink Sheet, 12 Jun, 2019.)
Oppenheimer analyst Alexandra Heller suggested that Catalyst has little to worry about: “We continue to find evidence lacking of marketplace competition posed by Jacobus' Ruzurgi,” she said. Nonetheless, the company points to Rizurgi’s potential for off-label use for treating adults as a threat to its brand. Additional information should be available when Catalyst reports third quarter sales and earnings on 13 November.
Heller also dismissed the CMS trial failure as “a minor disappointment,” and said “investors remain focused on Firdapse's current launch in LEMS that has outpaced initial expectations as well as on significant expansion opportunities that may be borne out by ongoing clinical trials.”
New Opportunities Ahead
Catalyst is recruiting patients for a Phase III study of amifampridine phosphate as a treatment for muscle-specific receptor tyrosine kinase myasthenia gravis (MuSK-MG), which it expects will be fully enrolled by the end of 2019. Catalyst also expects to report top-line results from a proof-of-concept study in spinal muscular atrophy (SMA) type 3 in the first half of 2020.
Catalyst doesn’t expect the same complications with these studies as with CMS-001, as the new indications involve more homogeneous patient populations.
Whatever new indications are gained will not bring a new price, however. “Our initial thought is that it’s going to be priced the same,” said McEnany. “Because it’s a very small population, and with the percentage of that population that might be effectively treated, it becomes even smaller. So I don’t see a different price point; I think it would be confusing in the marketplace.”