Dr Silvia BonannoSilvia Bonanno, MD
Despite being observed in a small number of patients, amifampridine phosphate (Firdapse, Catalyst Pharmaceuticals), an investigational agent for the treatment of patients with MuSK antibody positive myasthenia gravis (MuSK-MG), has shown success in clinical study.1

The phase 2b MuSK-001 study’s topline results were announced previously, but the full results show that both of the co-primary objectives were met. The end points included Quantitative Myasthenia Gravis (QMG) score (P = .0003), the Myasthenia Gravis-specific Activities of Daily Living Profile score (P = .0006).2

Secondary end points included the Myasthenia Gravis Composite score (P <.0001), the Myasthenia Gravis Quality of Life scale (P = .0025), Fatigue Severity Scale (P = .0061), and the Carlo Besta Neurological Institute-Myasthenia Gravis scale (P = .0014).

“The results of the pilot study are very encouraging, such that our multi-center pivotal phase 3 trial evaluating Firdapse for the treatment of MuSK-MG is currently underway. Our pivotal trial is being conducted under an FDA Special Protocol Assessment (SPA),” said Gary Ingenito, MD, PhD, the chief medical officer of Catalyst Pharmaceuticals, in a statement. “If our phase 3 trial is successful, we hope that Catalyst will be able to offer physicians and patients alternatives in the treatment of MuSK-MG.”

Led by Silvia Bonanno, MD, from the Department of Clinical Neurosciences at the Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, the trial enrolled 10 patients and randomized them in a 1:1 fashion with a double-blind, placebo-controlled, switchback, double-crossover design. Patients were either randomized to 1 of 2 treatment sequences: amifampridine-placebo-amifampridine (APA; n = 3) and placebo-amifampridine-placebo (PAP; n = 4). The overall treatment compliance during the 3 double-blind periods was 99.6% in the APA group and 94.7% in the PAP group.

The original target for recruitment was 20 patients. However, the authors noted that “due to the difficulty in recruiting from a single center and an apparent clinical effect, the trial was terminated early, when 10 patients were enrolled. Moreover, the decision to stop study recruitment was taken for ethical reasons because the degree of clinical improvement did not justify the continuation of a pilot study with a placebo arm.”

Notably, Bonanno and colleagues noted that no carry-over effect was detectable during the different randomization periods, and that the clinical improvement and worsening was rapidly detected and associated strictly with administration of amifampridine phosphate.

“Speed of improvement or worsening, occurring within the next day of drug change (AP or placebo), negated an ‘order effect’ as well as a ‘learning effect,’ confirming the fast action of AP as a symptomatic treatment,” they wrote.

As for safety end points, 60% (n = 6) of patients reported oral or limb-related paresthesias, with it resolving within a 10-day  period (mean, 9.5 days; range, 5 to 15 days). In total, 28.6% (n = 2) of the patients experienced intermittent paresthesia after being randomized. A single patient (14.3%) reported chalazion, corneal abrasion, and cystitis post-randomization, though each AE was graded as mild and unrelated to the study drug. No serious AEs were reported in any phase and no patients discontinued treatment due to AEs.

Amifampridine phosphate was granted an Orphan Drug designation by the FDA for MG in September 2016, shortly after receiving a Refusal to File letter from the FDA for its submission for the treatment of congenital myasthenic syndromes and  Lambert Eaton myasthenic syndrome (LEMS).3 It was approved for LEMS in November 2018, and should become commercially available for those patients in the first quarter of 2019.4
REFERENCES
1. Catalyst Pharmaceuticals Announces Publication of Clinical Data from the Investigator-Sponsored Phase IIb Study Evaluating Firdapse® for the Treatment of MuSK Antibody Positive Myasthenia Gravis [press release]. Coral Gables, FL: Catalyst Pharmaceuticals Inc; Published January 4, 2019. globenewswire.com/news-release/2019/01/04/1680618/0/en/Catalyst-Pharmaceuticals-Announces-Publication-of-Clinical-Data-from-the-Investigator-Sponsored-Phase-IIb-Study-Evaluating-Firdapse-for-the-Treatment-of-MuSK-Antibody-Positive-Myas.html. Accessed January 10, 2019.
2. Bonanno S, Pasanisi MB, Frangiamore R, et al. Amifampridine phosphate in the treatment of muscle-specific kinase myasthenia gravis: a phase IIb, randomized, double-blind, placebo-controlled, double crossover study. SAGE Open Med. 2018;6:1-9. 
doi: 10.1177/2050312118819013
3. Radke J. Firdapse Gets Orphan Designation for Myasthenia Gravis. Rare Disease Report website. Published September 4, 2016. raredr.com/news/firdapse-mg. Accessed January 10, 2019.
4. FDA Approves Firdapse® (amifampridine) for the Treatment of Lambert-Eaton Myasthenic Syndrome (LEMS) [press release]. Coral Gables, FL: Catalyst Pharmaceuticals Inc; Published November 29, 2018. ir.catalystpharma.com/news-releases/news-release-details/fda-approves-firdapser-amifampridine-treatment-lambert-eaton. Accessed January 10, 2019.