AMIFAMPRIDINE PHOSPHATE (FIRDAPSEVR ) IS EFFECTIVE AND SAFE IN A PHASE 3 CLINICAL TRIAL IN LEMS SHIN J OH, MD,1 NATALYA SHCHERBAKOVA, MD,2 ANNA KOSTERA-PRUSZCZYK, MD, PhD,3 MOHAMMAD ALSHARABATI, MD,1 MAZEN DIMACHKIE, MD,4 JOSE MUNOZ BLANCO, MD,5 THOMAS BRANNAGAN, MD,6 DRAGANA LAVRNIC´ , MD, PhD,7 PERRY B SHIEH, MD, PhD,8 CHRISTOPHE VIAL, MD,9 ANDREAS MEISEL, MD,10 SAMUEL KOMOLY, MD, PhD, DSc,11 BENEDIKT SCHOSER, MD,12 KUMARASWAMY SIVAKUMAR, MD,13 YUEN SO, MD, PhD,14 and LEMS STUDY GROUP 1 Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA 2 Russian Academy of Medical Sciences, Scientific Center of Neurology, Moscow, Russia 3 Department of Neurology, Medical University of Warsaw, Poland 4 University of Kansas Medical Center, Kansas City, Kansas, USA 5 Gregorio Maranon Hospital, Madrid, Spain 6 Columbia University Medical Center, New York, New York, USA 7 Clinical Center of Serbia, Clinic of Neurology, Belgrade, Serbia 8 Department of Neurology, University of California, Los Angeles, California, USA 9 Hospital of Lyon, ENMG Service and Neuromuscular Pathology Hospital, Lyon, France 10 Charite Universitatsmedizin Berlin-NeuroCure Clinical Research Center, Berlin, Germany 11 University of Pecs, Department of Neurology, Pecs, Hungary 12 Ludwig-Maximilians-University Munich Friedrich-Baur-Institute, Munich, Germany 13 Neuromuscular Research Center, Phoenix, Arizona, USA [email protected] 14 Stanford University, Stanford, California, USA Accepted 4 February 2016 ABSTRACT: Objective: We evaluated the efficacy and safety ated; the most common adverse events were oral and digital of amifampridine phosphate (FirdapseVR ) for symptomatic treat- paresthesias, nausea, and headache. Conclusions: This study ment in Lambert-Eaton myasthenic syndrome (LEMS). Methods: provides Class I evidence of efficacy of amifampridine phos- Phase 3, randomized, double-blind, study. Patients were treated phate as a symptomatic treatment for LEMS. initially with amifampridine phosphate for 7–91 days, followed by Muscle Nerve 000:000–000, 2016 randomization to continue amifampridine phosphate for 14 days or placebo (7-day taper, 7-day placebo). The primary efficacy endpoints were changes from baseline at day 14 in Quantitative Myasthenia Gravis and Subject Global Impression scores. Results: The coprimary efficacy end points and 1 of the second- INTRODUCTION ary efficacy end points were met, showing a significant benefit Lambert-Eaton myasthenic syndrome (LEMS) is a of aminfampridine phosphate over placebo at Day 14. All 5 primary, secondary, and tertiary endpoints achieved statistical rare, frequently disabling autoimmune neuromus- significance at Day 8. Amifampridine phosphate was well toler- cular disorder that produces serious muscle Abbreviations: 3,4-DAP, 3,4-diaminopyridine; ACh, acetylcholine; AEs, received honoraria from serving on the Steering Committee for the LMS- adverse events; Ca21, calcium ions; CGI-I, Clinical Global Impression of 002 study (BioMarin). Dr. Meisel served on the LEMS registry publication Improvement; CMAP, compound muscle action potential; CK, creatine advisory board for BioMarin. Dr. Meisel is funded by German Research kinase; ECG, electrocardiogram; EU, European Union; FDA, Food and Foundation (Exc257, SFB-TRR84, SFB-TRR43), German Federal Ministry Drug Administration; FVC, forced vital capacity; GMP, Good manufacture of Education and Research (01EO0801), European Community FP7 practice; IND, Investigational new drug; LEMS, Lambert-Eaton myasthenic (201024), and obtained research support from ThermoFisher Scientific and syndrome; MeDRA, Medical Dictionary for Regulatory Activities; mg, milli- Novartis. Dr. Meisel also has a speaker’s engagement with Novartis. Dr. gram; MMRM, mixed-effect model repeated measure; NS, not significant; Meisel is a co-inventor and co-owner of a patent on anti-infective agents QMG, Quantitative Myasthenia Gravis score; SGI, Subject Global Impres- and immunomodulators used for preventative therapy after an acute cere- sion of improvement; T25FW, Timed 25-foot Walk test; US, United States; brovascular accident that has been filed to the European Patent Office VGCC, voltage-gated calcium channel (PCT/EP03/02246). Dr. Komoly has received honoraria for talks and pay- Key words: 1. Amifampridine phosphate; 2. 3,4-diaminopyridine; 3. 3,4- ment for occasional consultancy or research funding from Teva, Bayer- DAP; 4. Lambert-Eaton myasthenic syndrome; 5. LEMS; 6. Potassium Schering, Serono, and Biogen. Dr. Schoser serves on the scientific advi- channel blockers; 7. Small cell lung cancer (SCLC) sory boards for Genzyme, a Sanofi company; BioMarin Pharmaceutical This study was supported by Catalyst Pharmaceuticals Inc. and BioMarin Inc.; and Audentes Therapeutics. Dr. Sivakumar reports no disclosures. Pharmaceutical Inc. Dr. So has received an honorarium from Catalyst Pharmaceuticals Inc. LEMS Study Group: 2 Disclosure of conflict of interest: Dr. Oh reports he has been a Vitaly Rudnichenko, MD , Oksana Galkina, MD, PhD2 Beata Szyluk, MD3, Richard J. Barohn, MD4, April L McVey, MD4, consultant to Catalyst Pharmaceuticals Inc. Dr. Shcherbakova reports no 4 5 disclosures. Dr. Kostera-Pruszczyk reports no disclosures. Dr. Alsharabati Mamatha Pasnoor, MD , Irene Catalina-Alvarez, MD , Alfredo Traba- Lopez, MD5, Siegfried Kohler, MD10, Sarah Hoffmann, MD10, Gabriella reports no disclosures. Dr. Dimachkie has received research support from 11 11 6 BioMarin Pharmaceutical Inc. and Catalyst Pharmaceuticals Inc. Dr. Deli, MD , Zoltan Pfund MD PhD , Jacqueline Scoon, MD , Louis H Weimer, MD6, Khosro Farhad, MD6, Katherine M Ruzhansky, MD6, Sujata Munoz Blanco has received research support from BioMarin Pharmaceuti- 6 6 cal Inc. and Catalyst Pharmaceuticals Inc. Dr. Brannagan has received P Thawani, MD, MPH research support from Alnylam, Catalyst Pharmaceuticals Inc., ISIS Phar- Corresponding author’s address: Department of Neurology, University maceuticals, and Novartis. He has been a consultant for Baxter, Catalyst of Alabama at Birmingham, University Station, Birmingham, Alabama, Pharmaceuticals Inc., Daishi Sanko, and Grifols. Dr. Lavinic has received 35294. Email address: [email protected]. Tel number: 205-934-2121. Fax speaker honoraria and travel grants from Pfizer, Berlin Chemie, Worwag number: 205-956-6758. Pharma, and Gideon Richter; and research grant support from the Ministry of Education, Science and Technological Development of the Republic of VC 2016 Wiley Periodicals, Inc. Serbia (projects #175031 and #175083). Dr. Shieh has served as an ad- Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary. hoc consultant for Catalyst Pharmaceuticals Inc., Sarepta Therapeutics, com). DOI 10.1002/mus.25070 PTC Therapeutics, Cytokinetics, Biogen, and Novartis. He also serves on the Speakers Bureau for Grifols for their immunoglobulin product. Dr. Vial Amifampridine phosphate in LEMS MUSCLE & NERVE Month 2016 1 FIGURE 1. Study Design weakness and symptoms of autonomic dysfunc- Societies9 and was approved for use in this indica- tion.1 Sanders estimated the prevalence of LEMS tion by the European Medicines Agency in Decem- in the United States (US) to be 1/100,000 on the ber 2009. Amifampridine phosphate has received basis of prevalence of small cell lung cancer.2 orphan drug designation by the FDA and has also In LEMS, voltage-gated calcium channel (VGCC) been granted Breakthrough Therapy designation. 6 auto-antibodies block influx of calcium ions (Ca21) The multicenter, randomized, double-blind, pla- into the nerve terminal, inducing insufficient release cebo-controlled withdrawal study we report was of acetylcholine (ACh) that produces muscle weak- designed to evaluate the efficacy and long-term ness.3,4 About 50% of patients with LEMS, particu- safety of the phosphate salt form of amifampridine larly male smokers, present with an underlying in patients with LEMS. malignancy, usually small cell lung cancer.5 MATERIALS AND METHODS For symptomatic treatment, pyridostigmine, This multicenter, randomized, phase 3 guanidine, 4-aminopyridine, and 3,4-diaminopyri- “withdrawal trial” was conducted at 18 sites in the dine (3,4-DAP) have been tried. Among these, 3,4- US, European Union (EU), and Russian Federa- DAP (amifampridine) in its base form has been tion. This study was approved by the local ethics found to be most effective and safe.6 committees or institutional review boards for com- 3,4-DAP base has not received Food and Drug pliance with the international and US regulations Administration (FDA) approval for the sympto- and good practice guidelines for pharmaceuticals matic management of LEMS in the United States for human use. All patients gave written informed (US), and at present has limited availability consent. This study was registered as NCT01377922 through Treatment Investigational New Drugs at www.ClinicalTrials.gov. This study was designed (IND) studies, expanded-access programs, clinical and sponsored by Biomarin Pharmaceutical Inc and trials, and compounding pharmacies.6 The poten- Catalyst Pharmaceuticals Inc. tial exists for batch-to-batch variability and issues of lack of reliability in drug quality, potency, and risk Patients. Patients enrolled in the study were at of under- and overdose due to compounding least age 18 years and had a confirmed LEMS errors.7 A review and analysis of compounded 3,4- diagnosis, either previously treated with 3,4-DAP DAP products concluded that they are subject to base (treatment-experienced) or na€ıve (treatment- substantial