CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 207145Orig1s000 MEDICAL REVIEW(S) Clinical Review Leonard P. Kapcala, M.D. NDA 207145 XADAGO (SAFINAMIDE) CLINICAL REVIEW Application Type NDA Application Number 207145 Priority or Standard Standard Submit Date 9/21/16 Received Date 9/21/16 PDUFA Goal Date 3/21/17 Division / Office DNP/ODE 1 Reviewer Name Leonard P. Kapcala, M.D. Review Completion Date 2/7/17 Established Name SAFINAMIDE (Proposed) Trade Name XADAGO Therapeutic Class Monoamine Oxidase B Inhibitor Applicant Newron Formulation(s) Tablet Dosing Regimen Once daily orally Indication(s) Treatment of signs and symptoms of Parkinson's disease Intended Population(s) Patients with early and advanced Parkinson's disease 1 Reference ID: 4071416 Clinical Review Leonard P. Kapcala, M.D. NDA 207145 XADAGO (SAFINAMIDE) Table of Contents 1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ......................................... 4 1.1 Recommendation on Regulatory Action ............................................................. 4 1.2 Risk Benefit Assessment .................................................................................... 4 1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ... 5 1.4 Recommendations for Postmarket Requirements and Commitments ................ 5 2 INTRODUCTION AND REGULATORY BACKGROUND ........................................ 5 2.1 Product Information (Based Upon Sponsor Summary) ....................................... 5 2.2 Other Relevant Background Information ............................................................ 6 3 SAFETY UPDATE .................................................................................................... 7 2 Reference ID: 4071416 Clinical Review Leonard P. Kapcala, M.D. NDA 207145 XADAGO (SAFINAMIDE) Table of Tables Table 1 Serious Adverse Events in Ongoing Double-Blind Japanese Study ME2125-3 .................................................................................................. 11 Table 2 Serious Adverse Events in an Ongoing Open-label, Long-term, Japanese study – ME2125-4 .................................................................... 13 Table 3 Estimation of Patients Treated with Xadago in EU Countries Based on Volume of Blister Pack Sales .................................................................. 14 Table 4 Listing of Spontaneously Reported Post-Marketing Serious Adverse Events ....................................................................................................... 15 3 Reference ID: 4071416 Clinical Review Leonard P. Kapcala, M.D. NDA 207145 XADAGO (SAFINAMIDE) 1 Recommendations/Risk Benefit Assessment 1.1 Recommendation on Regulatory Action • I recommend approval of this NDA for adjunctive treatment with levodopa/carbidopa in patients with Parkinson’s disease to reduce “off” episodes. 1.2 Risk Benefit Assessment • It is my opinion that this risk benefit assessment for safinamide supports the approval of safinamide for treatment of signs and symptoms of patients experiencing “off” episodes and taking concomitant levodopa/carbidopa (i.e., patients with advanced Parkinson's disease). The two pivotal trials (Studies 16 and SETTLE) conducted for advanced Parkinson's disease were positive and demonstrated adequate efficacy of safinamide. The safety profile of safinamide for treating this population was acceptable. My previous review (entered in DARRTS on 3/27/16) includes my detailed assessment risk benefit assessment of the efficacy and safety of safinamide. • After completing my review of the sponsor’s Safety Update, I find the information did not suggest any, new or significant adverse reactions that would change my impression of the safety profile for safinamide or my recommendation to approve safinamide as a safe and effective drug. • I do, however, recommend that a new safety finding discovered in my review of this Safety Update be described in the label. Based upon my review of postmarket case 201600064DEU, I believe that hypersensitivity to safinamide should be described in the label as a Contraindication. The adverse reaction of hypersensitivity has the potential being a medically serious event, with potentially a fatal outcome. I conclude that there is a quite reasonable probability that safinamide caused this hypersensitivity reaction and that this hypersensitivity reaction recurred upon rechallenge with safinamide. • I also recommend that the safinamide label should include additional information regarding taking safinamide with two drugs (i.e., linezolid and isoniazid-INH) with monoamine oxidase (MAO) inhibitory activity. During our review of the sponsor’s Complete Response re-submission, we became aware that two antimicrobial drugs (i.e., linezolid and isoniazid) have MAO inhibitory activity. Linezolid is a reversible, nonselective MAO inhibitor which is indicated in adults and children for the treatment of the following infections caused by susceptible Gram-positive bacteria: Nosocomial pneumonia ; Community-acquired pneumonia; Complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis; Uncomplicated skin and skin structure infections; and Vancomycin-resistant Enterococcus faecium infections for a treatment period ranging between 10-28 days. Oral 4 Reference ID: 4071416 Clinical Review Leonard P. Kapcala, M.D. NDA 207145 XADAGO (SAFINAMIDE) tyramine challenge testing with linezolid has shown an increase in tyramine sensitivity but the label does not require dietary tyramine restriction. However, concomitant use of an MAO inhibitor is contraindicated in the linezolid label. The INH label notes that it has some MAO inhibiting activity, and that an interaction with tyramine-containing foods (cheese, red wine) may occur when taking INH. However, the INH label does not require dietary tyramine restriction nor does it contraindicate concomitant use of MAO inhibitors. A review of the published literature did not find results from any formal tyramine challenge testing. In view of this new information, I recommend that the safinamide label contraindicate the use of linezolid because the linezolid label notes that it is an MAO inhibitor and the safinamide label contraindicates drugs (selective or nonselective) which are MAO inhibitors. Adding this contraindication in the safinamide label would make both labels consistent with each other relative to contraindicating concomitant MAO inhibitors with the use of safinamide or linezolid. I also recommend that safinamide label describes in the Drug Interactions section of the label that because INH has some MAO inhibitory activity, that patients taking safinamide together with INH could possibly experience a hypertensive reaction when ingesting tyramine containing food or drink. Patients taking safinamide and INH should be monitored for such a hypertensive reaction. Because the precise quantitative extent of MAO inhibition from INH is not clear, I do not believe that a contraindication for INH is necessary. 1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies • I do not have any recommendations for the postmarket risk evaluation and mitigation strategies for safinamide. 1.4 Recommendations for Postmarket Requirements and Commitments • I do not have any recommendations for postmarket requirements or commitments for safinamide. 2 Introduction and Regulatory Background 2.1 Product Information (Based Upon Sponsor Summary) Safinamide, an alpha-aminoamide derivative is structurally unrelated to any other drug for treatment of Parkinson’s disease (PD), but is related to milacemide, a glycine prodrug. Safinamide may have multiple mechanisms of action. The sponsor describes properties such as state-dependently inhibits voltage-gated sodium channels (IC50:1.6-4.9 μM for different subtypes), and at higher concentrations it inhibits calcium channels. The expected physiological 5 Reference ID: 4071416 Clinical Review Leonard P. Kapcala, M.D. NDA 207145 XADAGO (SAFINAMIDE) effect is the modulation of the hyper-active neurons and the consequent regulation of the neurotransmitter release: safinamide reduces the stimulated release of glutamate (~0.6 μM) without affecting basal glutamate levels. Safinamide is also a reversible and selective Monoamine Oxidase B (MAO-B) inhibitor (IC50 79-98nM: >1000-fold selective over MAO-A). It also binds at the WIN 35,428 site of the dopamine transporter (DAT) with IC50 of 8.8 μM and displaces the serotonin transporter (SERT) ligand citalopram from its binding with IC50 of 5.6 μM. leading to dopamine and the serotonin uptake inhibition in brain synaptosomes with IC50s of 12.5 and 21 μM, respectively. Safinamide enters the brain, and in animal models of PD has shown both dopaminergic benefits (increased brain dopamine content; extended efficacy of a given dose of L-dopa on motor symptoms) and non-dopaminergic effects (reduced L-dopa induced dyskinesia) associated with plasma safinamide levels corresponding to therapeutic doses in clinical trials. The sponsor also notes that results of some studies in preclinical models of PD and other CNS diseases suggest the possibility that safinamide may have a neuroprotective effect. The initial non-clinical and clinical programs were performed by the Sponsor (Newron). In 2006 Merck-Serono acquired the exclusive worldwide rights to further develop, manufacture and commercialize safinamide. In October 2011, Merck-Serono announced their decision to discontinue the co-development agreement with Newron.