Supplement Safinamide – A New Therapeutic Option to Address Motor Symptoms and Motor Complications in Mid- to Late-stage Parkinson’s Disease C Warren Olanow 1 and Fabrizio Stocchi 2 1. Department of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, USA; 2. Department of Neurology, University and Institute of Research and Medical Care, IRCCS San Raffaele, Rome, Italy L evodopa is the cornerstone of therapy for Parkinson’s disease (PD) and remains the most effective treatment available. Over time, however, the beneficial motor response to levodopa gradually shortens (this is known as ‘wearing off’) and motor complications (motor fluctuations and dyskinesias) increasingly affect so-called ‘on-time’. The risk of developing motor complications is strongly linked to levodopa dose, independently of other predictive factors including disease severity. This provides a strong rationale for using other drugs, either alone or in combination with low-dose levodopa, to preserve the efficacy of levodopa for as long as possible. Several classes of drugs, including dopamine agonists, catechol-O-methyltransferase inhibitors, and monoamine oxidase B (MAO-B) inhibitors, are used as add-ons to levodopa, but all have significant drawbacks. Recently, safinamide (Xadago ® ) was approved for the treatment of PD patients as an add-on therapy to levodopa alone or in combination with other PD agents in mid- to late-stage fluctuating patients. Safinamide has a dual mechanism of action that includes modulation of dopaminergic metabolism through selective, reversible inhibition of MAO-B, and blockade of voltage and use-dependent sodium (Na+) channels, leading to inhibition of stimulated glutamate release. This article reviews the pathophysiology of PD and current treatment options, together with a comprehensive discussion of the pharmacokinetic, preclinical and clinical data relating to safinamide, including results from the 016/018 and the Safinamide in Idiopathic Parkinson’s Disease With Motor Fluctuations, as add-on to Levodopa (SETTLE) studies and exploratory post hoc analyses. In these pivotal studies, safinamide 50–100 mg/day demonstrated efficacy in the treatment of motor fluctuations and motor symptoms in stabilised levodopa patients (improving the Unified Parkinson’s Disease Rating Scale III score, and motor complications, as indicated by a significant reduction versus placebo in the primary endpoint of on-time without troublesome dyskinesias). Safinamide treatment was also effective for improving other motor complications (such as ‘off-time’, early-morning akinesia), motor symptoms, non-motor symptoms, activities of daily living and quality of life. These effects have been proved in the short term (six months) and maintained in the long term (24 months). Together, the data suggest that safinamide could be an appropriate choice as a first-line add-on therapy to levodopa in PD patients experiencing motor fluctuations. Keywords Safinamide, Parkinson’s disease, motor symptoms, non-motor symptoms, motor fluctuations, add-on therapy, wearing-off, dopaminergic, non- dopaminergic, anti-glutamate, monoamine oxidase B inhibitor, dyskinesia Disclosure: Fabrizio Stocchi receives consultant fees and honoraria for educational symposia from Zambon and has been a consultant to TEVA, Novartis, GSK, Lundbeck, Merck Serono, MSD, UCB, Chiesi Pharma, IMPAX, Newron, Zambon and Britannia. C. Warren Olanow receives consultant fees from Abbvie, Addex, Lundbeck, Newron, Novartis, Teva, Zambon. He is on the board for Michael J Fox Foundation, National Space Board Research Institute, Zambon. He has stock in Clintrex which provides consulting services for AstraZeneca, Accorda/Civitas, Biotie, Britannia, Corium, Cynapsus, Cytokinetics, Dart, EMD Serono, Flex, Forward, GeNeuro, Intec, Jazz, Melior, Michael J Fox Foundation, Lundbeck, Lysosomal Therapeutics, Medday, Neuroderm, Neuromedix, Neuropore, Osmotica, Otonomy, Otsuka/INC, Pfizer, Pharma2B, Prana, Raptor, Remedy, Sanofi/Genzyme, Serina, Sunovion, Synagile, Teva, Titan, Ultragenyx, Upsher Smith, US WorldMeds, Vaccinex, Weston Foundation. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: 4 July 2016 Published Online: 29 September 2016 Citation: European Neurological Review,2016;11(Suppl. 2): 2–15 Corresponding Author: Fabrizio Stocchi, IRCCS San Raffaele Pisana di Roma, Dipartimento di Neurologia, Via della Pisana 216, 00163 Rome, Italy. E: fabrizio.stocchi@tin.it, deep@medidata.it Support: The publication of this article was funded by Zambon. The views and opinions reported are those of the authors and not necessarily those of Zambon. 2 Overview of Parkinson’s disease Epidemiology Parkinson’s disease (PD) is a common, chronic and progressive neurological condition. It is estimated to affect 100–180 people per 100,000 of the population and has an annual incidence of 4–20 per 100,000 people. 1 The prevalence of PD rises sharply with age, from a mean of 41 per 100,000 in those aged 40–49 years to 1,903 per 100,000 in those aged over 80 years. 2 The prevalence and incidence of PD is higher in men than in women. 1 Risk factors for Parkinson’s disease A number of putative risk factors for developing PD have been identified from systematic review and meta-analysis of observational studies. These include genetic and environmental risk factors, associated comorbidities and medication exposures, as well as early non-motor features that may represent the earliest stages of PD. The strongest risk factors associated with later PD diagnosis are having a family history of PD or tremor, and lack of smoking history. Other risk factors may include a history of mood disorder, exposure to pesticides, rural living, employment in farming or agriculture. 3 Factors associated with the development of classic motor features of PD, which may represent an early pre-motor stage of the disease, include impaired sense of smell, sleep disturbances, rapid-eye movement (REM) behaviour disorder and constipation. A reduced risk of developing PD is associated with smoking, coffee-drinking, hypertension, and use of non-steroidal anti-inflammatory drugs (NSAIDs) or calcium (Ca 2+ ) channel blockers. 3 TOUC H ME D ICA L ME D IA