Safinamide – A New Therapeutic Option to Address Motor Symptoms and Motor Complications in Mid- to Late-stage Parkinson’s Disease

European Neurological Review,2016;11(Suppl. 2): 2–15

Abstract:

Levodopa 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, nondopaminergic, 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.
Published Online: 29 September 2016
Received: July 04, 2016
Correspondence: 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.
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.

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 (Ca2+) channel blockers.3

Clinical Features
The cardinal motor symptoms of PD are (see Figure 1):4

• bradykinesia (poverty/slowness of movement);
• rigidity;
• rest tremor; and
• postural and gait disturbance.

Patients with PD may present with all four cardinal symptoms or just one or two. However, a diagnosis of PD cannot be firmly made without features of bradykinesia with sequence effect, usually with asymmetry. Tremor is the presenting symptom in 70% of patients.5

Although PD is predominantly a disorder of motor function, patients with PD frequently develop non-motor symptoms. Non-motor symptoms are now recognised as a major determinant of quality of life and overall burden of disease.1 Non-motor symptoms in PD include:6

• sensory disorders (hyposmia and pain);
• autonomic dysfunction (orthostatic hypotension, neurogenic bladder disturbance, erectile dysfunction, constipation);
• neuropsychiatric symptoms (anhedonia, apathy, anxiety, depression, bradyphrenia, frontal executive dysfunction, dementia, psychosis); and
• sleep disorders (sleep fragmentation, reduced sleep efficiency, reduced slow-wave sleep, reduced REM sleep, REM sleep behavioural disorders, excessive daytime sleepiness, nocturnal akinesia/tremor, restless legs syndrome, periodic limb movements during sleep).

Non-motor symptoms were assessed in the Parkinson and Non Motor Symptoms (PRIAMO) study, a cross-sectional cohort of more than 1,000 patients with PD.7 In all, 98.6% of patients reported the presence of nonmotor symptoms, with a mean number 7.8 per patient (range 0–32). The most common were fatigue (58%), anxiety (56%), leg pain (38%), insomnia (37%), urgency and nocturia (35%), drooling of saliva and difficulties in maintaining concentration (31%). The frequency of non-motor symptoms increased in line with disease duration and severity (see Figure 2).

Diagnosis
The diagnosis of PD is primarily clinical, based on the history and examination.1 An example of a widely accepted diagnostic criteria is that developed by the United Kingdom Parkinson’s Disease Society (UK PDS) Brain Bank (see Table 1).8

In 2015, clinical diagnostic criteria for PD were published by the Movement Disorder Society (MDS).9 Again, the benchmark for these criteria is expert clinical diagnosis; the criteria aim to systematise the diagnostic process, to make it reproducible across centres and applicable by clinicians with less expertise in PD diagnosis. Although motor abnormalities remain central, increasing recognition has been given to non-motor manifestations; these are incorporated into both the current criteria and separate criteria for prodromal PD.9

The new MDS diagnostic criteria retain motor parkinsonism as the core feature of the disease, defined as bradykinesia plus rest tremor or rigidity, and include explicit instructions for defining these cardinal features. After documentation of parkinsonism, determination of PD as the cause of parkinsonism relies on three categories of diagnostic features: absolute exclusion criteria (which rule out PD), red flags (which must be counterbalanced by additional supportive criteria to allow diagnosis of PD), and supportive criteria (positive features that increase confidence of the PD diagnosis). The MDS criteria define two levels of diagnostic certainty: clinically established PD (maximising specificity at the expense of reduced sensitivity) and probable PD (which balances sensitivity and specificity).9

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Keywords: Safinamide, Parkinson’s disease, motor symptoms, non-motor symptoms, motor fluctuations, add-on therapy, wearing-off, dopaminergic, nondopaminergic, anti-glutamate, monoamine oxidase B inhibitor, dyskinesia