Background

Safinamide is a reversible monoamine oxidase B inhibitor, taken as a pill by mouth. MAO-B degrades the neurotransmitter dopamine, and safinamide raises dopamine levels in synapses. It serves as an add-on treatment to shorten periods of lost motor control in people with mid- to late-stage Parkinson's disease who are taking levodopa. Safinamide was approved in Europe in 2015, and in the U.S. in 2017. 

As an MAO-B inhibitor, safinamide acts in the same way as selegiline and rasagiline. However, it also modulates sodium and calcium channels and reduces glutamate release. Glutamate is thought to contribute to the involuntary, uncontrolled movements called dyskinesia that develop over time in patients on levodopa; safinamide is also being investigated for its potential to reduce dyskinesias.  

The therapeutic dose for Parkinson's is 50 or 100 mg daily. In clinical trials, safinamide’s most common side effects were reported to be dyskinesia, falls, nausea, and insomnia.

Findings

Between 2007 and 2012, two pivotal Phase 3 trials evaluated the efficacy of safinamide to reduce periods of fluctuating motor control in PD patients on a stable levodopa regimen. In the six-month SETTLE study of 549 patients, safinamide increased daily ON time of motor control without dyskinesias (Schapira et al., 2017). In a two-year study of more than 544 people, safinamide extended ON time by 0.5 to 0.9 hours per day. It improved scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), and on quality-of-life measures, depressive symptoms, and activities of daily living. Safinamide did not change scores on the Dyskinesia Rating Scale in the group as a whole after two years, but improvement was seen in patients who were at least moderately dyskinetic at the start of the study (Borgohain et al., 2014). In both trials, patients tolerated safinamide well and few dropped out.

Other trials during the same time period examined safinamide effects on levodopa-induced dyskinesia  or on cognitive impairment in people with PD. A large trial of 679 people with early PD tested safinamide as an add-on to a dopamine agonist. No results have been published.

From 2017 to 2020, a Phase 4 observational study evaluated motor and non-motor symptoms in 164 people with PD who were newly prescribed safinamide. Raw results are available on ClinicalTrials.gov.

An open-label study, from May 2019 to February 2020, suggested that safinamide improved non-motor symptoms including pain, mood, and sleep (Garcia et al., 2021; see also Huang et al., 2021). A placebo-controlled trial tested safinamide for pain relief in 71 people with PD; the trial ended in 2021 and results have not been disclosed. Another study is looking at the effect of open-label safinamide on sleep quality in 23 people with PD.

In August 2019, Zambon began a study in China, testing safinamide as an add-on to levodopa in 307 PD patients. The primary outcome is total OFF time when patients lose motor control. Study completion is slated for August 2021.

Beginning in September 2019, Zambon tested safinamide in multiple-system atrophy, a rare neurodegenerative disease that shares with Parkinson’s the pathological hallmark of α-synuclein deposition. Forty-nine people with MSA received 200 mg safinamide or placebo daily for 12 weeks. The primary endpoint was safety, and secondary outcomes spanned clinical, quality of life, cognition, and movement measures. The trial finished in January 2021.

Zambon registered a study to start in October 2019 to assess a 26-week course of 100 or 150 mg of safinamide on a primary outcome of levodopa-induced dyskinesia in 300 patients. The trial was withdrawn before starting, for the given reason that the drug development plan had been updated. In March 2021, Newron announced to investors that the companies would jointly run a study in patients with PD and levodopa-induced dyskinesia, expected to start in 2021 (see company report).

In December 2019, Newron began an observational study comparing safinamide to rasagiline or other standard-of-care medications in 1,235 PD patients. The primary outcome is function and well-being, as measured by the PDQ-39 self-report questionnaire. Other endpoints assess motor function, pain, other medication use, healthcare resource use, days lost from work, and safety. The study will run through April 2024.

For details on safinamide trials, see clinicaltrials.gov.