The safety and efficacy of safinamide mesylate for the treatment of Parkinson’s disease

ABSTRACT

Safinamide (brand name Xadago®, Zambon S.p.A) is a third-generation reversible MAO-B inhibitor, which also blocks sodium voltage-sensitive channels and modulates stimulated release of glutamate. Safinamide was recently licensed by EMA for the treatment of PD as add-on therapy to a stable dose of levodopa alone or in combination with other PD medicinal products in mid-to advanced-stage fluctuating patients. It is also under review by the US FDA. Studies in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys and 6OHDA-lesioned rats suggest antiparkinsonian efficacy and antidyskinesic effects. Randomized, double-blind, placebo-controlled trials have shown efficacy for the treatment of motor symptoms in stable PD patients on dopamine agonists and in fluctuating PD patients on levodopa. Significant improvement in daily ON time was also observed in the latter. This effect was maintained for at least 2 years in double-blind conditions and, interestingly, without significant worsening of dyskinesia. Clinical studies have not detected any specific safety issue other than those already known with MAO-B inhibitors.

KEYWORDS:

• Parkinson’s disease
• safinamide
• MAO-B inhibitors
• motor fluctuations
• dyskinesia
• antiparkinsonian treatment
• dopamine agonists
• levodopa

Financial & competing interests disclosure

O Rascol has acted as a scientific advisor for most drug companies developing and marketing antiparkinsonian medications (Abbvie, Acorda, Adamas, Boehringer-Ingelheim, Britania, GSK, Lundbeck, Neuroderm, Novartis, Impax, Osmotica, Oxford-Biomedica, Pfizer, Sanofi, TEVA, UCB, Zambon) and has received unrestricted scientific grants from academic non-profit entities (Toulouse University Hospital, French Health Ministry, European Community, MJFox Foundation, France-Parkinson) and pharmaceutical companies developing or marketing antiparkinsonian medications. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Safinamide is a third-generation reversible MAO-B inhibitor, which also blocks sodium voltage-sensitive channels and modulates stimulated release of glutamate.

• Safinamide was recently licensed by EMA for the treatment of PD as add-on therapy to a stable dose of levodopa alone or in combination with other PD medicinal products in mid- to late-stage fluctuating patients. It is also under review by the FDA.

• Studies in MPTP-treated monkeys and 6OHDA-lesioned rats suggest antiparkinsonian efficacy and a potential dyskinesia sparing effect.

• Randomized, double-blind, placebo-controlled trials with safinamide 50 mg and 100 mg have shown significant benefits on PD motor symptoms both in early patients on a dopamine agonist and in levodopa-treated fluctuating ones.

• Randomized, double-blind, placebo-controlled trials have also shown increases in daily ON time without dyskinesia or with non-troublesome dyskinesia for up to 2 years with the drug. The lack of significant worsening of dyskinesia on such a follow-up is original and seems interesting but remains to be confirmed and to be fully elucidated.

• There are no clinical trial comparing head-to-head safinamide with other antiparkinsonian medications, and this makes difficult to assess its real place and advantages among other existing options, including MAO-B inhibitors like rasagiline or selegiline, COMT inhibitors like entacapone and dopamine agonists like pramipexole, ropinirole, or rotigotine, which are all already marketed for the management of motor fluctuations in levodopa-treated PD patients suffering from motor fluctuations.

• Clinical studies have not detected any significant safety issue, but important topics, such as the possibility of serotonin syndrome when safinamide is concomitantly used with monoaminergic drugs, and the occurrence of impulse-control disorders and other dopaminergic adverse reactions, remains to be studied using a pharmaco-epidemiological approach to complement the data coming for the development program, as for any drug in general and MAO-B in particular. Food restrictions are not needed during treatment with safinamide.