The FDA approved Newron Pharmaceuticals, Zambon and US WorldMeds’ Xadago (safinamide) as an add-on therapy to levodopa/carbidopa for patients with Parkinson’s disease, the companies announced Tuesday, March 21, 2017.
The new drug received European marketing authorization in February 2015 for the treatment of Parkinson’s disease (PD). The approval covers the indication “safinamide as add-on therapy to levodopa alone or in combination with other Parkinson’s disease treatments” in mid-to late stage Parkinson’s disease patients.
Safinamide is an oral, once-a-day adjunctive therapy for advanced stage PD. Safinamide is a highly selective and reversible MAO-B inhibitor. This differs from rasagiline and selegiline, which are selective and irreversible MAO-B inhibitors. Several other mechanisms of action of safinamide have been identified by in-vitro data, including the reduction of excessive glutamate release and sodium channel inhibition, but it seems that non-dopaminergic effect does not contribute to the overall clinical effect of safinamide.
New PD Therapy used as Add-on to levodopa/carbidopa
The FDA and EMEA decisions were based on three double-blind, placebo-controlled randomized controlled trials (RCTs) of safinamide in people with PD of at least three years duration who were experiencing motor fluctuations. All participants were taking a stable dose of levodopa and many were also taking other Parkinson’s disease medicines, most commonly a dopamine agonist (taken by 61% to 74% of participants). Study 0161 and the SETTLE study2 were 24-week studies. Study 0183 was an 18-month extension of study 016. Study 016 included 2 treatment arms of safinamide 50 mg daily and 100 mg daily, while in the SETTLE study the starting dose of 50 mg daily was increased to 100 mg daily if no tolerability issues arose by day 14.
Primary outcome in study 016 was “on time without troublesome dyskinesia,” which was increased by 31 minutes in subjects with 50 mg dose and 33 minutes in 100 mg dose, compared to placebo. In SETLE study the mean difference with safinamide 50–100 mg compared with placebo was 0.96 hours (95% CI 0.56 to 1.37, p<0.001). A similar reciprocal reduction in off time was also seen in both studies.
The statistically significant improvement in “on time without troublesome dyskinesia” and “off” time was continued at 2 years in study 018 (although these were secondary outcomes). The mean difference in on time without troublesome dyskinesia with safinamide 50 mg compared with placebo was 0.67 hours (95% CI 0.23 to 1.11, p=0.003); with safinamide 100 mg it was 0.83 hours (95% CI 0.39 to 1.27, p=0.0002); and with similar reciprocal reductions in off time seen. In all three studies safinamide did not show significant effect on dyskinesia, although the primary objective in 018 study was improvement of levodopa induced dyskinesia.
In study 016 and SETTLE, there were statistically significant improvements in motor symptoms with safinamide of about 2-3 points in UPDRS-III score compared with placebo. An improvement of 2.5 to 5 points from baseline is considered to be the minimum clinically important difference4-5. The improvement in UPDRS-III score was maintained with safinamide 100 mg daily (p<0.05), in 018 study, but there was no statistically significant difference between safinamide 50 mg daily and placebo at 2 years.
Safinamide 100 mg daily showed improvement of quality of life by 16 points in PDQ-39 (p=0.036) compared with placebo at 24 weeks. This result continued at 2 years in study 018. In the SETTLE study, there was a statistically significant improvement of about 2 points in PDQ-39 summary index score (range 0 to 100) with safinamide 50–100.
The percentage of participants with an improvement in clinical global impression (CGI-C) was significantly higher with safinamide compared with placebo at the end of both 24-week RCTs. In study 018, this statistically significant improvement was maintained in the safinamide 50 mg group, but not in the 100 mg group.
No Comparison yet in a Head-to-head Study with an Active Comparator
Safinamide has not been compared with an active comparator in a head-to-head study, for example, other MAO-B inhibitors, dopamine agonists or COMT inhibitors. The indirect comparisons of data on safinamide with historical data on other treatments, such as rasagiline and pramipexole seems favourable. In addition, a company sponsored meta-analysis and indirect comparison of placebo-controlled RCTs of safinamide and entacapone as add-on treatment to levodopa has been published6. Although safinamide is licensed as add-on treatment to levodopa alone, very few participants in the studies were taking levodopa only (89/971, 9.2%)7. Therefore, there are limited data on its use as a first-choice add-on treatment to levodopa.
The manufacturer applied for a marketing authorization for treating early-stage Parkinson’s disease in adults, as add-on treatment to a stable dose of a single dopamine agonist. The efficacy of safinamide in early PD as add-on treatment to a dopamine agonist was considered insufficient and safinamide was not approved for this indication.
Overall, safinamide was generally well tolerated with a relatively low incidence of adverse events compared with placebo. Safinamide should not be taken in combination with other MAO inhibitors, and serious interactions may occur with SSRIs, SNRIs and tricyclic antidepressants. The drug is contraindicated in patients with severe hepatic impairment, or a personal or family history of retinal disease.
Safinamide is the first new chemical entity for Parkinson’s disease to be approved after several years, but its effect size should be evaluated after head-to-head studies with other MAO-B or COMT inhibitors.
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- Borgohain R, Szasz J, Stanzione P et al. Randomized trial of safinamide add-on to Levodopa in Parkinson’s disease with motor fluctuations. Movement disorders 2014:29: 229–37
- Schapira A, Fox S, Hauser R et al. Assessment of safety and efficacy of safinamide as a levodopa adjunct in patients with Parkinson disease and motor fluctuations. A randomized clinical trial. JAMA Neurology 2017 doi:10.1001/jamaneurol.2016.4467
- Borgohain R, Szasz J, Stanzione P et al. Two-year, randomized, controlled study of safinamide as add-on to levodopa in mid to late Parkinson’s disease. Movement disorders 2014:29:1273–80
- Schrag A, Sampaio C, Counsell N et al. (2006) Minimal clinically important change on the unified Parkinson’s disease rating scale. Movement disorders 2006:21: 1200–07
- Shulman L, Gruber-Baldini A, Anderson K et al. The clinically important difference on the Unified Parkinson’s Disease Rating Scale. JAMA Neurology 2010: 67: 64–70
- Schnitker J, Muller T. Meta-analysis of placebo-controlled clinical trials of safinamide and entacapone as add-on therapy to levodopa in the treatment of Parkinson’s disease. European Neurological Review 2015:10: 15–22
- Cattaneo C, Sardina M, Bonizzoni E (2016) Safinamide as add on therapy to levodopa in mid- to late-stage Parkinson’s disease fluctuating patients: Post-hoc analyses of studies 016 and SETTLE. Journal of Parkinson’s disease 6: 165–73
