Parkinson’s disease is a progressive and incurable disease of the central nervous system. The main symptoms initially are motor-related, such as the characteristic tremor, plus rigidity and slowness; as the disease progresses, problems with thinking and behaviour can arise. These motor symptoms come from the death of cells in the brain that make dopamine. Treatment focuses on trying to manage the motor symptoms in the early stages of the disease with either dopamine itself or dopamine agonists. However, the effectiveness of these drugs decreases over time as more and more dopamine-producing cells die.
Safinamide,1 a potential new treatment, designed as an add-on therapy to be used alongside levodopa, is being developed by Newron Pharmaceuticals in association with Zambon; for a time it was being developed by Merck Serono, but all rights to the molecule are now back with Newron.
The drug acts as a monoamine oxidase B inhibitor, which reduces the rate at which dopamine is degraded in the brain. It also appears to have a number of other effects that may contribute to its activity, including the inhibition of dopamine uptake, inhibiting glutamate release, and blocking sodium and calcium ion channels.
Several clinical trials have been carried out. In one randomised, double blind, placebo-controlled study, 269 patients in the early stages of Parkinson’s disease were given daily safinamide doses of 100 or 200mg or placebo as an add-on to their existing dopamine agonist therapy.2 The difference in improvement in motor scores between 200mg doses and placebo was not significant; however, those given the lower dose of safinamide did have a significant improvement over placebo. There were no clinically meaningful differences in any safety variables.
A long term efficacy and safety extension to this trial has also been carried out.3 In the 12-month study, the primary efficacy endpoint was the time from randomisation in the initial study to the point at which the subject’s dopamine agonist dose had to be increased, or another agonist or levodopa or other Parkinson’s treatment added to their regimen. A total of 227 of the subjects enrolled in the extension, and 187 completed it. The median time to intervention was 559 days for the safinamide group, compared with 466 days in those given placebo.
A Phase III trial has also been carried out. The six-month randomised, double blind, placebo-controlled trial took place in 549 patients with mid to late stage idiopathic Parkinson’s disease who had been symptomatic for at least three years, and had been treated with optimised, stable doses of levodopa and standard of care for at least four weeks.4 Those who experienced at least 1.5 hours of ‘off’ time during the day were randomised to treatment with 50 to 100mg safinamide or placebo, on top of levodopa therapy. The most common adverse events were nausea, urinary tract infections, falls, back pain and dyskinesia. The treated group had a typical increase in ‘on’ time of an hour. The company plans to file for regulatory approval by the end of 2013.
References
1. P. Pevarello et al. Bioorg. Med. Chem. Lett. 1999, 9, 1783
2. F. Stocchi et al. Mov. Disord. 2012, 27, 106
3. A.H. Schapira et al. Eur. J. Neurol. 2013, 20, 271
4. R. Anand et al. 17th Intl Cong. Parkinson’s Disease & Movement Disorders, 2013 (Sydney, 16–20 Jun)