Safinamide mesilate, discovered and developed by Newron Pharmaceuticals ( Milan, Italy ), is a selective monoamine oxidase B ( MAO-B ) inhibitor, which reduces the degradation of excreted dopamine, helping to maintain the density of dopamine in the brain.
Additionally, Safinamide mesilate blocks sodium ion channels and inhibits glutamate release, and possesses both dopaminergic and non-dopaminergic mechanisms.
Safinamide mesilate is marketed under the name Xadago in 15 countries in Europe, the United States and Australia, and under the name Onstryv in Canada.
In Japan, Meiji holds the manufacturing and marketing approval for Equfina, and Eisai exclusively sells Equfina.
Global clinical studies of Safinamide mesilate in combination with Levodopa for the treatment of mid- to late-stage Parkinson's disease have shown extended ON time and an improvement in motor function.
Parkinson's disease is a neurodegenerative disease that causes motor impairment such as shaking in the limbs, muscular rigidity and shuffling gait, as well as non-motor impairment such as sensation impairment with pain, insomnia, and autonomic failure. It is caused by degeneration of the dopamine nervous system, which leads to a shortage of dopamine, a neurotransmitter in the brain.
According to the estimation of Japanese Society of Neurology, there are approximately 200,000 patients suffering from Parkinson’s disease in Japan.
Also, the approximate 3 million patients suffer from Parkinson’s disease in Asia.
The number of patients is increasing due to the aging of the population.
Levodopa is widely used to treat Parkinson's disease by replenishing the brain's supply of dopamine. However, as the disease progresses, the duration of a drug containing Levodopa of effect ( ON time ) decreases, and there are cases of Parkinson's disease symptoms returning before the next dose ( wearing-off phenomenon ). To prevent the wearing-off phenomenon, combination therapy with a drug that has a different mechanism of action to a drug containing Levodopa is administered.
In Japan, the approval is based on a double-blind, placebo-controlled phase II/III study ( study ME2125-3 ) to evaluate the efficacy and safety of Safinamide as add-on therapy as well as an open label phase III study ( study ME2125-4 ) to evaluate the safety and efficacy of long-term administration of Safinamide in Japanese patients with Parkinson’s disease with wearing-off phenomena who are currently receiving Levodopa.
Study ME2125-3 was a multicenter, double-blind, placebo-controlled, randomized, parallel group study to evaluate the efficacy and safety of two doses of Safinamide ( 50 and 100 mg, once a day for 24 weeks ) administered orally as add-on therapy in Japanese patients with Parkinson's disease with wearing-off phenomenon who are currently receiving a drug containing Levodopa.
In this study, the primary endpoint was the change in mean daily ON time from baseline to 24 weeks of the treatment phase, and verified the superiority of each dose of Safinamide over placebo.
Regarding the change in mean daily ON time from baseline to 24 weeks of the treatment phase with Safinamide 50 mg and 100 mg, the ON time showed the statistically significant increases compared to placebo-controlled treatment [ 50mg of Safinamide: 1.39 hours increase ( 95% CI: 0.67, 2.11 ), 100mg of Safinamide: 1.66 hours increase ( 95% CI: 0.93, 2.39 ) ].
The ADR ( Adverse Drug Reaction ) incidence rates in this study were 24.8% for placebo, 31.6% for Safinamide 50mg, and 30.3% for Safinamide 100mg.
The most common ADRs ( incidence 3% and higher ) observed with patients with Safinamide were dyskinesia and visual hallucination.
Study ME2125-4 was an open-label, multicenter study to evaluate the long-term efficacy and safety of two doses of Safinamide ( 50 and 100 mg, once a day for 52 weeks ) administered orally as add-on therapy in Japanese patients with Parkinson’s disease with wearing-off phenomenon who are currently receiving a drug containing Levodopa.
In this study, in addition to evaluating the safety of long-term administration of Safinamide, the study evaluated the change in mean daily ON time from baseline to 52 weeks of the treatment phase as the primary efficacy endpoint.
Regarding the changes ( LSM ± SDLP ) from baseline of mean daily ON time of 52 weeks of treatment, it was 1.42±2.72 hours, and the continuous efficacy of long-term administration was shown.
The ADR incidence rate was 38.9% for Safinamide. The most common ADRs ( incidence 3% and higher ) observed were dyskinesia, falls, and constipation. ( Xagena )
Source: Eisai, 2019