Merck Serono, a division of Merck KGaA, and its partner Newron announced preliminary results of a 12-month extension study of a 6-month phase III trial of safinamide as an add-on treatment to dopamine agonist therapy in patients with early stage Parkinson's disease. Results from the initial 6-month trial were presented in May at the American Academy of Neurology 59th Annual Meeting.

The objective of the study was to assess the long-term safety and efficacy of safinamide, an investigational drug, as add-on treatment to dopamine agonist therapy. The primary efficacy endpoint, time to intervention, did not reach statistical significance when data from both safinamide dose groups (50-100 mg, 150-200 mg) were pooled, although a delay of 93 days in median time to intervention was observed; the lack of a significant effect might be explained by the lack of response with the high dose group (150-200 mg) as seen in the analysis of the first six months.

A post-hoc analysis showed that the addition of safinamide at a dose of 50 to 100 mg once daily to dopamine agonist therapy significantly reduced the number of patients who experienced an intervention, maintained improvement in motor symptoms and improved quality of life compared with dopamine agonist monotherapy.

"These 18-month data suggest that, at a dose of 50 to 100 mg once daily, safinamide may delay the time to intervention for therapeutic adjustment and provide sustained improvement of Parkinson's disease symptoms when added to dopamine agonist therapy," said Professor Anthony Schapira, chairman of the University Department of Clinical Neuroscience, Royal Free and University College London Medical School, and an investigator of the study.

"Additional phase III studies are planned to further assess the efficacy of this dose of safinamide. Because Parkinson's disease is a neurodegenerative disease, if approved, safinamide could meet an important unmet medical need."

The primary efficacy endpoint of the 18-month trial was time from baseline to intervention. Intervention was defined by the onset of one of the following events: increase in dose of dopamine agonist; or addition of another dopamine agonist, levodopa or another Parkinson's disease therapy; or discontinuation due to lack of efficacy. Analysis of the primary efficacy measure indicated that safinamide treatment (data from all doses pooled) delayed the onset of the above events by 93 days (3 months) as measured by the median time to event (559 days versus 466 days; p=0.334, not statistically significant). As the risk of experiencing an intervention (hazard ratio) was not constant over time, a post-hoc analysis permitting an evaluation of events beyond the initial phase (>240 days) was performed. This indicated that patients receiving safinamide at a dose of 50 to 100 mg once daily experienced a significantly lower rate of events compared with patients receiving dopamine agonist monotherapy (25% versus 51%; p=0.049).

A post-hoc analysis of the mean change in motor symptoms, as measured by the Unified Parkinson's Disease Rating Scale Part III Motor Score (UPDRS III) (secondary efficacy endpoint) demonstrated that the addition of safinamide at a dose of 50 to 100 mg once daily to a stable dose of a single dopamine agonist resulted in a statistically significant improvement in motor symptoms over the 18-month treatment period (minus 4.7±9.34 versus minus 1.95±7.41; p=0.019). This improvement in motor symptoms was accompanied by a statistically significant improvement in quality of life as measured by the Euro quality of life (EuroQoL) scale (tertiary endpoint), both in the pooled dose group (safinamide: 0±1.85, placebo: 0.42±1.69; p=0.0046) and in the individual dose groups versus dopamine agonist monotherapy (safinamide 50-100 mg: 0.03±1.95; safinamide 150-200 mg: minus 0.03±1.73; placebo: 0.42±1.69; p low dose versus placebo =0.017; p high dose versus placebo =0.011).

As observed in the initial 6-month trial, the higher safinamide dose-range of 150 to 200 mg per day did not offer any incremental advantage over placebo over an 18-month period. Side effects, ECG changes and vital signs abnormalities were reported with similar frequency in patients receiving safinamide as an add-on to dopamine agonist therapy and in patients receiving dopamine agonist monotherapy. The most frequent adverse events were back pain (safinamide 50-100 mg: 12.5%; safinamide 150-200 mg: 1.4%; placebo: 6.4%), peripheral edema safinamide 50-100 mg: 3.8%, safinamide 150-200 mg: 4.3%; placebo: 10.3%, cataract (safinamide 50-100 mg: 5.0%, safinamide 150-200 mg: 10.1%; placebo: 6.4%), scotoma (safinamide 50-100 mg: 8.8%, safinamide 150-200 mg: 2.9%; placebo: 7.7%), and dizziness (safinamide 50-100 mg: 7.5%, safinamide 150-200 mg: 4.3%; placebo: 5.1%).

A Phase III trial evaluating safinamide at the 50 to 100 mg once daily dose-range as add-on to levodopa therapy is ongoing in patients with mid-to-late stage Parkinson's disease. Additional Phase III trials evaluating this safinamide dose-range either as add-on to dopamine agonist or as add-on to levodopa therapy are expected to be initiated in 2007 in early and mid-to-late stage Parkinson's disease respectively. Merck Serono has exclusive worldwide rights to develop, manufacture and commercialize safinamide in Parkinson's disease, Alzheimer's disease, and other therapeutic applications, as per the agreement signed with Newron.