ImageMerck KGaA and its Merck Serono division together with partner Newron Pharmaceuticals SpA announced that the first phase III trial of investigational agent safinamide as adjunctive therapy to levodopa (study 016) met its primary endpoint by increasing daily "ON" time in mid- to late-stage Parkinson's disease patients with motor fluctuations by 1.3 hours. "ON" time represents periods when Parkinson's patients experience their best level of motor functioning.

The two safinamide treatment groups of the study (receiving either safinamide 50 mg orally once daily or safinamide 100 mg orally once daily as adjunctive therapy to levodopa) demonstrated a statistically significant increase of daily total "ON" time compared to placebo.

Throughout the six months of the study, patients treated with both doses of safinamide experienced an average increase of "ON" time of 1.3 hours per day compared to baseline. Patients in the placebo group (receiving placebo in addition to levodopa and other anti-Parkinson therapies) reported an average increase of daily "ON" time of 0.7 hour compared to baseline. The differences between both safinamide dose groups and placebo were statistically significant with p-values of 0.008 (safinamide 50 mg daily) and 0.005 (safinamide 100 mg daily).

Safinamide, an alpha-aminoamide derivative that is orally formulated, is currently being developed by Merck Serono and Newron as an add-on treatment for patients with Parkinson's disease. Safinamide is believed to have a novel dual mechanism of action based on the enhancement of the dopaminergic function (through reversible inhibition of monoamine oxidase-B [MAO-B] and dopamine uptake) and reduction of glutamatergic activity by inhibiting glutamate release.

"The results indicate that safinamide, when used adjunctively to existing dopaminergic therapies for study patients in mid-to-late stages of Parkinson's disease, increases daily "ON" time of motor functioning," said Dr. Bernhard Kirschbaum, Merck Serono's executive vice president for Global Research and Development. "These results represent a further step toward our goal to provide patients and doctors with urgently needed new treatment possibilities in the Neurodegenerative Diseases therapeutic area."

Dr Ravi Anand, Newron's chief medical officer, said: "These results are extremely encouraging. In addition to increasing "ON" time and reducing total "OFF" time, as well as "OFF" time after morning dose in patients with mid- to late-stage Parkinson's disease receiving optimized treatment with drugs including levodopa, dopamine agonists, COMT inhibitors, anti-cholinergics and amantidine, the results indicate a statistically significant improvement of motor function. Previously reported results from phase II and phase III studies have shown improvement of motor symptoms in early Parkinson's disease patients on dopamine agonist monotherapy. These results from both early and advanced Parkinson's disease patients underline safinamide's potential to be used as adjunctive therapy along the continuum of Parkinson's disease."

This phase III study was a six-month (24-week), randomized, double-blind, placebocontrolled international trial. It enrolled 669 patients with mid- to late-stage idiopathic Parkinson's disease (more than three years of disease duration) receiving stable doses of levodopa, who had motor fluctuations with >1.5 hours of "OFF" time1 during the day. Additionally, patients may have received concomitant treatment with stable doses of a dopamine agonist and/or an anti-cholinergic drug. After a four-week levodopa dosage stabilization phase, study participants were randomized to one of the three arms of the trial (1:1:1) to receive either one of two different doses of safinamide (50 or 100 mg once daily: 223 and 224 patients, respectively) or matching placebo tablets (222 patients), as adjunctive treatment to their levodopa therapy. The primary efficacy endpoint of the study was the increase in mean daily "ON" time ("ON" time without dyskinesia plus "ON" time with minor dyskinesia) during an 18-hour period as assessed by patients' recordings on diary cards.

Out of the 669 randomized patients, 89% of patients treated with safinamide completed the study (91% in the 50 mg dose group and 87% in the 100 mg dose group) compared to 89% in the placebo group. Over 90% of patients who completed the initial 24 weeks of treatment elected to enter a 78-week, placebo-controlled double-blind extension study, which is ongoing, to specifically assess the effect on dyskinesias as primary endpoint.

Secondary efficacy endpoints of this study were also met, including decrease in daily "OFF" time, decrease in mean "OFF" time following first morning dose of levodopa, mean change from baseline in the Unified Parkinson's Disease Rating Scale (UPDRS)2 Section III (motor) score during "ON" time and mean change in Clinical Global Impression of severity of disease and change from baseline (CGI)3. The incidence of dropouts, serious adverse events or clinically notable events among the three groups of the study was comparable.

Full study results after completion of ongoing analyses will be submitted for presentation at upcoming scientific meetings. 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 in 2006.