Merck Serono Announces 18-Month Safety and Efficacy Dataof Phase III Trial of Safinamide in Parkinson's Disease
• The primary endpoint, time to intervention, did not reach statistical significance when data from both safinamide dose groups (50-100 mg, 150-200 mg) were pooled
• A post-hoc analysis per dose group 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
• Further trial with 50-100 mg dose is ongoing and
additional trials with safinamide are expected to be
GENEVA, Switzerland, August 22, 2007 – Merck Serono, a division of Merck KGaA, and its partner Newron (SWX: NWRN) announced today 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 (as described below) 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)1 (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)2 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.
The 18-month, Phase III, randomized, double blind, placebo-controlled, international trial enrolled patients with early stage Parkinson’s disease (less than 5 years of disease) treated with a stable dose of a single dopamine agonist. Patients were randomized to one of the three arms of the study to receive either safinamide at a dose of 50 to 100 mg once daily, safinamide at a dose of 150 to 200 mg once daily, or matching placebo tablets, as an add-on treatment to dopamine agonist therapy. Patients who entered the initial 6-month Phase III trial were given the opportunity to continue the study for an additional 12 months, receive other treatments for Parkinson’s disease, or to discontinue therapy. Of the 270 patients originally enrolled in the trial, 227 entered the 12-month extension; 187 patients completed the 12-month extension period. The main reasons for discontinuation were side effects (safinamide 50-100 mg: 3.8%; safinamide 150-200 mg: 1.4%; placebo: 3.9%), lack of efficacy (safinamide 50-100 mg: 2.5%; safinamide 150-200 mg: 5.8%; placebo: 6.4%) and withdrawal of consent (safinamide 50-100 mg: 10.0%; safinamide 150-200 mg: 4.3%; placebo: 6.4%).
The UPDRS is one of the most widely used rating scales used to follow the course of Parkinson’s disease.
It is made up of 42 items, scored from 0 to 4, to establish individual patients’ mental status, activities of daily living, motor function and complications of therapy.
These are evaluated by interview and clinical observation. Clinicians and researchers alike use the UPDRS and the motor section in particular to follow the progression of a person's Parkinson's disease.
The EuroQoL is a 5-item scale that is used to assess quality of life in patients with Parkinson’s disease. The 5 items rated are mobility, self-care, usual activities (e.g., work or leisure activities), pain/discomfort, and anxiety/depression. Patients are asked to tick one of the three statements under each item, which best describes their current status with regard to their ability to perform a particular activity or the severity of the specific symptom assessed.
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About Merck Serono
Merck Serono, the new division for innovative small molecules and biopharmaceuticals of Merck was established following the acquisition of Serono and the integration of its business with the former Merck Ethicals Division. Headquartered in Geneva, Switzerland, Merck Serono discovers, develops, produces and commercializes innovative products to help patients with diseases with unmet needs. Our North American business operates in the United States and Canada under EMD Serono.
Merck Serono has leading brands serving patients with cancer (Erbitux®), multiple sclerosis (Rebif®), infertility (Gonal-f®), metabolic and cardiometabolic disorders (Glucophage®, Concor®, Saizen®, Serostim®), as well as psoriasis (Raptiva®). With an annual R&D investment of EUR 1bn, we are committed to growing our business in specialist-focused therapeutic areas such as Neurology and Oncology, as well as new therapeutic areas potentially arising out of our research and development in autoimmune and inflammatory diseases.
Merck is a global pharmaceutical and chemical company with sales of EUR 6.3 billion in 2006, a history that began in 1668, and a future shaped by 35,091 employees in 62 countries. Its success is characterized by innovations from entrepreneurial employees. Merck's operating activities come under the umbrella of Merck KGaA, in which the Merck family holds an approximately 70% interest and free shareholders own the remaining approximately 30%. In 1917 the U.S. subsidiary Merck & Co. was expropriated and has been an independent company ever since.
Posted: August 2007