Promising Data on Cognitive Effects of Safinamide in Early Parkinson's Disease

• Data presented at Movement Disorder Society’s 11th International Congress
• Management of cognitive impairment in early Parkinson’s disease patients is a critical unmet medical need

http://www.pharmalive.com/News/index...&categoryid=40

GENEVA, Switzerland, June 8, 2007 – Merck Serono S.A. (virt-x: SEO) and its partner Newron Pharmaceuticals S.p.a. (SWX: NWRN) announced today data, which suggest that safinamide, a new agent in Phase III development for the treatment of Parkinson’s disease, has an effect on cognitive performance in study patients with early Parkinson’s disease. These data were presented yesterday in a poster session at the Movement Disorder Society’s 11th International Congress in Istanbul, Turkey.

The data are from a 6-month (24 weeks), randomized, double blind, placebo-controlled, international Phase III trial. Some results from this trial were presented last month at the American Academy of Neurology 59th Annual Meeting and showed that safinamide significantly improved motor symptoms and activities of daily living for patients in the trial, as an add-on treatment to dopamine agonist therapy1. The cognition testing was carried out in an exploratory manner in selected centers, which agreed to conduct this part of the trial.

“Parkinson’s disease affects several cognitive functions even at an early stage of the disease”, 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. "These study results suggest that safinamide may have an effect on cognitive performance in patients with early Parkinson’s disease, and has the potential to address a critical unmet medical need”.

The data demonstrated that the addition of safinamide to a stable dose of a single dopamine agonist in study patients with early stage Parkinson’s disease resulted in an improvement in cognitive domains often impaired in these patients, in particular executive function (the ability for planning, organizing, strategizing and paying attention to and remembering details) and working memory.

Treatment with safinamide at a dose of 50 to 100 mg once daily over a 24-week period resulted in a statistically significant improvement in tests assessing executive function, such as the Strategic Target Detection Test2 (STDT), compared with dopamine agonist monotherapy. A statistically significant improvement was also observed in tests for working memory such as Auditory Number Sequencing3 (ANS). Tests assessing manual dexterity and attention/vigilance were not statistically different across treatment groups.

From baseline to the 24th week, cognitive data were available for 41 patients randomized to safinamide 50 to 100 mg once daily, 38 to safinamide 150 to 200 mg once daily and 44 to placebo. Cognitive effects were seen as early as 12 weeks after starting safinamide treatment. The higher safinamide dose range of 150 to 200 mg per day did not offer any incremental advantage over safinamide 50 to 100 mg per day dose range based on STDT and ANS.
The side effects observed in the safinamide group were similar to those observed in the placebo group. The most frequent side effects were gastro-intestinal disorders (nausea, vomiting, abdominal pain upper).

The cognitive effects of safinamide will be further investigated in other clinical trials.

Merck Serono has exclusive worldwide rights to develop, manufacture and commercialize safinamide in Parkinson’s disease, Alzheimer’s disease, other cognitive disorders and restless leg syndrome, as per the agreement signed with Newron in October 2006.

1...Phase III data presented at American Academy of Neurology 59th Annual Meeting in Boston, Massachusetts, USA:

The data are from a trial conducted in Europe, South America and Asia. A total of 270 early stage Parkinson’s disease patients (less than 5 years of disease) treated with a stable dose of a single dopamine agonist for at least 4 weeks 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 (90 patients), or safinamide at a dose of 150 to 200 mg once daily (90 patients) or matching placebo tablets (90 patients), as an add-on treatment to dopamine agonist therapy.

Trial data were presented last month at the American Academy of Neurology 59th Annual Meeting in Boston, Massachusetts, USA.

The data demonstrated that the addition of safinamide to a stable dose of a single dopamine agonist in study patients with early stage Parkinson’s disease resulted in a statistically significant improvement in motor symptoms, as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III Motor Score (primary endpoint). After 24 weeks of treatment with safinamide at the dose of 50 to 100 mg once daily, the UPDRS Part III Motor Score was significantly improved over the effect of dopamine agonist monotherapy (difference between end of study and baseline of minus 6.0 ± 7.2 in the safinamide-treated group versus minus 3.6 ± 7.1 in the placebo group; p=0.0419; 95% CI=[-3.7;-0.1]).

In addition, treatment with safinamide at the dose of 50 to 100 mg once daily over a 24-week period resulted in a significant improvement of UPDRS Part II Activities of Daily Living Score, compared with dopamine agonist monotherapy (difference between end of study and baseline of minus 2.2 ± 3.8 in the safinamide-treated group versus minus 1.2 ± 3.5 in the placebo group; p=0.0248; 95% CI=[-1.8;-0.1]).

The side effects observed in the safinamide group were similar to those observed in the placebo group.

The higher safinamide dose-range of 150 to 200 mg per day did not offer any incremental advantage over safinamide 50 to 100 mg per day dose-range based on UPDRS scoring.

The cognition component of the trial was a secondary endpoint and was carried out in selected centers, equipped to perform this type of assessment.

2...Strategic Target Detection Test (complex attention, executive function): This test requires the subject to touch the target stimuli (shapes) directly of a touch screen. The participant must learn which target is correct by choosing one of the stimuli following computer-generated feedback.

3...Auditory Number Sequencing (attention, working memory, executive function): Subjects hear a series of numbers (e.g. “9.. 3.. 6“; minimum=2 digits, maximum=8 digits) and are asked to repeat the numbers in order, from lowest to highest, requiring both working memory maintenance and manipulation.

About safinamide
Safinamide is an alpha-aminoamide derivative which is orally administered. Safinamide is believed to have a novel mode of action as a dopamine modulator (comprising both selective and reversible MAO-B inhibition and also blockade of dopamine reuptake) complemented by an effect on the glutamate pathway. Studies suggest that safinamide may combine the inhibition of dopamine re-uptake and MAO-B, two key mechanisms involved in the control of dopamine concentration in the brain, and inhibition of glutamate release. If regulatory approvals are obtained, Merck Serono and Newron believe that safinamide, as an adjunctive treatment to dopamine agonists and levodopa, may have a competitive advantage over current therapies for Parkinson’s disease.

About Parkinson’s disease
Parkinson's disease is a degenerative disorder of the central nervous system that often impairs the sufferer's motor skills and speech. Parkinson's disease belongs to a group of conditions called movement disorders. It is characterized by muscle rigidity, tremor, a slowing of physical movement (bradykinesia) and, in extreme cases, a loss of physical movement (akinesia). The primary symptoms are the results of decreased stimulation of the motor cortex by the basal ganglia, normally caused by the insufficient formation and action of dopamine, which is produced in the dopaminergic neurons of the brain. Secondary symptoms may include high level cognitive dysfunction and subtle language problems. Parkinson’s disease is both chronic and progressive.

Forward-looking statements
Some of the statements in this press release are forward looking. Such statements are inherently subject to known and unknown risks, uncertainties and other factors that may cause actual results, performance or achievements of Merck Serono S.A. and affiliates to be materially different from those expected or anticipated in the forward-looking statements. Forward-looking statements are based on Merck Serono’s current expectations and assumptions, which may be affected by a number of factors, including those discussed in this press release and more fully described in Serono’s Annual Report on Form 20-F filed with the U.S. Securities and Exchange Commission on February 28, 2006. These factors include any failure or delay in Merck Serono’s ability to develop new products, any failure to receive anticipated regulatory approvals, any problems in commercializing current products as a result of competition or other factors, our ability to obtain reimbursement coverage for our products, the outcome of any government investigations and litigation. Merck Serono is providing this information as of the date of this press release, and has no responsibility to update the forward-looking statements contained in this press release to reflect events or circumstances occurring after the date of this press release.

About Newron Pharmaceuticals
Newron Pharmaceuticals S.p.A. (www.newron.com) is a biopharmaceutical company focused on novel therapies for diseases of the Central Nervous System and pain. Newron is undertaking phase III trials with safinamide, a unique molecule with multiple mechanisms of action, for the treatment of PD in conjunction with its partner, Merck Serono S.A., which has the rights to develop the compound in PD, Alzheimer´s disease, other cognitive disorders and Restless Legs Syndrome. Recent results of a six-month phase III trial of safinamide in PD demonstrated its benefit in motor symptoms and activities of daily living, as well as its improvement in cognitive function, and good tolerability. Newron and Merck Serono are planning to expand the development of safinamide to exploit its potential in Alzheimer´s disease. Phase II trials with safinamide in Restless Legs Syndrome have shown promising results. Newron is also conducting phase II trials with ralfinamide for the treatment of neuropathic pain. The drug has potential benefit in inflammatory pain, as well. Newron´s clinical pipeline is supported by a portfolio of early-stage proprietary compounds generated by its ion channel drug discovery platform. Newron is headquartered in Bresso, near Milan, Italy. The company is listed at SWX Swiss Exchange, trading symbol NWRN.

About Merck Serono S.A.
Merck Serono S.A. is a global biotechnology leader, with sales in over 90 countries. The Company is the world leader in reproductive health, with Gonal-f®, Luveris® and Ovidrel®/Ovitrelle®. It has strong market positions in neurology, with Rebif®, as well as in metabolism and growth, with Saizen®, Serostim® and Zorbtive™. The Company has recently entered the psoriasis area with Raptiva®. Merck Serono's research programs are focused on growing these businesses and on establishing new therapeutic areas, including oncology and autoimmune diseases.

Bearer shares of Merck Serono S.A., the holding company, are traded on the virt-x (SEO).

About Merck
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.