Merck Serono: REFLEX Study Results Show Treat

News Release

October 25, 2010

Merck Serono: REFLEX Study Results Show Treatment with Rebif®
Delays Conversion to MS in Patients with First Clinical Signs of the Disease

• Study met its primary endpoint
• Risk of converting to multiple sclerosis (McDonald criteria) was reduced by half in patients treated with Rebif® 44 mcg three times a week

Geneva, Switzerland, October 25, 2010 – Merck Serono, a division of Merck KGaA, Darmstadt, Germany, announced today that the two-year Phase III REFLEX 1 study met its primary endpoint by demonstrating that Rebif® (interferon beta-1a) significantly delayed conversion to multiple sclerosis (MS) diagnosed according to the McDonald criteria 2 in patients with a first clinical event suggestive of the disease.

The international REFLEX study with 517 patients was conducted with the serum-free formulation of Rebif® 3, which was first introduced in 2007 and is now available in all European Union countries, Australia, Canada and Switzerland, as well as a number of countries in Asia, Latin America, Africa and the Middle East. The serum-free formulation of Rebif® is currently not available in the United States.

The risk of conversion to MS (McDonald criteria) over two years was reduced by 51% (p<0.00001) in patients who received Rebif® 44 mcg three times a week compared to placebo. A risk reduction of 31% (p=0.008) compared to placebo was observed in patients who received once-weekly administration of Rebif® 44 mcg. The probability of conversion to MS (McDonald criteria) over two years was 86% in the placebo group, 62% in patients who received Rebif® 44 mcg three times a week and 76% in patients who received once-weekly administration of Rebif® 44 mcg.

“We are committed to provide treatments that meet the individual needs of people living with multiple sclerosis at the various stages of the disease,” said Dr. Roberto Gradnik, Executive Vice President for Neurodegenerative Diseases at Merck Serono. “Over the years we have continuously worked on enhancing the product profile of Rebif® with new formulations, new injection devices and new clinical data. We are very pleased with these new clinical data as they show that patients in the study with the first clinical signs of multiple sclerosis benefited from treatment with Rebif®.”

The safety profile of Rebif® observed in the REFLEX study was similar to that seen in other recent studies with the serum-free formulation of Rebif®. No unexpected adverse reactions were identified. The majority of adverse events were mild or moderate. The most frequent undesirable effect was flu-like symptoms, which is typical of interferon therapy; most were mild in severity. Flu-like symptoms are transient and can be managed with prophylactic treatment.
Full results of the REFLEX study will be submitted for presentation at upcoming scientific meetings.

A three-year double blind extension of the REFLEX study, called REFLEXION 4, is currently ongoing in order to provide long-term follow-up data (up to five years).

1 REFLEX: REbif FLEXible dosing in early multiple sclerosis
2 The primary endpoint of the REFLEX study was time to conversion to MS according to the revised McDonald criteria (2005). The McDonald criteria are the current reference criteria for the diagnosis of MS.
According to the McDonald criteria, the diagnosis of MS is based on one attack and subsequent dissemination of lesions evidenced by either a positive magnetic resonance imaging (MRI) scan or a new clinical relapse.
3 In previous communications, the serum-free formulation of Rebif® was referred to as the “new formulation of Rebif®”

About the REFLEX study design
The REFLEX study was a two-year (24-month), randomized, double-blind, placebo-controlled, international Phase III trial. It randomized 517 patients considered at risk of developing MS due to a recently experienced isolated demyelinating event (e.g. optic neuritis, myelopathy or brainstem syndrome) and having magnetic resonance imaging (MRI) brain scans consistent with early signs of MS. Study participants were randomized in a 1:1:1 ratio to receive either Rebif® 44 mcg three times a week, Rebif® 44 mcg once a week, or placebo as a subcutaneous injection. Patients were treated for a period of two years, or up to the time when they experience a second attack leading to a diagnosis of clinically definite MS. At this point, patients were offered open-label treatment with Rebif® 44 micrograms three times a week. The primary endpoint of the study was “time to conversation to Mc Donald MS”. Further endpoints include “time to conversion to clinically definite MS” (the main secondary endpoint), assessments of magnetic resonance imaging (MRI) brain scans and clinical relapses.

About Rebif®
Rebif® (interferon beta-1a) is a disease-modifying drug used to treat relapsing forms of multiple sclerosis (MS) and is similar to the interferon beta protein produced by the human body. The efficacy of Rebif® in chronic progressive MS has not been established. Interferons are thought to help reduce inflammation. The exact mechanism is unknown.

Rebif®, which was approved in Europe in 1998 and in the US in 2002, is registered in more than 90 countries worldwide. Rebif® has been proven to delay the progression of disability, reduce the frequency of relapses and reduce MRI lesion activity and area*. Rebif® is available in a 22 micrograms and 44 micrograms ready-to-use pre-filled syringe and a titration pack (8.8 micrograms). Rebif® is also now available in two multidose cartridges [132 micrograms (three doses of 44 micrograms) and 66 micrograms (three doses of 22 micrograms)] for the use with the RebiSmart™ device, in several EU member countries, Switzerland and Canada, as well as in Australia.

Rebif® should be used with caution in patients with a history of depression, liver disease and seizures. Most commonly reported side effects are flu-like symptoms, injection site disorders, elevation of liver enzymes and blood cell abnormalities. Patients, especially those with depression, seizure disorders, or liver problems, should discuss treatment with Rebif® with their doctors.

* The exact correlation between MRI findings and the current or future clinical status of patients, including disability progression, is unknown.

About multiple sclerosis
Multiple sclerosis (MS) is a chronic, inflammatory condition of the central nervous system and is the most common, non-traumatic, disabling neurological disease in young adults. It is estimated that approximately two million people have MS worldwide. While symptoms can vary, the most common symptoms of MS include blurred vision, numbness or tingling in the limbs and problems with strength and coordination. The relapsing forms of MS are the most common.

About Merck Serono
Merck Serono is the division for innovative prescription pharmaceuticals of Merck KGaA, Darmstadt, Germany, a global pharmaceutical and chemical company. Headquartered in Geneva, Switzerland, Merck Serono discovers, develops, manufactures and markets innovative small molecules and biopharmaceuticals to help patients with unmet medical needs. In the United States and Canada, EMD Serono operates through separately incorporated affiliates.

Merck Serono has leading brands serving patients with cancer (Erbitux®, cetuximab), multiple sclerosis (Rebif®, interferon beta-1a), infertility (Gonal-f®, follitropin alfa), endocrine and metabolic disorders (Saizen® and Serostim®, somatropin), (Kuvan®, sapropterin dihydrochloride) as well as cardiometabolic diseases (Glucophage®, metformin), (Concor®, bisoprolol), (Euthyrox®, levothyroxine). Not all products are available in all markets.

With an annual R&D expenditure of more than € 1 billion, Merck Serono is committed to growing its business in specialist-focused therapeutic areas including neurodegenerative diseases, oncology, fertility and endocrinology, as well as new areas potentially arising out of research and development in autoimmune and inflammatory diseases.

About Merck
Merck is a global pharmaceutical and chemical company with total revenues of € 7.7 billion in 2009, a history that began in 1668, and a future shaped by approximately 40,000 (including Merck Millipore) employees in 64 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.

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