Merck KGaA: Oral Investigational Treatment Cladribine Tablets for Multiple Sclerosis Significantly Reduced Relapse Rate in Phase III Pivotal Trial

• Two-year primary efficacy endpoint of CLARITY trial met: 58% relative
reduction in annualized relapse rate in the low total dose treatment group
and 55% in the high total dose treatment group

• Submission for registration of cladribine tablets planned for mid-2009

• Cladribine tablets are the first oral investigational multiple sclerosis
treatment to complete a two-year pivotal study

Darmstadt, Germany, January 23, 2009 – Merck KGaA and its Merck Serono division
announced today that the CLARITY1 Phase III pivotal trial of its proprietary oral
formulation of cladribine (cladribine tablets) met the two-year primary endpoint of
clinical relapse rate reduction in patients with relapsing-remitting multiple sclerosis
(MS).

The two cladribine tablet treatment groups of the study, assessing different dose
regimens, demonstrated a statistically significant reduction in the annualized rate of
relapses compared to placebo. Patients from the lower total dose group experienced a
58% relative reduction in annualized relapse rates with respect to placebo (0.14 versus
0.33 for the placebo group; p<0.001). Patients from the higher total dose group
experienced a 55% relative reduction in annualized relapse rates with respect to
placebo (0.15 versus 0.33; p<0.001).

Overall, the frequencies of adverse events were low in the cladribine tablet treatment
groups and were comparable to that observed in the placebo group. Lymphopenia, an expected event based on the presumed mechanism of action of cladribine, occurred
more frequently in the cladribine tablet treatment groups. With the exception of
lymphopenia, the most frequently reported adverse events in the three study groups
were headaches and nasopharyngitis.

“We believe the CLARITY data mark an important milestone in the assessment of
investigational oral treatments for multiple sclerosis and that cladribine tablets have the potential to make a real difference in the lives of patients,” said Elmar Schnee, Executive Board Member with responsibility for the Pharmaceuticals business sector.

“Based on the successful completion of the CLARITY study, we plan to submit cladribine tablets for registration to the EMEA and to the FDA for mid-2009."

Secondary endpoints of the CLARITY study were also met, including reduction of lesion activity as measured by magnetic resonance imaging (MRI), proportion of subjects relapse-free and disability progression. Full study results will be submitted for
presentation at an upcoming scientific meeting.

The CLARITY study was a two-year (96 weeks), randomized, double-blind, placebo controlled, international trial. It enrolled 1,326 patients with relapsing-remitting MS
according to the revised McDonald criteria2. Study participants were randomized to one
of three different treatment groups consisting of two different dose regimens of
cladribine tablets or matching placebo tablets (1:1:1 ratio). Cladribine tablets were
given in two or four treatment courses in the first year, with each course consisting of once daily administration for four to five consecutive days, which means study patients took cladribine tablets for only 8 to 20 days during the year. In the second year, two treatment courses were administered to all patient groups. The primary endpoint of the CLARITY study was the qualifying relapse rate at 96 weeks. Secondary endpoints included MRI endpoints3, proportion of subjects relapse-free and disability progression at 96 weeks. Out of the 1,326 randomized patients, 90% of patients treated with cladribine tablets completed the study (92% in the lower total dose group and 89% in the higher total dose group) compared to 87% in the placebo group.

1 CLARITY: CLAdRIbine Tablets Treating MS OrallY

2 The McDonald criteria are diagnostic criteria for MS. In April 2001 an international panel in association with the National Multiple Sclerosis Society (NMSS) of America recommended revised diagnostic criteria for MS. They make use of advances in MRI imaging techniques and are intended to replace the Poser criteria. The new criteria facilitate the diagnosis of MS in patients who present with signs and symptoms
suggestive of the disease. The McDonald criteria for the diagnosis of multiple sclerosis were revised in 2005 to simplify and speed diagnosis, while maintaining adequate sensitivity and specificity.

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

About cladribine tablets

Merck Serono’s proprietary oral formulation of cladribine (cladribine tablets) is currently being evaluated in Phase III as a treatment for patients with relapsing forms of multiple sclerosis (MS). Cladribine is a small molecule that may interfere with the behavior and the proliferation of certain white blood cells, particularly
lymphocytes, which are thought to be involved in the pathological process of MS.
The clinical development program for cladribine tablets includes:

- The CLARITY (CLAdRIbine Tablets Treating MS OrallY) extension study: a two-year placebo-controlled extension of the CLARITY study, designed to provide data on the long-term safety and efficacy of extended administration of cladribine tablets for up to four years

- The ORACLE MS (ORAl CLadribine in Early MS) study: a two-year Phase III placebo-controlled trial designed to evaluate the efficacy and safety of cladribine tablets as a monotherapy in patients at risk of developing MS (patients who have experienced a first clinical event suggestive of MS). This trial was announced in September 2008.

- The ONWARD (Oral Cladribine Added ON To Rebif New Formulation in Patients With Active Relapsing Disease) study: a Phase II placebo-controlled trial designed primarily to evaluate the safety and tolerability of adding cladribine tablets treatment to patients with relapsing forms of MS, who have experienced breakthrough disease while on established interferon-beta therapy. This trial was announced in January 2007.

Cladribine tablets have been granted a fast track designation by the US Food and Drug Administration based on the need for an oral therapy in a subset of patients with relapsing forms of multiple sclerosis.

About Merck Serono and multiple sclerosis

Merck Serono is a leader in multiple sclerosis (MS) with Rebif® (interferon beta-1a), a disease-modifying drug used to treat relapsing forms of MS, which is registered in more than 80 countries worldwide. Full prescribing information for this product can be obtained by contacting the Company or visiting its website.

Additional therapeutic options are currently under development at Merck Serono, including cladribine tablets, currently in Phase III and potentially the first oral therapy for MS, as well as several products in early stage development. Merck Serono also is taking a leading role in developing an understanding of the role of genetics in MS.

About multiple sclerosis

Multiple sclerosis (MS) is a chronic, inflammatory condition of the nervous system and is the most common, non-traumatic, disabling neurological disease in young adults. The World Health Organization estimates that up to 2.5 million people suffer from 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.


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Merck is a global pharmaceutical and chemical company with total revenues of € 7.1 billion in 2007, a history that began in 1668, and a future shaped by 32,458 employees in 59 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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Apitope and Merck Serono Announce Licensing Agreement on Novel Peptide Therapeutics for the Treatment of Multiple Sclerosis

Apitope and Merck Serono to collaborate on development and commercialization of ATX-MS-1467, Apitope’s peptide therapeutic for the treatment of multiple sclerosis (MS)

Bristol, England and Hasselt, Belgium, January 13, 2009 – Apitope Technology (Bristol) Ltd., a wholly owned subsidiary of Apitope International NV, announced today the signature of a research, development and commercialization agreement with Merck Serono, a division of Merck KGaA, Darmstadt, Germany. Under this agreement, Apitope has granted exclusive worldwide rights to Merck Serono to develop and commercialize Apitope’s product ATX-MS-1467. This peptide therapeutic has completed an initial clinical study in patients with MS. It is designed to induce immunological tolerance of the body’s T-cells to key autoantigens involved in the pathogenesis of MS.

ATX-MS-1467 is a novel peptide-based therapeutic derived from Apitope’s proprietary technology platform. Under the terms of the agreement, Apitope will receive an upfront payment and will initially be responsible for the further development of ATX-MS-1467, for which Merck Serono will fund the costs. Merck Serono will be responsible for all development activities from the beginning of Phase II clinical trials. Merck Serono will also provide committed funding to Apitope for research on other novel therapeutic peptides for the treatment of MS.

Under the terms of the agreement, Apitope is eligible to receive up to € 154 million in upfront, development and commercialization milestone payments, in addition to royalties on the net sales of products resulting from the collaboration.

“This partnership with Apitope strengthens our position as a leader in the field of innovative research and development in multiple sclerosis,” said Bernhard Kirschbaum, Executive Vice President Research and Development at Merck Serono. “ATX-MS-1467 represents a novel, targeted approach and may have the potential to complement existing MS drugs by offering a novel mode of action. By applying our existing stratified medicine approaches, we will also identify those MS patients who should benefit most from this potential treatment.”

“We are very pleased that ATX-MS-1467 has attracted a major pharmaceutical partner such as Merck Serono with extensive experience and leadership in the development of therapies for multiple sclerosis,” said Keith Martin, CEO of Apitope. “We view this collaboration as confirmation of Apitope's ability to develop early-stage first-in-class therapies for autoimmune diseases. In addition to continuing to build our in-house diagnostic platform in MS, we look forward to progressing ATX-MS-1467 with Merck Serono.”

ATX-MS-1467 consists of four short peptides that are derived from myelin basic protein, a key autoantigen in MS. It is specifically designed to target up to 70 % of MS patients who have a specific genetic profile.

About Apitope

Apitope International NV is a biopharmaceutical company with headquarters in Hasselt, Belgium, and a subsidiary in Bristol, England. The Company is developing novel products to revolutionize the diagnosis and treatment of chronic autoimmune and allergic disorders. Apitope’s therapeutic peptide technology platform is based on established scientific evidence showing that soluble, synthetic peptides can reinstate tolerance and selectively attenuate pathological immune responses. The ApitopesTM (Antigen Processing Independent epiTOPES) inhibit the immune system's harmful attack on the body while preserving normal immune responses to harmful antigens, such as infections. Apitope’s portfolio includes novel peptide therapies for MS as well as other autoimmune diseases and common allergies. Apitope is also developing novel diagnostic products for the early detection of autoimmune diseases such as MS and rheumatoid arthritis (RA). Apitope is backed by LRM; Vesalius Biocapital; Fast Forward, VINNOF; Hasselt University; The Wellcome Trust; the Daniels family, Wyvern Seedcorn Fund and the University of Bristol; Innovator Capital Limited advised on the recent funding rounds.

For more information, please go to www.apitope.com

About multiple sclerosis

Multiple sclerosis (MS) is a chronic, inflammatory condition of the nervous system and is the most common, non-traumatic, disabling neurological disease in young adults. The World Health Organization estimates that up to 2.5 million people suffer from 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 and multiple sclerosis

Merck Serono is a leader in multiple sclerosis (MS) with Rebif® (interferon beta-1a), a disease-modifying drug used to treat relapsing forms of MS, which is registered in more than 80 countries worldwide. Full prescribing information for this product can be obtained by contacting the Company or visiting its website. Additional therapeutic options are currently under development at Merck Serono, including oral cladribine, currently in Phase III and potentially the first oral therapy for MS, as well as several products in early stage development. Merck Serono is also taking a leading role in developing an understanding of the role of genetics in MS.

About Merck Serono

Merck Serono is the division for innovative prescription pharmaceuticals of Merck, a global pharmaceutical and chemical group. Headquartered in Geneva, Switzerland, Merck Serono discovers, develops, manufactures and markets innovative small molecules and biopharmaceuticals to help patients with unmet medical needs. Its North American business operates in the United States and Canada as EMD Serono.

Merck Serono has leading brands serving patients with cancer (Erbitux®), multiple sclerosis (Rebif®), infertility (Gonal-f®), endocrine and cardiometabolic disorders (Glucophage®, Concor®, Euthyrox®, Saizen®, Serostim®), as well as psoriasis (Raptiva®).

With an annual R&D expenditure of around € 1bn, 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 € 7.1 billion in 2007, a history that began in 1668, and a future shaped by 32,458 employees in 59 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.

For more information, please visit www.merckserono.net or www.merck.de

Results from IMPROVE Study Show Therapeutic Effect of New Formulation of Rebif® at 16 Weeks in Patients with Multiple Sclerosis

• Study meets primary endpoint by demonstrating significant effect of new formulation of Rebif® on disease activity as measured by MRI after 16 weeks of treatment

• Data presented at late-breaking session of the World Congress on Treatment and Research in Multiple Sclerosis in Montreal, Canada

Geneva, Switzerland, September 22, 2008 - Merck Serono, a division of Merck KGaA, Darmstadt, Germany, announced today that the ongoing IMPROVE (Investigating MRI Parameters with Rebif imprOVEd formulation) study met its primary endpoint. The primary objective of the study was to evaluate the efficacy of the new formulation of Rebif®, compared to placebo, in patients with relapsing-remitting multiple sclerosis (RRMS) and active disease by means of magnetic resonance imaging (MRI) at the end of 16 weeks of treatment. The 16-week study results show that the mean number of combined unique active brain MRI lesions per patient was reduced by 69% in patients treated with the new formulation of Rebif® compared with those receiving placebo, a statistically significant result (p<0.001). These data were presented at the late-breaking session of the World Congress on Treatment and Research in Multiple Sclerosis in Montreal, Canada.

"Patients who received Rebif® experienced far fewer new active brain MRI lesions than the placebo group after 16 weeks of treatment,” said Dr. Mark Freedman, Professor of Neurology at the University of Ottawa, Director of the MS Research Clinic at the Ottawa Hospital, and an investigator of the IMPROVE trial. “These data demonstrate a
significant effect of the new formulation of Rebif® on disease activity and provide further evidence of its benefit in treating patients with relapsing-remitting multiple sclerosis.”

The IMPROVE study is a two-arm, randomized, double-blind, controlled, multicenter, international Phase IIIb study to evaluate the efficacy, safety and tolerability of the new formulation of Rebif® in patients with RRMS according to the revised McDonald criteria and evidence of active disease. A total of 180 patients were randomized in a 2:1 ratio to receive either the new formulation of Rebif® 44 micrograms three times a week subcutaneously, or placebo for an initial period of 16 weeks. At the end of this initial 16-week treatment period, patients from the placebo group have been switched in a single-blinded fashion to treatment with the new formulation of Rebif® 44 micrograms three times a week subcutaneously for a period of 24 weeks (the physician assessing treatment response and side effects is blinded). Patients who were initially assigned to the new formulation of Rebif® group continue to receive active treatment for an additional period of 24 weeks. The duration of the whole treatment period is 40 weeks.

The primary endpoint of the study is the difference between the number of combined unique active MRI lesions at week 16 in the group treated with the new formulation of Rebif® versus the placebo group. Combined unique active MRI lesions are defined as an active lesion on T1 sequence with gadolinium or T2 sequence, or both, avoiding double counting. The primary endpoint mainly reflects inflammatory activity (gadolinium-enhancing T1 lesions), but also reflects disease progression (T2 lesions).

The primary efficacy analysis showed that, at week 16, the number of combined unique active brain lesions was significantly lower in patients treated with the new formulation of Rebif® than in patients who received a placebo (p<0.001). The mean number of combined unique active brain lesions per patient was reduced by 69% in patients treated with the new formulation of Rebif® compared with those receiving placebo (0.7 versus 2.2). The median number of combined unique active brain lesions at week 16 was 0.0 in the group treated with the new formulation of Rebif® and 1.0 in the placebo group. Over half (53%) of patients treated with the new formulation of Rebif® had zero combined unique active brain lesions at week 16, compared to only 16.7% in the placebo group.

Results for the secondary and tertiary endpoints of the IMPROVE study will be available at the end of the 40-week treatment period.

The safety profile of the new formulation of Rebif® reported in this study is consistent with the known safety profile of Rebif®. No unexpected safety concerns were identified in this study.

The new formulation of Rebif® was approved in the European Union in August 2007 and in Canada in September 2007. It is now marketed in all EU countries and in Canada. The new formulation of Rebif® is not available in the United States.

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 modulate the body’s immune system and 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 80 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® 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. For more information about Rebif®, please visit www.mslifelines.com for prescribing information.

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

About Merck Serono and multiple sclerosis

Merck Serono is a leader in multiple sclerosis (MS) with Rebif® (interferon beta-1a), a disease-modifying drug used to treat relapsing forms of MS, which is registered in more than 80 countries worldwide. Full prescribing information for Rebif® can be obtained by contacting the Company or visiting its website. Additional therapeutic options are currently under development at Merck Serono, including oral cladribine, currently in Phase III and potentially the first oral therapy for MS, as well as several products in early stage development. Merck Serono also is taking a leading role in developing an understanding of the role of genetics in MS.

About multiple sclerosis

Multiple sclerosis (MS) is a chronic, inflammatory condition of the nervous system and is the most common, non-traumatic, disabling, neurological disease in young adults. The World Health Organization estimates that up to 2.5 million people suffer from 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, a global pharmaceutical and chemical group. Headquartered in Geneva, Switzerland, Merck Serono discovers, develops, manufactures and markets innovative small molecules and biopharmaceuticals to help patients with unmet medical needs. Its North American business operates in the United States and Canada as EMD Serono.

Merck Serono has leading brands serving patients with cancer (Erbitux®), multiple sclerosis (Rebif®), infertility (Gonal-f®), endocrine and cardiometabolic disorders (Glucophage®, Concor®, Euthyrox®, Saizen®, Serostim®), as well as psoriasis (Raptiva®).
With an annual R&D expenditure of around € 1bn, 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 € 7.1 billion in 2007, a history that began in 1668, and a future shaped by 31,946 employees in 60 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.

For more information, please visit www.merckserono.net or www.merck.de

Merck Serono Announces Initiation of the ORACLE MS Trial to Evaluate Cladribine Tablets in Patients at Risk of Developing Multiple Sclerosis

• ORACLE MS Phase III trial will assess effectiveness of cladribine tablets in preventing conversion to definite multiple sclerosis in addition to the fully enrolled Phase III pivotal trial – the CLARITY study – for treatment of relapsing forms of multiple sclerosis

Geneva, Switzerland, September 18, 2008 – Merck Serono, a division of Merck KGaA, Darmstadt, Germany, announced today the initiation of a Phase III trial to evaluate the therapeutic effects of its proprietary oral formulation of cladribine (cladribine tablets) in patients at risk of developing multiple sclerosis (MS).

The trial, called ORACLE MS (ORAl CLadribine in Early MS) will evaluate the safety and efficacy of two dosage regimens of cladribine tablets versus placebo in the treatment of patients who have experienced a first clinical event suggestive of MS. Cladribine tablets are currently also being evaluated in a fully enrolled Phase III pivotal trial – the CLARITY1 study – for treatment of relapsing forms of MS. As announced in January 2007, CLARITY was the first pivotal trial among all Phase III oral compounds in development for MS to complete enrollment. Cladribine tablets have been granted a fast track designation by the US Food and Drug Administration.

“There is increasing evidence supporting the initiation of treatment with a disease-modifying drug in patients who have experienced a first clinical event suggestive of multiple sclerosis, an initial stage of the disease when clinical manifestations are not necessarily pronounced but where the potential exists for irreversible neurological damage to take place,” said Dr. Thomas Leist, Associate Professor of Neurology and Director of the Comprehensive MS Center at Thomas Jefferson University, Philadelphia, PA, and an investigator in the ORACLE MS study. “The ORACLE MS study will evaluate the effectiveness and safety of cladribine tablets in preventing conversion to definite multiple sclerosis.”

“As a leader in multiple sclerosis treatments, we are committed to providing new options that can further improve the course of the disease and the quality of life for people living with this disease,” said Dr. Richard Douge, Executive Vice President, Global Marketing, Merck Serono. “The initiation of the ORACLE MS study further demonstrates our commitment to continue to build a solid portfolio of products for use in a broad multiple sclerosis patient population. We believe that our proprietary oral formulation of cladribine has the potential to address an important unmet medical need at a critical time of disease development.”

The ORACLE MS study is a randomized, double-blind, placebo-controlled, international trial. It will involve more than 600 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 MRI brain scans consistent with early signs of MS. Study participants will be randomized in one of the three arms of the study to receive one of two different dosage regimens of cladribine tablets or matching placebo tablets (1:1:1 ratio).

Patients will be treated for a period of two years (96 weeks), or up to the time when they experience a second attack leading to a diagnosis of clinically definite MS, in which case they would be offered open-label treatment with Rebif® 44 mcg three times a week for a 96-week maintenance treatment period. Patients who do not convert to clinically definite MS within the initial 96-week period of the study will be eligible to enroll in a 96-week long-term follow-up treatment period. These maintenance and long-term follow-up periods of the study are intended to assess the effect of early treatment with cladribine tablets on relapses and subsequent treatment response to disease-modifying therapy for relapsing-remitting MS and to evaluate the sustained effect of cladribine tablets in delaying the development of definite MS.

In the study, cladribine tablets are given in two or four treatment cycles in the first year, with each cycle consisting of once daily administration for four to five consecutive days, which means study patients take cladribine tablets for only 8 to 20 days during that year. In the second year, two treatment cycles are administered to all patient groups.

The primary endpoint of the ORACLE MS trial is time to conversion to MS, according to the McDonald criteria. Other endpoints include time to conversion to clinically definite MS according to the Poser criteria (the main secondary endpoint), assessments of MRI brain scans, and disability progression.

Approximately 200 medical centers globally are expected to participate in this trial.
1 CLARITY: CLAdRIbine Tablets Treating MS OrallY

About cladribine tablets

Merck Serono’s proprietary oral formulation of cladribine is currently being evaluated in Phase III as a treatment for patients with relapsing forms of multiple sclerosis (MS). Cladribine is a small molecule that may interfere with the behavior and the proliferation of certain white blood cells, particularly lymphocytes, which are thought to be involved in the pathological process of MS.

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 modulate the body’s immune system and 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 80 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 microgram and 44 microgram ready-to-use pre-filled syringe and a titration pack (8.8 micrograms).

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. For more information about Rebif®, please visit www.mslifelines.com for prescribing information.

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

About Merck Serono and multiple sclerosis

Merck Serono is a leader in multiple sclerosis (MS) with Rebif® (interferon beta-1a), a disease-modifying drug used to treat relapsing forms of MS, which is registered in more than 80 countries worldwide. Full prescribing information for this product can be obtained by contacting the Company or visiting its website. Additional therapeutic options are currently under development at Merck Serono, including cladribine tablets, currently in Phase III and potentially the first oral therapy for MS, as well as several products in early stage development. Merck Serono also is taking a leading role in developing an understanding of the role of genetics in MS.
About multiple sclerosis

Multiple sclerosis (MS) is a chronic, inflammatory condition of the nervous system and is the most common, non-traumatic, disabling neurological disease in young adults. The World Health Organization estimates that up to 2.5 million people suffer from 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, a global pharmaceutical and chemical group. Headquartered in Geneva, Switzerland, Merck Serono discovers, develops, manufactures and markets innovative small molecules and biopharmaceuticals to help patients with unmet medical needs. Its North American business operates in the United States and Canada as EMD Serono.

Merck Serono has leading brands serving patients with cancer (Erbitux®), multiple sclerosis (Rebif®), infertility (Gonal-f®), endocrine and cardiometabolic disorders (Glucophage®, Concor®, Euthyrox®, Saizen®, Serostim®), as well as psoriasis (Raptiva®).
With an annual R&D expenditure of around € 1bn, 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 € 7.1 billion in 2007, a history that began in 1668, and a future shaped by 31,946 employees in 60 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.

For more information, please visit www.merckserono.net or www.merck.de

Merck Serono Announces Initiation of Phase II Clinical Trial of Atacicept in Relapsing Multiple Sclerosis

Geneva, Switzerland, April 30, 2008 – Merck Serono, a division of Merck KGaA, Darmstadt, Germany, and its partner ZymoGenetics, Inc. (NASDAQ: ZGEN) today announced the initiation of a Phase II clinical trial to evaluate the safety and efficacy of atacicept in patients with relapsing multiple sclerosis (RMS).

“This trial with atacicept underlines Merck Serono’s long-term commitment to patients with multiple sclerosis,” said Dr. Anton Hoos, Head of Global Development at Merck Serono. “Atacicept has the potential to complement existing MS drugs by offering a novel mode of action and convenient administration.”

“Patients with multiple sclerosis need more treatment options,” said Nicole Onetto, M.D., Senior Vice President and Chief Medical Officer of ZymoGenetics. “Our preclinical models have shown biological activity of atacicept in multiple sclerosis and, because of the growing body of supporting data in the literature indicating the importance of B cells and antibodies in the pathology of multiple sclerosis, we believe there is strong rationale for the clinical testing of atacicept in patients with RMS.”
The four-arm randomized, double-blind, placebo-controlled, multicenter study will evaluate the safety and efficacy of atacicept in patients with RMS over 36 weeks of treatment. The primary objective of the study is to evaluate the efficacy of atacicept in reducing central nervous system inflammation in subjects with RMS as assessed by frequent MRI measures.

Approximately 300 RMS patients meeting the eligibility criteria will be randomly assigned to receive one of three subcutaneous doses of atacicept or placebo for 36 weeks. Patients will be followed up until week 48.

About atacicept

Merck Serono and ZymoGenetics are developing atacicept (formerly referred to as TACI-Ig) as a potential treatment of autoimmune diseases, such as systemic lupus erythematosus (SLE), lupus nephritis (LN), rheumatoid arthritis and multiple sclerosis, as well as B-cell malignancies.

Atacicept contains the soluble TACI receptor that binds to the cytokines BLyS and APRIL. These cytokines are members of the tumor necrosis factor family that promote B-cell survival and autoantibody production associated with certain autoimmune diseases such as systemic lupus erythematosus. Current data indicates that levels of BLyS and APRIL are elevated in patients with rheumatoid arthritis, lupus erythematosus, B-cell malignancies and multiple sclerosis. Atacicept has been shown to affect several stages of B-cell development and may inhibit the survival of cells responsible for making antibodies.

About Merck Serono and multiple sclerosis

Merck Serono is a leader in multiple sclerosis (MS) with Rebif® (interferon beta-1a), a disease-modifying drug used to treat relapsing forms of MS, which is registered in more than 80 countries worldwide. In addition to Rebif®, the Company also offers a second therapy within its US portfolio of MS therapies: Novantrone® (mitoxantrone for injection concentrate) for worsening forms of MS. Full prescribing information for these products can be obtained by contacting the Company or visiting its website. Additional therapeutic options are currently under development at Merck Serono, including oral cladribine, currently in Phase III and potentially the first oral therapy for MS, as well as several products in early stage development. Merck Serono also is taking a leading role in developing an understanding of the role of genetics in MS.

About multiple sclerosis

Multiple sclerosis (MS) is a chronic, inflammatory condition of the nervous system and is the most common, non-traumatic, neurological disease in young adults. The World Health Organization estimates that up to 2.5 million people suffer from 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, a global pharmaceutical and chemical group. Headquartered in Geneva, Switzerland, Merck Serono discovers, develops, manufactures and markets innovative small molecules and biopharmaceuticals to help patients with unmet medical needs. Its North American business operates in the United States and Canada as EMD Serono.

Merck Serono has leading brands serving patients with cancer (Erbitux®), multiple sclerosis (Rebif®), infertility (Gonal-f®), endocrine and cardiometabolic disorders (Glucophage®, Concor®, Saizen®, Serostim®), as well as psoriasis (Raptiva®).
With an annual R&D investment of around € 1bn, 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 EUR 7.1 billion in 2007, a history that began in 1668, and a future shaped by 31,681 employees in 60 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.

For more information, please visit www.merckserono.net or www.merck.de

Teva Pharmaceutical's Altered Peptide Ligand Copaxone Boasts the Greatest Patient Share Among First- and Second-Line Therapies for the Treatment of Mu

WALTHAM, Mass., March 11 /PRNewswire/ -- Decision Resources, one of the world's leading research and advisory firms focusing on pharmaceutical and healthcare issues, finds that Teva Pharmaceutical's Copaxone has the greatest patient share among first- and second-line therapies, and falls short of Merck Serono/Pfizer's Rebif (by 0.2 percent) in third-line treatment. However, in all three lines of therapy, the interferon-beta drug class (Biogen Idec's Avonex, Rebif, and Berlex's Betaseron) outpaces the altered peptide ligand drug class (consisting only of Copaxone) in patient share. Competition between the two drug classes is fiercest in first-line therapy.

"The low volume of patient share attributed to Avonex or Rebif compared with Copaxone in first- and second-line treatment illustrates a significant delay on the part of physicians and/or patients to engage in an interferon- beta therapy within a year of a patient's initial diagnosis for multiple sclerosis," said Madhuri Borde, analyst at Decision Resources. "However, the magnitudes of Rebif's first- and second-line patient shares suggest that some physicians are treating the disease more aggressively than might be expected, as this high-dose, high-frequency agent reaches patient shares close to and surpassing Avonex in first- and second-line treatment, respectively."

According to the new report entitled Treatment Algorithms in Multiple Sclerosis, neurologists note that Copaxone's better short-term and long-term side-effect/safety profile, together with its lower rate of induction of neutralizing antibodies, are critical reasons for choosing Copaxone instead of Avonex, Rebif and Betaseron. Although Copaxone is administered daily, 23-28 percent of neurologists we surveyed indicate that a key reason to prescribe the drug over any of the interferon-beta therapies is the drug's ability to foster greater patient compliance, an attribute that is closely tied to the Copaxone's lower incidence of flulike side effects.

About Treatment Algorithm Insight Series
Decision Resources combines in-depth primary research with the most extensive claims-based longitudinal patient-level data from PharMetrics(R) to provide exceptional insight into physicians' prescribing trends and the factors that drive therapy product choice, from diagnosis through multiple courses of treatment, for a specific disease.

For each disease examined, Decision Resources' Treatment Algorithm Insight Series provide the following:

-- Summary of U.S. medical practice based on interviews with leading experts in the field. -- Qualitative diagnosis/referral/treatment algorithm for the United States. -- Drug usage by lines of therapy (1st, 2nd, 3rd line). -- Discussion of key freeform combinations by lines of therapy. -- Product share (class and specific compound level) within each line of therapy (1st, 2nd, 3rd line). -- Progression of therapy from key 1st line products. -- Pathway to key therapies from previous therapies. -- Qualitative analysis of two-year forecast incorporating upcoming launches, changes in reimbursement, etc.

About Decision Resources
Decision Resources, Inc., (http://www.decisionresources.com/) is a world leader in healthcare market research publications, advisory services, and consulting designed to help clients shape strategy, allocate resources, and master their chosen markets.
All company, brand, or product names contained in this document may be trademarks or registered trademarks of their respective holders.

For more information, contact: Elizabeth Marshall Decision Resources, Inc. 781-296-2563 emarshall@dresources.com
Decision Resources

Interferon Beta-1a and Glatiramer Acetate in Relapsing-Remitting Multiple Sclerosis: Presented at ECTRIMS

By Chris Berrie

PRAGUE, CZECH REPUBLIC -- October 16, 2007 -- Interferon beta-1a (IFNbeta-1a) has no significant efficacy benefits or safety issues over the polypeptide glatiramer acetate for patients with relapsing-remitting multiple sclerosis (RRMS), according to results from a multicentre, randomised, comparative, assessor-blinded, open-label trial.

Principal investigator Dan D. Mikol, MD, PhD, Associate Professor of Neurology, Department of Neurology, University of Michigan, Michigan, United States, presented the findings here on October 14 at the 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

This was the first head-to-head study of IFNbeta-1a and glatiramer acetate.

"The planned sample size was 736 patients, and included in the expectations was that there would be an 80% power to detect a 30% difference between these two agents in the primary outcome, which was time to first relapse."

Dr. Mikol and colleagues enrolled 764 patients aged 18 to 60 years and diagnosed with relapsing-remitting MS by McDonald criteria, had experienced one or more attacks within the prior 12 months, and were clinically stable or had improving neurological state in the prior 4 weeks. They also had magnetic resonance imaging (MRI) evidence of brain lesions and an expanded disability status scale (EDSS) of 0 to 5.5.

Following prestudy evaluation, 386 patients were randomised to 44 mcg of subcutaneous IFNbeta-1a three times weekly and 378 patients to 20 mg of subcutaneous glatiramer acetate once daily, both for 96 weeks.

Key baseline clinical characteristics in the two treatment groups were similar for time since first relapse (5.93 years, 6.55 years, respectively), number of T1 Gd-enhancing lesions (1.47, 1.65), T1 Gd-enhanced lesion volume (254.81, 241.99 mm3), and T2 lesion volume (7915.61, 7560.38 mm3).

However, 60% of patients in the interferon arm had more than one relapse in the previous 24 months compared with 71% in the glatiramer acetate arm, Dr. Mikol noted.

The primary endpoint was time to first relapse; the predefined secondary endpoints were mean number of T2 active (new or enlarging) lesions per patient per scan, and mean number of T1 Gd-enhancing lesions per patient per scan.

Tertiary endpoints were: mean number of combined unique active (CUA) lesions per patient per scan, and proportion of scans per patient with CUA lesions; clinical assessment of relapse rate, and proportion of patients free of relapses.

For the primary, secondary and some of the tertiary analyses, results were also stratified by prespecified subgroups.

At 96 weeks, the researchers found no significant differences between the IFNbeta-1a and glatiramer acetate treatment arms in terms of the primary outcome (hazard ratio [HR], 0.943; 95% confidence interval [CI], 0.74-1.21; P =.643). Dr. Mikol noted that these two patient groups experienced 45% fewer relapses than expected.

Due to this slow relapse rate, the researchers included a series of prespecified subgroup analyses relating to baseline T1 Gd-enhancing lesions (0 vs >=1), relapses 2 years prior to baseline (1 vs >=2), geographic region (non-Russia vs Russia), EDSS at baseline (<=median 2.0 vs >median 2.0), baseline T2 lesion volume (<=median 3707.5 vs >median 3707.5 mm3), and MS therapy in the prior 6 months (e.g. steroids; no vs yes).

The only subgroup where the researchers found a significant difference at the 96-week evaluation was EDSS at baseline in favor of IFNbeta-1a (n = 207) over glatiramer acetate (n = 211) in the group with EDSS scores below the median (HR, 0.648; 95% CI, 0.45-0.94; P =.022)

Although the researchers observed no significant difference between IFNbeta-1a and glatiramer in the number of T2 active lesions per patient per scan (0.7 vs 0.8; P =.178), within the prespecified subgroup analyses, they found significantly fewer T2 active lesions in patients treated with IFNbeta-1a both in the subgroup of patients with EDSS scores lower than the median (P =.035) and in non-Russian patients versus Russian patients (P =.043).

Significant benefit in favor of IFNbeta-1a versus glatiramer was seen for the secondary endpoint of T1 Gd-enhancing lesions (0.2 vs 0.4; P <.001) and for mean CUA lesions per patient per scan (0.9 vs 1.2; P =.010). Within the subgroups, IFNbeta-1a was better than glatiramer in patients who were non-Russian (P <.001), had baseline scores that were lower than the median on the EDSS (P <.001), with baseline lesion volume greater than the median (P <.001) and had prior MS therapy (P <.001).

For the tertiary endpoints of mean number of CUA lesions/patient/scan, and proportion of scans/patient with CUA lesions, these both indicated significant benefit for IFNbeta-1a, with mean treatment differences of -0.31 (P =.010) and -5.9 (P =.009), respectively.

Finally, for the annualized relapse rates for IFNbeta-1a and glatiramer acetate, there were no significant differences between these two treatment groups (0.30 vs 0.29; P =.828). "What is intriguing and certainly stands out in this trial is the fact that the relapse rate on-study was so low, 0.3, which is certainly much lower than was anticipated and is different to what has been seen in previous clinical trials," added Dr. Mikol.

Thus Dr. Mikol summarized, "There were no significant difference in primary endpoint of time to first relapse; the safety outcomes were consistent with the known profiles of both treatments; and there was significant difference in favor of IFNbeta-1a for T1 Gd-enhancing lesions and for some of the additional pre-specified subgroup analyses.

Funding for this study was provided by Merck Serono International S.A. and Pfizer Inc.


[Presentation title: The REGARD Trial: A Randomised Assessor-Blinded Trial Comparing Interferon Beta-1a and Glatiramer Acetate in Relapsing-Remitting Multiple Sclerosis. Abstract 119]

Interferon Beta-1a Offers A Near 3-fold Improvement In Injection Tolerability Compared With The Original Formulation - 2-Year Phase IIIb Data

Merck Serono, a division of Merck KGaA, announced today new results of a two year (96 week) Phase IIIb study in 260 patients which has shown that the new formulation of Rebif® (interferon beta-1a) offers a near three-fold improvement in injection tolerability for patients with relapsing remitting multiple sclerosis (RRMS). These results are compared with historical data for the previous formulation of Rebif® (30.8% versus 85.8%) (1).

These study results will be presented today at a satellite symposium and tomorrow at a poster session at the 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Prague, Czech Republic.

"Rebif is an established first-line disease modifying treatment for relapsing types of MS" said Professor Gavin Giovannoni from The Royal London Hospital. "Injection site reactions can lead to withdrawal from treatment. The reduction in these reactions with the new formulation should improve treatment benefit to patients."

Rebif® has a favourable benefit-to-risk profile (2) and has a proven efficacy and safety profile, which has been demonstrated consistently across numerous phase III clinical trials and clinical practice (1, 3-5). The new study results have also confirmed consistent efficacy of the new formulation of Rebif® compared with previous experience (1). At 96 weeks, 53.3% of patients remained relapse-free and overall the expanded disability status scale (EDSS) score remained stable throughout the study.

The new formulation of Rebif® was approved on August 10, 2007, by the European Commission and is due to be launched in the UK in early 2008. The new formulation of Rebif® is the first and only therapy for multiple sclerosis that is serum free, both from animal and human-derived components (HSA-free and FBS-free) and is the latest product development from Merck Serono. Other recent enhancements have included the launch of a new initiation pack designed to make starting Rebif® therapy easier and more convenient.

References

1. Panitch H, Goodin DS, Francis G, Chang P, Coyle PK, O'Connor P, et al. Randomized, comparative study of interferon beta-1a treatment regimens in MS: the EVIDENCE trial. Neurology 2002; 59: 1496-506.
2. Francis GS. Importance of benefit-to-risk assessment for disease-modifying drugs used to treat MS. J Neurol 2004; 251 (Suppl 5): v42-9.
3. Li D, Paty D, UBC MS/MRI Analysis Research Group, PRISMS Study Group. Magnetic resonance imaging results of the PRISMS trial: a randomized, double-blind, placebo controlled study of interferon-b1a in relapsing-remintting multiple sclerosis. Ann Neurol 1999; 46: 197-206
4. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcultaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet 1998; 352: 1498-504, Erratum inLancet 1999; 353; 678.
5. PRISMS Study Group, University of British Columbia MS/MRI Analysis Group. PRISMS-4: Long-term efficacy of interferon-β-1a in relapsing MS. Neurology 2001; 56: 1628-36.

About the Study

The study was a two-year (96 weeks) Phase IIIb, international, multicenter, single-arm, open-label study with historical controls, evaluating the safety and immunogenicity of the new formulation of Rebif® (interferon beta-1a) 44 micrograms (mcg) subcutaneously (sc) three times weekly (tiw) in 260 patients with relapsing forms of multiple sclerosis (MS).

No unexpected adverse events were reported with the new formulation of Rebif®. Safety outcomes were consistent with the known profile of Rebif®. The majority of adverse events were mild or moderate in severity. The most frequent side effect was flu-like symptoms (71.5%), which is typical of interferon therapy; most were mild in severity. Flu-like symptoms are transient. Prophylactic antipyretic treatment is recommended.

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. Interferon helps modulate the body's immune system and reduce inflammation.

Rebif®, which was approved in Europe in 1998 and in the US in 2002, is registered in more than 80 countries worldwide. Rebif® has been proven to delay the progression of disability, reduce the frequency of relapses and reduce MRI lesion activity compared to placebo*. Rebif® is not approved for treatment of chronic progressive MS. Rebif® is available in a 22 mcg and 44 mcg ready-to-use pre-filled syringe and a titration pack (8.8 mcg and 22mcg).

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 Merck Serono and Multiple Sclerosis

Merck Serono is a leader in multiple sclerosis (MS) with Rebif® (interferon beta-1a), a disease-modifying drug used to treat relapsing forms of MS, which is registered in more than 80 countries worldwide. In addition to Rebif®, the Company also offers a second therapy within its US portfolio of MS therapies: Novantrone® (mitoxantrone for injection concentrate). Product information can be obtained by contacting the Company or visiting its website. Additional therapeutic options are currently under development at Merck Serono, including cladribine, currently in Phase III, as well as several products in early stage development. Merck Serono also is taking a leading role in developing an understanding of the role of genetics in MS.

About Multiple Sclerosis

Multiple sclerosis (MS) is a chronic, inflammatory condition of the nervous system and is the most common, non-traumatic, neurological disease in young adults. The World Health Organization estimates that up to 2.5 million people suffer from 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, 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, metabolic and cardiometabolic disorders, as well as psoriasis. 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.

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.

-- http://www.merckserono.net
-- http://www.merck.de

New Formulation of Multiple Sclerosis Treatment Rebif Approved in European Union

New formulation of Rebif® designed to improve injection tolerability

GENEVA, Switzerland, August 30, 2007 – Merck Serono, a division of Merck KGaA, announced today that the European Commission has granted a marketing authorization for a new formulation of Rebif® (interferon beta-1a) for the treatment of relapsing multiple sclerosis (MS). The new formulation of Rebif® has been developed to increase treatment benefit by improving injection tolerability while targeting an improved immunogenicity profile. This new formulation originates from an innovative approach, using state-of-the-art technologies.

“The European approval of the new formulation of Rebif® is an important step in our efforts to continuously provide enhanced therapeutic solutions for patients with MS,” said Roberto Gradnik, Head of Merck Serono’s Operations for Europe. “We are pleased to bring this enhanced treatment option to patients throughout Europe.”

The European Commission decision applies to all 27 countries in the European Union1, as well as Iceland, Liechtenstein and Norway. Launches of the new formulation of Rebif® in the various countries of the European Union will start in September 2007. The new formulation of Rebif® will be available in the same strengths and pharmaceutical forms as currently registered, i.e. 8.8, 22 and 44 mcg, as a solution for injection in pre-filled syringes.

“The European approval of the new formulation of Rebif® is good news for patients with MS,” said Professor Per Soelberg Sørensen, Danish Multiple Sclerosis Research Center, Department of Neurology, Copenhagen University Hospital. “This new formulation will represent an improvement in the therapy of MS patients being treated with Rebif®.”

Rebif®, which was originally approved in Europe in 1998, has been proven effective on the following three key measures of treatment effectiveness: MRI lesion area and activity, relapse rates, and disability progression. The safety and efficacy of Rebif® are supported by a robust long-term clinical development program including comparative studies and 13 years of patient experience from around the world.

The new formulation of Rebif® is the latest of many product developments from Merck Serono to continuously enhance the convenience and tolerability of Rebif®. Other enhancements have included the Rebiject II auto-injector to facilitate injections; a 29 gauge-5 bevel needle pre-filled syringe, the thinnest needle in a ready-to-use pre-filled syringe for the treatment of MS; and a titration pack designed to make starting on Rebif® therapy easier and more convenient.

1 Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, The Republic of Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, United Kingdom


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. Interferon helps modulate the body’s immune system, fight disease and reduce inflammation.

Rebif®, which was approved in Europe in 1998 and in the US in 2002, is registered in more than 80 countries worldwide. Rebif® has been proven to delay the progression of disability, reduce the frequency of relapses and reduce MRI lesion activity and area[1]. Rebif® is not approved for treatment of chronic progressive MS. Rebif® is available in a 22 mcg and 44 mcg ready-to-use pre-filled syringe and a titration pack (8.8 mcg).

Most commonly reported side effects are injection site disorders, flu-like symptoms, 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.


About Merck Serono and multiple sclerosis

Merck Serono is a leader in multiple sclerosis (MS) with Rebif® (interferon beta-1a), a disease-modifying drug used to treat relapsing forms of MS, which is registered in more than 80 countries worldwide. In addition to Rebif®, the Company also offers a second therapy within its US portfolio of MS therapies: Novantrone® (mitoxantrone for injection concentrate) for worsening forms of MS. Full prescribing information for these products can be obtained by contacting the Company or visiting its website. Additional therapeutic options are currently under development at Merck Serono, including oral cladribine, currently in Phase III and potentially the first oral therapy for MS, as well as several products in early stage development. Merck Serono also is taking a leading role in developing an understanding of the role of genetics in MS.


About multiple sclerosis

Multiple sclerosis (MS) is a chronic, inflammatory condition of the nervous system and is the most common, non-traumatic, neurological disease in young adults. The World Health Organization estimates that up to 2.5 million people suffer from 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.


###

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 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.


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.


For more information, please visit www.merckserono.net or www.merck.de

New Rebif (Interferon Beta-1a) Initiation Pack For Patients With Relapsing Remitting Multiple Sclerosis

Merck Serono has announced the launch of a new Rebif initiation pack for patients with relapsing remitting multiple sclerosis (RRMS). It is important when patients begin interferon beta therapy that the dose is gradually increased over a four week period as this helps minimise possible side effects. The new pack consists of 12 pre-filled syringes at the recommended staged dosing to enable easy titration and minimal wastage as a patient begins therapy.

Gradual dose titration when starting treatment may minimise side effects such as flu-like symptoms that can occur with interferon beta therapy1. Flu-like symptoms occur in 40% of patients2 and are typically present within the first few days of commencing treatment. Most patients will also experience injection site reactions, predominantly mild inflammation. Whilst both side effects are in the majority of cases reversible and may alleviate over time, they have been shown to decrease the potential for concordance. In a retrospective study among 281 patients, injection site reactions and flu-like symptoms were cited among the top three reasons for interrupting interferon beta therapy3.

Debbie Quinn, MS Specialist Nurse at Northamptonshire Teaching PCT commented on the new initiation pack. "It is really important when you start a patient on interferon beta therapy that you manage their expectations in terms of the likely side effects, building up to the maintenance dose over an extended period of time limits these symptoms. Delivering the syringes in an easy to use pack simplifies the titration process for patients and is reassuring for them."

Starting treatment for MS can be a stressful experience for patients and their carers and it has been shown that patients who do have a more positive experience during the initial stages of therapy will be more likely to adhere to treatment in the long term. Long term follow up has demonstrated the benefits of interferon beta over a 7-8 year period and supports the importance of initial concordance4, 5.

-- The Rebif initiation pack contains 12 pre-filled syringes (six with 8.8μg and six with 22μg)

-- Rebif should be taken three times a week at approximately the same time each day and the injections should be at least 48 hrs apart

-- A Rebif initiation pack covering a four week course of treatment costs £586.196

-- The titration schedule consists of 2 weeks' treatment at 8.8μg, followed by a further 2 weeks at 22μg, building up to a maintenance dose of 44μg at week 5 and is based on the schedule used during the landmark trials7

About Merck Serono

Merck KGaA of Darmstadt, Germany, 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 about 35,000 employees (including Merck Serono) in 56 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 a 73% interest and free shareholders own the remaining 27%. The former U.S. subsidiary, Merck & Co., has been completely independent of the Merck Group since 1917.

http://www.serono.com

References

1. Wroe SJ. J Int Med Res. 2005;33:309-18
2. Rebif SPC
3. Tremlett and Oger. Neurology 2003;61:551-554
4. Kappos L et al. Neurology 2006;67:944-953
5. World Health Organisation Report 2003; Please click here.
6. Rebif Initiation Pack Prescribing Information, May 2007
7. PRISMS Study Group. Lancet 1998;352:1498-1504

Multiple Sclerosis Patients Benefit From High Dose, High Frequency Interferon Beta: Presented at ENS

By Thomas S. May

RHODES, GREECE -- June 20, 2007 -- Patients with relapsing-remitting multiple sclerosis (MS), the most common form of MS, derive greater benefit from interferon beta-1a when it is administered subcutaneously at a 44 mcg dose three times weekly than when it is given as a 30 mcg intramuscular injection once a week. This finding was announced here at the annual Meeting of the European Neurological Society (ENS), based on interim results of the Evidence of Interferon Dose-response: European North American Comparative Efficacy (EVIDENCE) trial.

"The EVIDENCE study was a head-to-head comparison of two important Interferon beta-1a products for MS, and it determined that there is a significant early and sustained benefit, both for clinical and MRI outcomes, from using a higher frequency and higher dose of interferon," said lead investigator Anthony Traboulsee, MD, clinical assistant professor, department of neurology, University of British Columbia Hospital, Vancouver, British Columbia, Canada. "The data presented here is an extension of the MRI results, specifically looking at T 2 burden of disease," Dr. Traboulsee added. "T 2 burden of disease represents the chronic accumulation of new and old MS lesions, and it was the first MRI measure approved by regulatory agencies for clinical trials."

The EVIDENCE trial compared T 2 burden of disease (BOD) between two groups of patients: subjects in one group (n=279) were given 44 mcg of Interferon beta-1a (IFN beta-1a) subcutaneously (sc) three times a week, while subjects in the other group (n=274) received 30 mcg of IFN beta-1a intramuscularly (im) once a week. The primary endpoint was percentage change in BOD over 48 weeks, and all patients with evaluable T 2 MRI scans at baseline and at week 48 were included in the analysis.

The investigators found that median percentage reduction in BOD from baseline to week 48 was greater in the 44 mcg sc treatment group than in the 30 mcg im group (–6.7 % [range –65, 431] versus –0.6 % [range –61, 197]). Median absolute reduction in BOD was also greater in the 44 mcg sc group (–189.5 mm3; range –23454, 56869) than the 30 mcg im group (–19.0 mm3; range –13337, 10161).

Based on these data, the investigators concluded that patients treated with 44 mcg of subcutaneous Interferon beta-1a three times per week had significantly greater reductions in T 2 burden of disease than those receiving 30 mcg intramuscular injections once a week. According to Dr. Traboulsee, "this study demonstrates the benefits of high dose, high frequency dosing on suppression T 2 BOD, and is consistent with previous results showing similar benefits on relapse rates."

Financial support for the EVIDENCE trial was provided by Merck Serono, the makers of Interferon beta-1a.


[Presentation title: Reduction in T2 Burden of Disease Is Greater With Interferon beta-1 a 44 mcg Administered Subcutaneously Three Times Weekly Than 30 mcg Administered Intramuscularly Once Weekly: 1-Year Analysis of the EVIDENCE Study Data. Abstract P539]