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

Mitoxantrone as Induction Followed by Interferon Beta-1b Versus Interferon Beta-1b: Presented at ECTRIMS

By Chris Berrie

PRAGUE, CZECH REPUBLIC -- October 18, 2007 -- Mitoxantrone induction in combination with methylprednisone prior to interferon beta (IFNbeta) treatment in patients with aggressive relapsing-remitting multiple sclerosis (RRMS) reduces the risk of developing fixed disability and increases relapse-free periods when compared with IFNbeta prior to methylprednisone.

These findings are from a multicentre, randomised, prospective, controlled, study presented here on October 13 at the 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

The study's principal investigator, Gilles Edan, MD, and Professor of Neurology, Istitut des Neurosciences Cliniques de Rennes, Rennes, France, presented the findings on behalf of the French-Italian Mitoxantrone-Interferon-beta-1b Study Group.

Although IFNbeta-1b can reduce relapse frequencies and new lesions on magnetic resonance imaging (MRI), the magnitude of these effects remains small, providing around 30% benefit. Furthermore, in the longer term of 3 to5 years, these beneficial effects can be lost, particularly for the 35% of patients with RRMS who develop neutralizing antibodies while under IFNbeta treatment.

"Mitoxantrone has a strong, rapid and sustained impact on the inflammatory processes, but its potential toxicity limits the duration of its prescription," Dr. Edan said. Therefore, Dr. Edan and colleagues conducted a study to determine whether the use of mitoxantrone induction prior to IFNbeta-1b therapy can provide further clinical benefits.

The main inclusion criteria were age 18 to 45 years, confirmed diagnosis of MS using Poser criteria and as defined by MRI. For disease status of aggressive RRMS, there was the requirement for two or more relapses in the preceding 12 months, at least one Gd+ lesion on MRI, and an expanded disability status scale (EDSS) score of 2.5 to 5.5 (significant disability).

Exclusion criteria were pregnancy and breast feeding, nonuse of efficient contraception, previous global immunosuppression, use of other specific agents, and associated disease.

The primary endpoint was time to 1 or greater-point increase on the EDSS during the 3 years of the study. There were also secondary endpoints of relapse frequency, relapse-free patients, time to first relapse after inclusion, and safety.

Of 123 patients randomized in the study, 109 were treated and analyzed, constituting the intention-to-treat population. The study design provided randomization to one of two treatment arms after 12 months of followup.

The 55 patients in the first arm started at baseline with mitoxantrone 20 mg/month plus methylprednisone 1 g/month for the first 6 months of treatment. They then had a 3-month break from treatment (months 7-9), followed by interferon 250 mcg SC every other day from months 10 to 36.

The 54 patients in the second arm started at month 0 with methylprednisone 1 g/month in combination with IFNbeta-1b. As with group 1, methylprednisone was stopped after 6 months, while IFNbeta-1b continued for the full 36 months of the study.

Patients in the two groups had similar mean ages (33.2 vs 32.2 years, respectively) and gender distribution (male 34.6% vs 33.3%, respectively).

At baseline, the disease characteristics across treatment groups 1 and 2, respectively, were not significantly different, including duration of MS (6.6 vs 5.1 years), time from last relapse to M0 (3 vs 3 months), annual relapse rate (2.65 vs 2.83) and EDSS score (4.1 vs 3.8).

The primary endpoint was time for a 1-point increase in EDSS (acquisition of fixed disability) within the 36 months of the trial. "This time was clearly longer in the group of patients using mitoxantrone and interferon beta," Dr. Edan said, and thus, there was mitoxantrone group obtained significant benefit compared with group 2 (P =.008). As only five of the total 19 patients who acquired this fixed disability by month 36 were in group 1, this represented a significant 65% reduction in clinical worsening in the mitoxantrone-pretreated patients (P <.024).

When variations in EDSS score were analyzed from baseline to the last recorded scores during the treatment period, the mitoxantrone group saw a small but significant decrease in mean EDSS score from 4.1 to 3.6 (P <.006), whereas in the absence of mitoxantrone there was no significant change (from 3.8 to 3.7).

For the annual relapse rate under study treatment, there was again a large, 61.5%, significant benefit with the use of mitoxantrone (annual relapse rate: group 1, 0.44; group 2, 1.14; P <.003). When further analyzed as annual relapse rate during the IFNbeta-1b alone treatment, benefits for mitoxantrone were again seen compared with treatment without mitoxantrone (group 1, 0.50; group 2, 1.14; P <.007).

Patients in the mitoxantrone group also had significantly improved time to first relapse from baseline (P <.002). Similarly, there was a significant increase in the percentage of relapse-free patients in group 1 over group 2 (53% vs 26%; P =.01).

Finally, the researchers also tested mitoxantrone benefits at the patient disability levels. Although not a pre-planned analysis, this was achieved in a subgroup analysis of EDSS at baseline, divided according to an EDSS of 4.0, and demonstrated a significant benefit for both the use of mitoxantrone and an EDSS score less than 4 at baseline (P <.02).

The safety analysis showed significantly more adverse events in the mitoxantrone group compared with the group not treated with mitoxantrone. These comprised upper respiratory tract infection (45.4% vs 24.1%, respectively; P <.02), leucopenia (36.4% vs 16.7%, respectively; P <.02) and nausea (21.8% vs 7.4%, respectively; P <.02).

"However, these [adverse effects] are exactly what you might expect from adding mitoxantrone to this treatment, and there was no serious adverse effect in this study," added Dr. Edan.

Thus, he concluded, this induction treatment of mitoxantrone combined with methylprednisone provides clinical benefits for patients with aggressive RRMS that include decreases in both acquisition of fixed disability and relapse rates.


[Presentation title: Comparison of Two Therapeutic Strategies in Aggressive Relapsing-Remitting MS: Mitoxantrone as Induction for 6 Months Followed by Interferon Beta-1b Versus Interferon Beta-1b. A 3-Year Randomised Trial. Abstract 74]