New Data at ECTRIMS Highlight Positive Benefit-Risk Profile of Cladribine Tablets in Relapsing Multiple Sclerosis

• Data suggest Cladribine Tablets may significantly increase proportion of patients exhibiting no evidence of disease activity versus placebo
• Analysis of 10,000 patient years of safety data provides further characterization of safety profile
• Further data suggest the relative selectivity of Cladribine Tablets for the adaptive immune system

MISSISSAUGA, ON, Oct. 27, 2017 /CNW/ - Merck KGaA, Darmstadt, Germany, a leading science and technology company, operating as EMD Serono in North America, announced positive benefit-risk data for its recently approved (by the European Medicines Agency) multiple sclerosis (MS) therapy, cladribine tablets, at MSParis2017 (7^th Joint ECTRIMS-ACTRIMS Meeting) in Paris, France. A post hoc analysis in high disease activity subgroups from the 2-year CLARITY study has confirmed that cladribine tablets significantly increased the proportion of patients with no evidence of disease activity (NEDA) compared with placebo (43.7% vs 9.0%)¹. This analysis is consistent with results seen in the broader CLARITY patient population, and further supports the efficacy of cladribine tablets for the treatment of relapsing MS.

Late-breaking safety analysis including patients with up to 8-years follow-up from the (3.5 mg/kg) cohorts of CLARITY, CLARITY Extension, ORACLE-MS studies and the PREMIERE registry also confirmed that despite the imbalance of malignancy cases in placebo-controlled trials, the overall incidence of malignancy in patients treated with cladribine tablets^® (3.5 mg/kg) was not significantly different to the incidence in a matched population based on GLOBOCAN (0.97, 95% CI 0.44-1.85). Within the pooled safety analyses the incidence per 100 patient-years of malignancy was 0.293 (95% CI 0.158-0.544) for cladribine tablets compared with 0.148 (95% CI 0.048-0.460) for placebo. The incidence of malignancies in the cladribine tablets arm was shown to be constant and did not increase over time, in contrast to placebo.²

"Cladribine tablets show a positive benefit-risk profile from the safety and efficacy analyses," said Professor Olaf Stuve, Department of Neurology and Neurotherapeutics at UT Southwestern Medical Center in Dallas. "The data presented across several posters show that the effect of the drug on lymphocytes is moderate, with a highly nuanced effect on different lymphocyte subsets. Whilst we need to further understand the qualitative effect of cladribine tablets on the adaptive response in MS, these results point to its selective mode of action which may contribute to its unique posology."

Additional cladribine tablets data presented at MSParis2017 showed:

• A detailed safety analysis from CLARITY, CLARITY Extension, ORACLE-MS studies and the PREMIERE registry was consistent with findings of previous integrated safety analyses and showed that during periods of severe (Grade 3/4) lymphopenia vs outside these periods the incidence of infection was increased. However, all but two of the infections were mild to moderate and non-serious, and the types of infections were generally similar during these periods.³
• An analysis of T lymphocyte (T cells) subpopulations from the ORACLE-MS study provided a detailed assessment of the changes that occur in the adaptive immune system following cladribine tablets treatment. Specifically, levels of CD4+ T cells were shown to be moderately and selectively reduced by up to 63% from baseline, and the greatest reductions in absolute cell numbers occurred at week 13 post-treatment for effector memory cells (54% reduction) and week 24 for central memory cells (63% reduction), with similar or slightly increased levels of these CD4+ cell subtypes at week 48.⁴
• An analysis of neutrophils and monocytes from patients in CLARITY or CLARITY Extension, including time spent in the PREMIERE registry, demonstrated that the effect of cladribine tablets treatment on these innate immune cell subsets was relatively minor, compared to patients treated with placebo.⁵

"The data demonstrated a reduction of the B and T cells, thought to be important in the pathogenesis of MS, followed by the gradual reconstitution of adaptive immune function, with only a relatively small effect on innate immune function throughout," said Dr. Andrew Galazka, Senior Vice President and Global Program Leader for cladribine tabletsat Merck KGaA Darmstadt, Germany. "These important data provide further insights on how cladribine tablets target the immune system in patients with MS. With a clinical program comprising over 10,000 patient-years in MS, unprecedented at time of launch, the cladribine tablets database provides key data in support of safety, efficacy and mode of action to physicians and patients considering this therapy."

About Cladribine Tablets
Cladribine tablets are not yet approved for the treatment for any use in the United States or Canada.

The clinical development program for cladribine tablets includes:

• The CLARITY (Cladribine Tablets Treating MS Orally) study: a two-year Phase III placebo-controlled study designed to evaluate the efficacy and safety of cladribine tablets as a monotherapy in patients with RRMS.
• The CLARITY extension study: a two-year Phase III placebo-controlled study following on from the CLARITY study, designed to evaluate the safety and efficacy of cladribine tablets over an extended administration for four years.
• The ORACLE MS (Oral Cladribine in Early MS) study: a two-year Phase III placebo-controlled study 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).
• The ONWARD (Oral Cladribine Added ON To Interferon beta-1a in Patients With Active Relapsing Disease) study: a Phase II placebo-controlled study 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.
• PREMIERE (Prospective Observational Long-term Safety Registry of Multiple Sclerosis Patients Who Have Participated in Cladribine Clinical Studies) study: interim long-term follow-up data from the prospective registry, PREMIERE, to evaluate the safety and efficacy of cladribine tablets.

The clinical development program of cladribine tablets in MS comprises more than 10,000 patient years of data with over 2,700 patients included in the clinical trial program, and more than 10 years of observation in some patients.

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 2.3 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 KGaA, Darmstadt, Germany
Merck KGaA, Darmstadt, Germany is a leading science and technology company in healthcare, life science and performance materials. Around 50,000 employees work to further develop technologies that improve and enhance life – from biopharmaceutical therapies to treat cancer or multiple sclerosis, cutting-edge systems for scientific research and production, to liquid crystals for smartphones and LCD televisions. In 2016, Merck KGaA, Darmstadt, Germany generated sales of € 15.0 billion in 66 countries.

Founded in 1668, Merck KGaA, Darmstadt, Germany is the world's oldest pharmaceutical and chemical company. The founding family remains the majority owner of the publicly listed corporate group. Merck KGaA, Darmstadt, Germany holds the global rights to the Merck name and brand. The only exceptions are the United States and Canada, where the company operates as EMD Serono, MilliporeSigma and EMD Performance Materials.

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¹ Giovannoni G. ECTRIMS ACTRIMS 2017 [Abstract No. P1143] Proportions of Patients with Highly Active RMS Achieving No Evidence of Disease Activity (NEDA) in Response to Cladribine Tablets in CLARITY
² Galazka A. ECTRIMS ACTRIMS 2017 [Abstract No. P1878] An Analysis of Malignancy Risk in the Clinical Development Programme of Cladribine Tablets in Patients With Relapsing Multiple Sclerosis (RMS).
³ Cook S. ECTRIMS ACTRIMS 2017 [Abstract No. P1142] Infections During Periods of Grade 3 or 4 Lymphopenia in Patients Taking Cladribine Tablets 3.5 mg/kg: Data from an Integrated Safety Analysis
⁴ Stuve O. ECTRIMS ACTRIMS 2017 [Abstract No. P667] Effects of Cladribine Tablets on CD4+ T Cell Subsets in the ORACLE-MS Study: Results from an Analysis of Lymphocyte Surface Markers
⁵ Soelberg-Sorensen P. ECTRIMS ACTRIMS 2017 [Abstract No. P1141] Innate Immune Cell Counts in Patients With Relapsing-Remitting Multiple Sclerosis (RRMS) Treated With Clabribine Tablets 3.5mg/kg in CLARITY and CLARITY Extension

SOURCE EMD Serono, Canada

Shikha Virdi, 416-561-6276