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

DARMSTADT, Germany, October 26, 2017/PRNewswire/ - Merck, a leading science and technology company, today announced positive benefit-risk data for its recently approved multiple sclerosis (MS) therapy, MAVENCLAD® (Cladribine Tablets), at MSParis2017 (7th 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 MAVENCLAD® 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 MAVENCLAD® 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 MAVENCLAD® (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 MAVENCLAD® compared with 0.148 (95% CI 0.048-0.460) for placebo. The incidence of malignancies in the MAVENCLAD® arm was shown to be constant and did not increase over time, in contrast to placebo.[2]

"MAVENCLAD® shows 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 MAVENCLAD® on the adaptive response in MS, these results point to its selective mode of action which may contribute to its unique posology."

Additional MAVENCLAD® 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 MAVENCLAD® 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 MAVENCLAD® 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 MAVENCLAD® at Merck. "These important data provide further insights on how MAVENCLAD® targets 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 MAVENCLAD® database provides key data in support of safety, efficacy and mode of action to physicians and patients considering this therapy."

In addition to MAVENCLAD® presentations, Merck also presented data on its well-established relapsing MS product, Rebif® (interferon beta-1a), focused on predicting long-term outcomes. A post-hoc analysis of patient data from the PRISMS study investigated the association between the MAGNIMS (Magnetic Resonance Imaging in MS) score at Year 1 and long-term clinical disease activity free (CDAF) status and disability progression. The score, when calculated in Year 1 of treatment with Rebif®, was shown to accurately predict the risk of a CDA (clinical disease activity) event or disability progression in patients with MS. [6] Further data on NEDA and real-world evidence will be presented.

For up-to-date information and activities during MSParis2017, follow Merck on Twitter (@MerckHealthcare) or #AddressMS or visit MerckNeurology.com (intended for Healthcare Professionals).

About MAVENCLAD®

In August 2017, the European Commission (EC) granted marketing authorization for MAVENCLAD® (cladribine tablets) for the treatment of relapsing forms of multiple sclerosis (RMS) in the 28 countries of the European Union (EU) in addition to Norway, Liechtenstein and Iceland. MAVENCLAD® is a short-course oral therapy that selectively and periodically targets lymphocytes thought to be integral to the pathological process of relapsing MS (RMS). MAVENCLAD® is currently under clinical investigation and not yet approved for the treatment for any use in the United States or Canada.

The clinical development program for MAVENCLAD® 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 MAVENCLAD® 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 MAVENCLAD® 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 MAVENCLAD® 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 MAVENCLAD® 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 MAVENCLAD®

The clinical development program of Cladribine 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.

EU Indication

MAVENCLAD® (cladribine tablets) is indicated for the treatment of adult patients with highly active relapsing multiple sclerosis (RMS) as defined by clinical or imaging features.

Important EU Safety Information

Contraindications:

MAVENCLAD® is contraindicated in patients with hypersensitivity to the active substance, human immunodeficiency virus (HIV), active chronic infection (tuberculosis or hepatitis), active malignancy, moderate to severe renal impairment (creatinine clearance

Special warnings and precautions for use:

The most clinically relevant adverse reactions were lymphopenia and herpes zoster.

Haematology Decreases in neutrophil count, red blood cell count, haematocrit, haemoglobin or platelet count compared to baseline values have been observed in clinical studies, although these parameters usually remain within normal limits.

Additive haematological adverse reactions may be expected if cladribine is administered prior to or concomitantly with other substances that affect the haematological profile

Lymphocyte counts must be determined:

- before initiating MAVENCLAD® in year 1,

- before initiating MAVENCLAD® in year 2,

- 2 and 6 months after start of treatment in each treatment year. If the lymphocyte count is below 500 cells/mm3, it should be actively monitored until values increase again.

Infections

Cladribine can reduce the body's immune defence and may increase the likelihood of infections. HIV infection, active tuberculosis and active hepatitis must be excluded before initiation of cladribine.

The incidence of herpes zoster was increased in patients on cladribine. If lymphocyte counts drop below 200 cells/mm3, anti-herpes prophylaxis according to local standard practice should be considered during the time of grade 4 lymphopenia. Interruption or delay of MAVENCLAD® may be considered until proper resolution of the infection.

Cases of progressive multifocal leukoencephalopathy (PML) have been reported for parenteral cladribine in patients treated for hairy cell leukaemia with a different treatment regimen.

In the clinical study data base of cladribine in MS (1,976 patients, 8,650 patient years) no case of PML has been reported. However, a baseline magnetic resonance imaging (MRI) should be performed before initiating MAVENCLAD® (usually within 3 months).

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. Interferon ß is thought to help reduce inflammation. The exact mechanism is unknown.

Rebif®, which was approved in Europe in 1998 and in the US in 2002, is registered in more than 90 countries worldwide. Rebif® has been proven to delay the progression of disability, reduce the frequency of relapses and reduce MRI lesion activity and area+.

Rebif® can be administrated with the RebiSmart® electronic auto-injection device (not approved in the US), or with the RebiDose® single-use disposable pen, or the manual multidose injection pen RebiSlide™. Rebif® can also be administered with the autoinjector Rebiject II® or by manual injection using ready-to-use pre-filled syringes. These injection devices are not approved in all countries.

In January 2012, the European commission approved the extension of the indication of Rebif® in early multiple sclerosis. The extension of the indication of Rebif® has not been submitted in the United States.

Rebif® should be used with caution in patients with a history of depression, liver disease, thyroid abnormalities 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.

Rebif® (interferon beta-1a) is approved in the United States for relapsing forms of MS.  RebiSmart®, an electronic device for self-injection of Rebif®, is also not approved in the United States. Cladribine Tablets is an investigational product and not approved for use in any indication in the United States.

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

About Multiple Sclerosis

Multiple sclerosis (MS) is a chronic, inflammatory condition of the central nervous system and is the most common, non-traumatic, disabling neurological disease in young adults. It is estimated that approximately 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.

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About Merck

Merck 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 generated sales of € 15.0 billion in 66 countries.

Founded in 1668, Merck is the world's oldest pharmaceutical and chemical company. The founding family remains the majority owner of the publicly listed corporate group. Merck 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.

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

6. Sormani MP. ECTRIMS ACTRIMS 2017 [Abstract No. P770] Disease Activity as Assessed by the MAGNIMS Score Predicts Long-Term Clinical Disease Activity Free Status and Disability Progression in Patients Treated with Subcutaneous Interferon Beta-1a

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Source: Merck

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