Data Provide Further Insight Into the Consistent Efficacy Benefits of Mavenclad in Relapsing MS

DARMSTADT, Germany, June 18, 2018 /PRNewswire/ --

Not intended for U.S or U.K based media

• Post-hoc analysis of CLARITY study suggests consistent clinical and Magnetic Resonance Imaging efficacy in subgroups of both younger and older adults treated with MAVENCLAD (cladribine tablets) 
• Using an EMA-recommended methodology to compare benefit-risk profiles of MS treatments, Mavenclad had the highest overall weighted preference value in patients with highly active MS 

Merck, a leading science and technology company, today announced the presentation of new efficacy and benefit-risk assessment data for MAVENCLAD^® (Cladribine Tablets) at the 4^th Congress of the European Academy of Neurology (EAN), in Lisbon, Portugal. Results of a retrospective analysis of the Phase III CLARITY study showed benefits in patients with relapsing remitting MS (RRMS) aged ≤50 and >50 years and treated with MAVENCLAD^®, with improvements observed in both relapse rate and Magnetic Resonance Imaging (MRI) outcomes when compared with placebo.

The aim of the post-hoc analysis of the Phase III CLARITY study was to investigate whether the beneficial clinical and MRI effects of MAVENCLAD^® are consistent in both older and younger adult patients. The results highlight the improvements observed in annualized relapse rate (ARR) and MRI outcomes versus placebo in both subgroups of RRMS patients, ≤50 and >50 years; MAVENCLAD^® reduced relapse risk compared to placebo by 59% and 52%, respectively. In placebo treated patients, there were higher mean numbers of new T1 Gd+ and active T2 lesions for those aged ≤50 years compared to patients aged >50. Despite this, MAVENCLAD^® treatment demonstrated significant effects on MRI measures in both age groups (P<0.0001). These data have the potential to differentiate the efficacy of MAVENCLAD^® from that of other high efficacy disease-modifying drugs (DMDs) in the treatment of older patients with MS.

"These data have provided further evidence, which confirms Mavenclad as an effective treatment for younger and older adults," said Prof. Gavin Giovannoni, a lead investigator in the CLARITY studies and Chair of Neurology, Barts and The London School of Medicine and Dentistry, UK. "This is something that we have not seen consistently across all clinical endpoints with some of the newer high-efficacy RRMS treatments and so provides a valuable insight into the treatment options available."

Additional data presented at EAN 2018 provide the results of the first application of the EMA-recommended Multi-Criteria Decision Analysis (MCDA) methodology to assess the benefit-risk profile of MAVENCLAD^® versus other recently approved DMDs^[*] in MS patients with high disease activity.

Results of this systematic application of MCDA methodology indicate either comparable or more favorable benefit-risk profile for MAVENCLAD^® in patients with high disease activity when compared to that of other DMDs. Specifically, in patients with high disease activity, MAVENCLAD^® had the highest overall weighted preference value compared to the other DMDs evaluated, followed by alemtuzumab and natalizumab. In the overall RRMS population MAVENCLAD^® was very close to dimethyl fumarate in being ranked as having the best benefit-risk balance, with an overall weighted preference value of 62 versus 63, respectively.

"The presentation of these data highlight our ongoing commitment to understanding the full benefit-risk profile of Mavenclad in a broad range of patients. Post hoc data from the CLARITY study, coupled with results from a Multi-Criteria Decision Analysis, which are based on expert physician assessment and practice-relevant treatment considerations, form a potentially useful tool for physicians considering therapy options for patients with high disease activity," said Luciano Rossetti, Head of Global R&D for the Biopharma business of Merck. "The MCDA methodology is one that is recommended by EMA, and we are pleased that Mavenclad performed well using this approach, compared with other disease-modifying therapies."

Furthermore, additional post hoc data from clinical studies of patients treated with Rebif (subcutaneous interferon beta-1a) showed that the MAGNIMS score at Year 1 reliably predicted long-term clinical disease activity (CDA)-free status and disability progression. At Year 1 the median time to a CDA event was longer in patients with a MAGNIMS score of 0, versus those with score 1 or 2. Additionally, median time to Expanded Disability Status Scale (EDSS) progression was found to be longer in patients with a Year 1 MAGNIMS score of 0 (7.5 years), versus those with 1 (4.0 years) or 2 (2.5 years).

Additionally, a presentation from the Merck-sponsored MS in the 21^st Century joint patient-physician steering group highlighted the results of an international unmet needs survey, suggesting a disconnect between patients' and physicians' perspectives of MS treatment decisions. The results of this survey indicate that MS patients have different perceptions of the current unmet needs in the disease area compared to healthcare professionals (HCPs). Whilst 87.7% of HCPs considered that they involved their patients in the decision-making process, only 38.9% of patients reported that they felt involved in that process. Addressing this disconnect between patients' and physicians' perspectives during treatment discussions could lead to an improved dialogue between HCPs and patients, an integral step towards finding appropriate individualised treatment approaches for each patient.

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About MAVENCLAD^®  
MAVENCLAD^® (cladribine tablets) is a short-course oral therapy that selectively and periodically targets lymphocytes thought to be integral to the pathological process of multiple sclerosis (MS). In August 2017, the European Commission (EC) granted marketing authorization for MAVENCLAD^® for the treatment of relapsing forms of MS (RMS) in the 28 countries of the European Union (EU) in addition to Norway, Liechtenstein and Iceland. MAVENCLAD^® is now available in over 10 countries in Europe, plus Australia, Argentina and the United Arab Emirates. MAVENCLAD^® is not yet approved for any use in the United States.

The clinical development program of MAVENCLAD^® in MS comprises more than 10,000 patient years of data with over 2,700 patients included in the clinical trial program, and up to 10 years of observation in some patients. These clinical trials include the Phase III CLARITY, CLARITY extension and ORACLE MS trials, the Phase II ONWARD trial and the PREMIERE Long-term Safety Registry.

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 <60 mL/min), and those who are pregnant and breast-feeding. MAVENCLAD^® is also contraindicated in immunocompromised patients, including patients currently receiving immunosuppressive or myelosuppressive therapy.

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.

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

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.

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.

Merck in Multiple Sclerosis  
Merck has a long-standing legacy in neurology and immunology, with significant R&D and commercial experience in multiple sclerosis (MS). Merck's current portfolio includes two products for the treatment of relapsing MS, with a robust pipeline focusing on discovering new therapies that have the potential to modulate key pathogenic mechanisms in MS. Merck aims to improve the lives of those living with MS, by addressing areas of unmet medical needs.

About Merck  
Merck is a leading science and technology company in healthcare, life science and performance materials. More than 53,000 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 2017, Merck generated sales of € 15.3 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. 

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*. Recently approved DMDs available in European Union countries at the time of assessment (December 2015): alemtuzumab, dimethyl fumarate, fingolimod, natalizumab, and teriflunomide

SOURCE Merck KGaA

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