Mavenclad (Cladribine Tablets) Receives First Approval in the Middle East & Africa Region

DARMSTADT, Germany, April 9, 2018 /PRNewswire/ -- Merck, a leading science and technology company, today announced that the United Arab Emirates Ministry of Health and Prevention has approved the registration of MAVENCLAD^® (cladribine tablets) for the treatment of adult patients with highly active relapsing multiple sclerosis (MS) as defined by clinical or imaging features. This marks the first approval for MAVENCLAD^® in the Middle East & Africa region and, following local regulatory processes, the product is expected to be available in the coming months. The United Arab Emirates (UAE) is the first country in the region to approve the adoption of this breakthrough therapy, which is a direct outcome of accelerated processes by the Ministry of Health and Prevention, aimed at making the latest advances and best quality of healthcare services and medications available within the country.

"The accelerated processes implemented by the Ministry of Health and Prevention allow for significant advancements in care, and we applaud them for fostering an environment in which patients gain expedited access to innovations such as Mavenclad," said Rehan Verjee, Chief Marketing and Strategy Officer at the Biopharma business of Merck.

MAVENCLAD^® is the first oral short-course treatment to provide efficacy across key measures of disease activity in patients with highly active relapsing MS, including disability progression, annualized relapse rate and magnetic resonance imaging (MRI) activity. The approval of MAVENCLAD^® is based on more than 10,000 patient years of data with over 2,700 patients included in the clinical trial program,^[1] and up to 10 years of observation in some patients. The clinical development program included data from three Phase III trials: CLARITY,^[2],[3] CLARITY EXTENSION^[4] and ORACLE MS;^[5] the Phase II ONWARD study;^[6] and long-term follow-up data from the 8-year prospective registry, PREMIERE.^[7] The efficacy and safety results of these studies allowed for a full characterization of the benefit-to-risk profile of MAVENCLAD^®.

MAVENCLAD^® is a selective immune reconstitution therapy^[8],[9] which simplifies treatment administration by giving patients just 2 short annual courses of tablets with a maximum of 20 days of treatment over 2 years providing a lasting treatment benefit up to 4 years. MAVENCLAD^® works by selectively targeting B & T lymphocytes followed by a distinct pattern of lymphocyte reconstitution, without continuous suppression of the immune system.^[10] 

In patients with high disease activity, post hoc analyses of the two-year Phase III CLARITY trial^[3],[4] demonstrated that MAVENCLAD^® reduced the annualized relapse rate by 67% and the risk of 6-month confirmed expanded disability status scale (EDSS) progression by 82% versus placebo. As demonstrated in the Phase III CLARITY EXTENSION^[4] study, no further MAVENCLAD^® treatment was required in Years 3 and 4. The comprehensive dataset has informed the posology and monitoring requirements. The most clinically relevant adverse reactions were lymphopenia and herpes zoster. Lymphocyte counts must be assessed before, and during, treatment with MAVENCLAD^®. MAVENCLAD^® is contraindicated in certain groups including immunocompromised patients and pregnant women.

About MAVENCLAD^®

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 Germany, Canada, Australia, Argentina, United Arab Emirates, Israel, Luxembourg, Denmark, Norway, Scotland and the UK. MAVENCLAD^® is not yet approved for any use in the United States.

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). 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 <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 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 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. 

1. Merck data on file

2. Giovannoni G, Comi G, Cook S et al. A Placebo-Controlled Trial of 1Oral Cladribine for Relapsing Multiple Sclerosis. 2010 New England Journal of Medicine 362:416-426

3. Giovannoni G et al. Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis Lancet Neurol 2011; 10:329-337

4. EU Clinical Trials Register. A Phase IIIb, Double-Blind, Placebo-Controlled, Multicenter, Parallel Group, Extension Trial to Evaluate the Safety and Tolerability of Oral Cladribine in Subjects with Relapsing-Remitting Multiple Sclerosis Who Have Completed Trial 25643 (CLARITY). Available at https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-000381-20/results. Last accessed August 2017

5. Leist T, Comi G, Cree B et al. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial. Lancet Neurol 2014; 13: 257-67

6. EU Clinical Trials Register. A phase II, multicenter, randomized, double-blind, placebo-controlled, safety, tolerability and efficacy study of add-on Cladribine tablet therapy with Rebif New Formulation in Multiple Sclerosis Subjects with Active Disease. Available at https://www.clinicaltrialsregister.eu/ctr-search/trial/2006-003366-33/results. Last accessed August 2017

7. Schreiner T, Miravalle A,. Current and Emerging Therapies for the Treatment of Multiple Sclerosis: Focus on Cladribine. Journal of Central Nervous System Disease. 2012; 4: 1-14

8. Giovannoni G. Personalized medicine in multiple sclerosis. 2017 Neurodegenerative Disease Management; 7 (6s) 13-17

9. Giovannoni G. Cladribine to Treat Relapsing Forms of Multiple Sclerosis. Neurotherapeutics. November 2017; DOI 10.1007/s13311-017-0573-4

10. 0 MAVENCLAD™ Product Monograph. November 2017

SOURCE Merck