Merck Announces New Data Strengthening Evidence for Continued Safe and Effective MAVENCLAD® Use During the COVID-19 Pandemic

• New analysis indicates a specific immune repopulation pattern in people treated with MAVENCLAD, which may contribute to their ability to fight infections and develop protective antibodies from vaccines
• Independent study from Israel showed MAVENCLAD-treated patients receiving COVID-19 vaccine were able to mount antibody response similar to that of healthy subjects
• Updated safety data show MAVENCLAD-treated patients with confirmed or suspected COVID-19 continue to have a disease course similar to the general population

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Merck, a leading science and technology company, today announced a new analysis from the MAGNIFY-MS sub-study showing a specific immune repopulation pattern in patients with relapsing multiple sclerosis (RMS) treated with MAVENCLAD^® (cladribine tablets), which may contribute to their ability to fight infections and develop protective antibodies from vaccines. The data were presented at the 2021 American Academy of Neurology (AAN) Annual Meeting that was held virtually 17-22 April 2021.

In the MAGNIFY-MS study, reduction of memory B cells occurred as early as one month after MAVENCLAD initiation with lowest levels sustained for up to 12 months, while naïve B cells, which are typically required for the generation of antibody responses following vaccination, began recovering immediately. Previously shared data from MAGNIFY-MS indicated that patients receiving MAVENCLAD are able to mount responses to influenza and varicella zoster vaccines, irrespective of lymphocyte count.

“The findings presented at AAN further our understanding of how MAVENCLAD impacts the immune system, and how it may exert a therapeutic effect in patients with multiple sclerosis while repopulating cells which support immune responses,” said Heinz Wiendl, MD, Department of Neurology with Institute of Translational Neurology, University of Muenster, Germany. “These important data indicate that in addition to addressing MS relapses and progression, patients treated with MAVENCLAD may be able to simultaneously mount a proper vaccine response – a particularly important finding at this time.”

In addition, a recent independent study conducted by Anat Achiron, MD, PhD, FAAN and colleagues, The Multiple Sclerosis Center at Sheba Medical Centre and Sackler School of Medicine Tel Aviv University, Israel, and recently published in Therapeutic Advances in Neurological Disorders, shows that patients who have taken MAVENCLAD were able to generate COVID-19 antibodies following the mRNA vaccine from Pfizer/BioNTech administered 4.4 months after last MAVENCLAD dosing. The observational analysis showed that all 23 relapsing-remitting MS patients treated with MAVENCLAD who received the Pfizer/BioNTech mRNA vaccine developed a protective SARS-COV-2 IgG antibody response [antibody titer >1.1 is considered positive; median=7.0], which was similar to the comparison group of MS patients not receiving any immunomodulatory treatments and healthy subjects. Humoral response to the COVID-19 vaccine was independent of lymphocyte count. These findings appeared unique to MAVENCLAD across other high-efficacy MS therapies. No unexpected safety findings post first and second dose of Pfizer/BioNTech COVID-19 vaccination were identified in MS patients, according to another recent publication in the Multiple Sclerosis Journal.

“Bringing MAVENCLAD-treated patients into a state where they can live their lives as normally as possible during a global pandemic is of utmost importance to us,” said Danny Bar-Zohar, MD, Global Head of Development, Healthcare business of Merck. “Beyond the convenient oral dosing schedule, proven efficacy, and well-characterized safety profile of MAVENCLAD, newly generated data now show encouraging initial evidence for these patients` ability to generate adequate antibody response to COVID-19 vaccination, which is so important for patients.”

The ability to mount an adequate immune response is critical as the COVID-19 pandemic impacts patients living with chronic disease around the world. As presented at AAN, and also published in MSaRD, an updated post-approval safety analysis provided a look at outcomes from cases of COVID-19 in MAVENCLAD-treated patients. The safety database analysis included cases of confirmed (n=160) or suspected (n=101) COVID-19 in MAVENCLAD-treated patients. Based on the analysis, the majority of patients had mild to moderate respiratory symptoms and none required mechanical ventilation. MAVENCLAD-treated patients had a similar disease course with COVID-19 compared with the general population who acquired COVID-19.

About MAVENCLAD^®
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). In August 2017, the European Commission (EC) granted marketing authorization for MAVENCLAD^® 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^® has since then been approved in over 80 countries, including Canada, Australia and the U.S. Refer to the respective prescribing information for further details.

The clinical development programme 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 Phase III placebo-controlled study following on from the CLARITY study, which evaluated the safety and exploratory efficacy of cladribine tablets over two additional years beyond the two-year CLARITY study, according to the treatment assignment scheme for years 3 and 4.

• 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) study: a long-term observational follow-up safety registry of MS patients who participated in cladribine tablets clinical studies.

In the two-year CLARITY study, the most commonly reported adverse event (AE) in patients treated with cladribine tablets was lymphopenia (26.7% with cladribine tablets and 1.8% for placebo). The incidence of infections was 48.3% with cladribine tablets and 42.5% with placebo, with 99.1% and 99.0% respectively rated mild-to-moderate by investigators. Adverse Events reported in other clinical studies were similar.

About the MAGNIFY-MS sub-study
The MAGNIFY-MS sub-study was conducted to evaluate the peripheral immune cell subset dynamics and repopulation patterns in the first 12 months of MAVENCLAD therapy in 57 patients. Absolute cell counts and percent change from baseline were assessed for adaptive immune cell subtypes and immunoglobulins. Results found that there is an early onset of action, with most B cell subtypes reaching nadir (or lowest achieved) levels by month two. T cell subtypes showed reductions at later time points (mainly between months three and six) and no changes were seen for other natural killer (NK) cell subtypes. Reduction in memory B cells was sustained to month 12; regulatory B cells recovered by month three, and then increased over baseline levels.

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 2.8 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 Neurology and Immunology
Merck has a long-standing legacy in neurology and immunology, with significant R&D and commercial experience in multiple sclerosis (MS). The company`s current MS portfolio includes two products for the treatment of relapsing MS – Rebif<sup>®</sup> (interferon beta-1a) and MAVENCLAD<sup>®</sup> (cladribine tablets). Merck aims to improve the lives of patients by addressing areas of unmet medical needs. In addition to Merck`s commitment to MS, the company also has a pipeline focusing on discovering new therapies that have potential in other neuroinflammatory and immune-mediated diseases, including systemic lupus erythematosus (SLE).

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About Merck
Merck, a leading science and technology company, operates across healthcare, life science and electronics. Around 58,000 employees work to make a positive difference to millions of people’s lives every day by creating more joyful and sustainable ways to live. From advancing gene-editing technologies and discovering unique ways to treat the most challenging diseases to enabling the intelligence of devices – the company is everywhere. In 2020, Merck generated sales of € 17.5 billion in 66 countries.

Scientific exploration and responsible entrepreneurship have been key to Merck’s technological and scientific advances. This is how Merck has thrived since its founding in 1668. The founding family remains the majority owner of the publicly listed company. Merck holds the global rights to the Merck name and brand. The only exceptions are the United States and Canada, where the business sectors of Merck operate as EMD Serono in healthcare, MilliporeSigma in life science and EMD Electronics.

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