Merck Shares Advances in MS Portfolio with Key Efficacy and Safety Data at AAN 2022

Merck, a leading science and technology company, today announced 13 abstracts from the Company’s multiple sclerosis (MS) portfolio will be presented at the 2022 American Academy of Neurology (AAN) Annual Meeting, being held April 2-7. Data being presented include presentations on investigational Bruton’s tyrosine kinase (BTK) inhibitor evobrutinib, including new 2.5-year efficacy and safety data in patients with relapsing multiple sclerosis (RMS) from a Phase II open-label extension study and a Phase II post-hoc analysis demonstrating that treatment with evobrutinib led to a reduction in slowly expanding lesions (SEL), which may be associated with chronic inflammation in the central nervous system (CNS). Additionally, retrospective real-world efficacy and safety data on MAVENCLAD^® (cladribine tablets) will be presented, including relapse data compared to other oral disease modifying therapies (DMTs) as well as COVID-19 outcomes.

“Focusing on the needs of people with MS is at the heart of everything we do. This includes innovative research with real-world data to better understand the effectiveness of MAVENCLAD in clinical practice to help inform treatment decisions,” said Jan Klatt, Senior Vice President, Head of Development Unit Neurology & Immunology at Merck. “Additionally, we are working tirelessly on the future of MS treatments with evobrutinib, which targets both acute and potentially also chronic inflammation to prevent disease progression and achieve better outcomes for patients. With new evobrutinib data at AAN, we now have two and a half years of efficacy and safety data in patients with relapsing MS from the largest Phase II BTK inhibitor clinical trial.”

Key evobrutinib data include:

• Safety and efficacy results from the evobrutinib Phase II open-label extension finding no new safety signals and maintained efficacy (annualized relapse rate of 0.12 for patients receiving evobrutinib 75mg twice-daily in the 48-week double-blind period) over 2.5 years in patients with RMS
• Data from a post-hoc analysis in the Phase II trial with evobrutinib demonstrating a reduction in volume of SELs, an in-vivo magnetic resonance imaging (MRI) correlate with chronic active inflammation and axonal loss within the CNS, which may be predictive of subsequent clinical disease progression in MS

Key MAVENCLAD^® (cladribine tablets) data include:

• Data from the Phase IV CLARIFY-MS and MAGNIFY-MS studies demonstrating MS patients treated with MAVENCLAD who acquired COVID-19 typically experienced mild to moderate disease symptoms/effects with no increased risk of serious outcomes from COVID-19 infection
• Data from the GLIMPSE study^*, a longitudinal, retrospective analysis of adult patients identified with RMS from the MSBase Registry, showing MAVENCLAD had lower annualized relapse rates and lower risk of relapse than fingolimod, dimethyl fumarate and teriflunomide in RMS patients

Additional Company activities at AAN 2022:

• Industry Therapeutic Update 1: “Early DMT Switch Considerations in MS and Discussing the Capacity to Mount an Immune Response” chaired by Ann Bass, MD, Medical Director of the comprehensive MS clinic at the Neurology Center of San Antonio (April 2, 7-8:30 pm PDT, Grand Ballroom, Sheraton Grand, Seattle)
• Industry Therapeutic Update 2: “Seeing What’s Unseen in MS” chaired by Jiwon Oh, MD, PhD, Medical Director, BARLO MS Centre, St. Michael’s Hospital, Toronto (April 4, 7-10 pm PDT, Grand Ballroom, Sheraton Grand, Seattle)

To keep up to date with our activities at AAN along with future data and information, visit merckneurology.com/newsroom or follow us on Twitter @MerckHealthcare and LinkedIn: Healthcare Business of Merck #AANAM #MSInsideOut

Below is the full list of Merck-related abstracts accepted for presentation at AAN 2022:

Abstract Name	Authors	Presentation Details
Evobrutinib Oral Presentations:
Effects of Evobrutinib, a Bruton's Tyrosine Kinase Inhibitor, on Slowly Expanding Lesions, an Emerging Imaging Marker of Chronic Tissue Loss in Multiple Sclerosis	Arnold D, Elliott C, Montalban X et al.	Program ID: 009 Session: S24 - MS Therapeutics Date: April 4, 2022 Time: 5:06 pm PDT/8:06 pm EDT Presenter: Arnold D
Safety Profile Characterization of Evobrutinib in Over 1000 Patients from Phase II Clinical Trials in Multiple Sclerosis, Rheumatoid Arthritis and Systemic Lupus Erythematosus	Montalban X, Wallace D, Genovese MC et al.	Program ID: 007 Session: S14 - MS Therapeutics Date: April 4, 2022 Time: 4:42 pm PDT/7:42 pm EDT Presenter: Montalban X
Evobrutinib Poster Presentations:
Safety and Efficacy of Evobrutinib, a Bruton’s Tyrosine Kinase Inhibitor in Relapsing Multiple Sclerosis Over 2.5 Years of the Open-label Extension to a Phase II Trial	Montalban X, Wolinsky JS, Arnold DL et al.	Program ID: 001 Neighborhood: 4 Session: P5 - MS Clinical Trials and Therapeutics 1 Date: April 3, 2022 Time: 11:45 am-12:45 pm PDT/2:45 pm-3:45 pm EDT Presenter: Montalban X
The Role of Human and Mouse BTK in Myeloid Cells	Bassani C, Molinari M, Martinielli V et al.	Program ID: 006 Session: P3 - MS Immunology and Basic Science 1 Date: April 2, 2022 Time: 5:30 pm-6:30 pm PDT/8:30 pm-9 30 pm EDT Presenter: Muzio L
MAVENCLAD® (cladribine tablets) Poster Presentations:
Clinical Outcomes in Patients With COVID-19 During Two Phase IV Studies of Cladribine Tablets for Treatment of Multiple Sclerosis: An Update	Yavorskaya V, Karan R, Borsi L et al.	Program ID: 005 Neighborhood: 4 Session: P11 - MS COVID 2 Date: April 5, 2022 Time: 11:45 am-12:45 pm PDT/2:45 pm-3:45 pm EDT Presenter: Salloukh H
Real-world Comparative Effectiveness and Persistence of Cladribine Tablets and Other Oral Disease-modifying Treatments for Multiple Sclerosis from GLIMPSE: Results from the MSBase Registry	Butzkueven H, Spelman T, Ozakbas S et al.	Program ID: 003 Neighborhood: 4 Session: P12 - MS Clinical Practice & Decision Making 4 Date: April 5, 2022 Time: 5:30 pm-6:30 pm PDT/8:30 pm-9:30 pm EDT Presenter: Verdun Di Cantogno E
Comparative Effectiveness of Cladribine versus Fingolimod in the Treatment of Highly Active Relapsing Multiple Sclerosis: The MERLYN (MavEnclad Real worLd comparative efficacy Non-iNterventional) Study	Brownlee W, Haghikia A, Hayward B et al.	Program ID: 005 Neighborhood: 4 Session: P7 - MS Clinical Trials & Therapeutics 3 Date: April 4, 2022 Time: 8:00 am-9:00 am PDT/11:00 am-12:00 pm EDT Presenter: Brownlee W
Cladribine Tablets In Patients With Relapsing Remitting Multiple Sclerosis Or Active Secondary Progressive Multiple Sclerosis After Suboptimal Response To A Disease Modifying Therapy (CLICK-MS and MASTER-2): Interim Baseline And Safety Review	Aldridge J, Bass A, Evans E et al.	Date: April 24-27, 2022 Virtual e-Poster Presenting: Miravalle A
Rebif® (interferon beta-1a) subcutaneous injection Poster Presentations:
Exploratory Analysis of Serum GDF-15 Levels in Patients Receiving Subcutaneous Interferon β-1a in the REFLEX Trial	Coray M, Seitzinger A, Roy S et al.	Program ID: 007 Neighborhood: 4 Session: P2 - MS Biomarkers Date: April 2, 2022 Time: 11:45 am-12:45 pm PDT/2:45 pm-3:45 pm EDT Presenter: Verdun di Cantogno E
Post-approval Safety of Subcutaneous Interferon Β-1a in the Treatment of Multiple Sclerosis, With Particular Reference to Respiratory Viral Infections	Freedman MS, Todorović M, Murgašová Z et al.	Program ID: 005 Neighborhood: 4 Session: P8 - MS Therapeutics MOA and Safety 3 Date: April 4, 2022 Time: 11:45 am-12:45 pm PDT/2:45 pm-3:45 pm EDT Presenter: Korick J
INFORM - Interferon beta Exposure in the 2nd and 3rd Trimester of Pregnancy a – Register-Based Drug Utilisation Study in Finland and Sweden	Sabidó M, Suzart Woischnik K, Grimes N et al.	Program ID: 009 Neighborhood: 4 Session: P8 - MS Special Populations 2 Date: April 4, 2022 Time: 11:45 am-12:45 pm PDT/2:45 pm-3:45 pm EDT Presenter: Verdun de Cantogno E
Non-Product Specific Poster Presentations:
Patient Practices and Experiences During COVID-19 Among Individuals Enrolled in MS LifeLines Patient Support Program	Costantino H, Lebson L, Mackie dMS et al.	Date: April 24-27, 2022 Virtual e-Poster Presenting: Nicholas J
A Cross-Sectional Survey Evaluating Cladribine Tablets Treatment Patterns Among Patients with Multiple Sclerosis Enrolled in the MS LifeLines Patient Support Program	Nicholas J, Mackie dMS, Castantino H et al.	Date: April 24-27, 2022 Virtual e-Poster Presenting: Nicholas J

^*Previously presented at ACTRIMS 2022

About Evobrutinib

Evobrutinib (M2951) is an oral, highly selective inhibitor of Bruton’s tyrosine kinase (BTK) in clinical development as a potential treatment for multiple sclerosis (MS). It is the first BTK inhibitor to demonstrate clinical efficacy in the largest Phase II study with follow-up beyond two years as well as demonstrate an impact on early biomarkers of chronic inflammation that correlate with disease progression. Evobrutinib is designed to inhibit primary B cell responses such as proliferation and antibody and cytokine release, without directly affecting T cells. Evobrutinib is currently under clinical investigation and not approved for any use anywhere in the world.

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 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. 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^® can be administered 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.

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.

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® (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 the 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 60,000 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 2021, Merck generated sales of € 19.7 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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