New Real-World MAVENCLAD® Data Show Sustained Effectiveness and Benefit on Quality-of-Life Measures in RMS Patients

EMD Serono, the Healthcare business sector of Merck KGaA, Darmstadt, Germany, in the U.S. and Canada, today announced new interim real-world data on MAVENCLAD^® (cladribine) tablets that show patients with relapsing multiple sclerosis (RMS) experienced a significant improvement in quality-of-life (QoL) scores after the first course of treatment in Year 1 with MAVENCLAD. Additionally, late-breaking real-world MAVENCLAD data evaluating long-term mobility and disability status suggested sustained benefit beyond the last treatment course and a reduced need for a wheelchair or ambulatory device among MAVENCLAD-treated patients. These data were presented at the 37^th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

A new interim analysis from the open-label Phase IV CLARIFY-MS study demonstrated improvements in QoL measures in 426 patients with RMS early in the treatment course (Year 1). After completing half the recommended cumulative dose of MAVENCLAD over two years, improvements from baseline were observed for physical and mental health composite scores (nominal p<0.0001) as measured by the Quality of Life-54 questionnaire. Safety data were consistent with the safety profile seen in the MAVENCLAD clinical development program.

"Those living with MS know the effect of a treatment goes beyond what is shown in MRIs or in bloodwork. Many patients express that the impact on physical and mental well-being is just as important," said Prof. Jeannette Lechner-Scott, PhD, FRACP, Senior Staff Specialist in the Department of Neurology and Conjoint Professor at the University of Newcastle, Australia. "The quality-of-life outcomes from the CLARIFY-MS study support that MAVENCLAD positively impacts these measures early in the treatment course."

Also presented were late-breaking final data from the Phase IV CLASSIC-MS, a follow-up study, which showed that 90.0% of patients with RMS treated with cladribine tablets did not need to use a wheelchair or were not confined to bed (i.e., with an Expanded Disability Status Scale <7) after a median follow-up of 10.9 years (range 9.3-14.9). Additionally, 81.2% of cladribine tablets-treated patients did not require an ambulatory device. CLASSIC-MS investigated the long-term efficacy in 435 patients with RMS ? 90.6% of whom were exposed to cladribine tablets during the CLARITY and CLARITY Extension trials. The study focused on long-term mobility and disability ? two areas of importance as MS can cause problems with movement, balance and coordination that can worsen over time.

An independent study, presented by Prof. Adi Vaknin-Dembinsky, MD, PhD, Senior Neurologist, Hadassah Medical Center at the Hebrew University, Jerusalem, Israel, evaluated antibody response after a complete course of the Pfizer/BioNTech mRNA COVID-19 vaccine in healthy controls and patients with MS (untreated, or treated with MAVENCLAD or interferon beta-1a). Consistent with previously reported data, MAVENCLAD-treated patients, as well as those treated with interferon beta-1a, who received the Pfizer/BioNTech mRNA COVID-19 vaccine were found to mount a positive serology response (AU/mL >19), similar to that of healthy controls. Specifically, all patients with MS treated with MAVENCLAD (n=30) had a positive serology response against the spike protein two to three weeks after vaccination (mean=226.3±121.4). In the study, the shortest interval between vaccination and the last dose of MAVENCLAD was 12 weeks. In the U.S., the MAVENCLAD label states that all immunizations should be administered according to immunization guidelines prior to starting MAVENCLAD.

"The long-term MAVENCLAD outcomes presented at ECTRIMS 2021 suggest the potential to positively impact future mobility and disability status, supporting why MAVENCLAD should be considered a disease-modifying therapy of choice for appropriate adult patients living with RMS," stated Danny Bar-Zohar, MD, Global Head of Development for the Healthcare business of Merck KGaA, Darmstadt, Germany. "As new strains of COVID-19 push the pandemic onward and guidance recommends booster vaccinations, we are encouraged to have new data that continues to show MAVENCLAD-treated patients with RMS who received an mRNA COVID-19 vaccine have a similar antibody response to the general population."

About MAVENCLAD^®

MAVENCLAD, approved by the U.S. Food and Drug Administration (FDA) on March 29, 2019, is the first and only short-course oral therapy for the treatment of adults with relapsing-remitting disease (RRMS) and active secondary progressive disease (SPMS). Because of its safety profile, use of MAVENCLAD is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of multiple sclerosis (MS), and MAVENCLAD is not recommended for use in patients with clinically isolated syndrome (CIS). Patients should follow healthcare provider instructions including cancer screening, contraception and blood tests. The approved dose of MAVENCLAD is 3.5 mg per kg body weight over two years, administered as one treatment course of 1.75 mg per kg per year, each consisting of two treatment weeks. The mechanism by which cladribine exerts its therapeutic effects in patients with multiple sclerosis has not been fully elucidated but is thought to involve cytotoxic effects on B and T lymphocytes through impairment of DNA synthesis, resulting in depletion of lymphocytes. MAVENCLAD causes a dose-dependent reduction in lymphocyte counts followed by recovery.

Because cladribine is cytotoxic, special handling and disposal instructions should be followed.

MAVENCLAD has been approved in over 80 countries, including the European Union (EU), Canada, Australia and Switzerland, for various relapsing MS indications. Visit www.MAVENCLAD.com for more information.

IMPORTANT SAFETY INFORMATION

WARNING: MALIGNANCIES and RISK OF TERATOGENICITY

• Treatment with MAVENCLAD may increase the risk of malignancy. MAVENCLAD is contraindicated in patients with current malignancy. In patients with prior malignancy or with increased risk of malignancy, evaluate the benefits and risks of the use of MAVENCLAD on an individual patient basis. Follow standard cancer screening guidelines in patients treated with MAVENCLAD
• MAVENCLAD is contraindicated for use in pregnant women and in women and men of reproductive potential who do not plan to use effective contraception because of the potential for fetal harm. Malformations and embryolethality occurred in animals. Exclude pregnancy before the start of treatment with MAVENCLAD in females of reproductive potential. Advise females and males of reproductive potential to use effective contraception during MAVENCLAD dosing and for 6 months after the last dose in each treatment course. Stop MAVENCLAD if the patient becomes pregnant

CONTRAINDICATIONS

• Patients with current malignancy.
• Pregnant women, and women and men of reproductive potential who do not plan to use effective contraception during and for 6 months after the last dose in each treatment course. May cause fetal harm.
• Patients with human immunodeficiency virus (HIV).
• Patients with active chronic infections (e.g., hepatitis or tuberculosis).
• Patients with a history of hypersensitivity to cladribine.
• Women intending to breastfeed while taking MAVENCLAD tablets and for 10 days after the last dose.

WARNINGS AND PRECAUTIONS

• Malignancies: Treatment with MAVENCLAD may increase the risk of malignancy. After the completion of 2 treatment courses, do not administer additional MAVENCLAD treatment during the next 2 years. In clinical studies, patients who received additional MAVENCLAD treatment within 2 years after the first 2 treatment courses had an increased incidence of malignancy. The risk of malignancy with reinitiating MAVENCLAD more than 2 years after the completion of 2 treatment courses has not been studied. Follow standard cancer screening guidelines in patients treated with MAVENCLAD.
• Risk of Teratogenicity: MAVENCLAD may cause fetal harm when administered to pregnant women. In females of reproductive potential, exclude pregnancy before initiation of each treatment course of MAVENCLAD and prevent by the use of effective contraception during MAVENCLAD dosing and for at least 6 months after the last dose of each treatment course. Women who become pregnant during treatment with MAVENCLAD should discontinue treatment.
• Lymphopenia: MAVENCLAD causes a dose-dependent reduction in lymphocyte count. In clinical studies, 87% of MAVENCLAD-treated patients experienced lymphopenia. The lowest absolute lymphocyte counts occurred approximately 2 to 3 months after the start of each treatment course and were lower with each additional treatment course. Concomitant use of MAVENCLAD with hematotoxic drugs may increase the risk of adverse reactions because of the additive hematological effects. Monitor lymphocyte counts before and during treatment, periodically thereafter, and when clinically indicated.
• Infections: MAVENCLAD can reduce the body's immune defense and may increase the likelihood of infections. Infections occurred in 49% of MAVENCLAD-treated patients compared to 44% of patients treated with placebo in clinical studies. The most frequent serious infections included herpes zoster and pyelonephritis. Single fatal cases of tuberculosis and fulminant hepatitis B were reported in the clinical program. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting MAVENCLAD. Screen patients for latent infections; consider delaying treatment until infection is fully controlled. Vaccinate patients antibody-negative to varicella zoster virus prior to treatment. Administer anti-herpes prophylaxis in patients with lymphocyte counts less than 200 cells per microliter. Monitor for infections. In patients treated with parenteral cladribine for oncologic indications, cases of progressive multifocal leukoencephalopathy (PML) have been reported. No case of PML has been reported in clinical studies of cladribine in patients with MS.
• Hematologic Toxicity: In addition to lymphopenia, decreases in other blood cells and hematological parameters have been reported with MAVENCLAD in clinical studies. In general, mild to moderate decreases in neutrophil counts, hemoglobin levels, and platelet counts were observed. Severe decreases in neutrophil counts were observed in 3.6% of MAVENCLAD-treated patients, compared to 2.8% of placebo patients. Obtain complete blood count (CBC) with differential including lymphocyte count before and during treatment, periodically thereafter, and when clinically indicated.
• Risk of Graft-versus-Host Disease With Blood Transfusions: Transfusion-associated graft-versus-host disease has been observed rarely after transfusion of nonirradiated blood in patients treated with cladribine for non-MS treatment indications.
• Liver Injury: In clinical studies, 0.3% of MAVENCLAD-treated patients had liver injury (serious or causing treatment discontinuation) compared to 0 placebo patients. Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels prior to treatment. Discontinue if clinically significant injury is suspected.
• Hypersensitivity: In clinical studies, 11% of MAVENCLAD-treated patients had hypersensitivity reactions, compared to 7% of placebo patients. Hypersensitivity reactions that were serious and/or led to discontinuation of MAVENCLAD, occurred in 0.5% of MAVENCLAD-treated patients, compared to 0.1% of placebo patients. If a hypersensitivity reaction is suspected, discontinue MAVENCLAD therapy. Do not use MAVENCLAD in patients with a history of hypersensitivity to cladribine.
• Cardiac Failure: In clinical studies, one MAVENCLAD-treated patient experienced life-threatening acute cardiac failure with myocarditis, which improved after approximately one week. Cases of cardiac failure have also been reported with parenteral cladribine used for treatment indications other than multiple sclerosis.

Adverse Reactions: The most common adverse reactions with an incidence of >20% for MAVENCLAD are upper respiratory tract infection, headache, and lymphopenia.

Drug Interactions/Concomitant Medication: Concomitant use of MAVENCLAD with immunosuppressive or myelosuppressive drugs and some immunomodulatory drugs (e.g., interferon beta) is not recommended and may increase the risk of adverse reactions. Acute short-term therapy with corticosteroids can be administered.

Avoid concomitant use of certain antiviral and antiretroviral drugs. Avoid concomitant use of BCRP or ENT/CNT inhibitors as they may alter bioavailability of MAVENCLAD.

Use in Specific Populations: Studies have not been performed in pediatric or elderly patients, pregnant or breastfeeding women. Use in patients with moderate to severe renal or hepatic impairment is not recommended.

Please see the full Prescribing Information, including boxed WARNING for additional information.

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.

EMD Serono, Inc. and Multiple Sclerosis

For more than 20 years, EMD Serono has been relentlessly focused on understanding the journey people living with MS face in order to create a meaningful, positive experience for them and the broader MS community. However, there is still much that is unknown about this complex and unpredictable disease. EMD Serono is digging deeper to advance the science.

About EMD Serono, Inc.

EMD Serono ? the Healthcare business sector of Merck KGaA, Darmstadt, Germany, in the U.S. and Canada ? is engaged in the discovery, research and development of medicines for patients with difficult to treat diseases. The business is committed to transforming lives by developing and delivering meaningful solutions that help address the therapeutic and support needs of individual patients. Building on a proven legacy and deep expertise in neurology, fertility and endocrinology, EMD Serono is developing potential new oncology and immuno-oncology medicines while continuing to explore potential therapeutic options for diseases such as psoriasis, lupus and MS. Today, the business has approximately 1,500 employees around the country with commercial, clinical and research operations based in the company's home state of Massachusetts. www.emdserono.com.

About Merck KGaA, Darmstadt, Germany

Merck KGaA, Darmstadt, Germany, 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 KGaA, Darmstadt, Germany, generated sales of ? 17.5 billion in 66 countries.

The company holds the global rights to the name and trademark "Merck" internationally. The only exceptions are the United States and Canada, where the business sectors of Merck KGaA, Darmstadt, Germany operate as EMD Serono in healthcare, MilliporeSigma in life science, and EMD Electronics. Since its founding in 1668, scientific exploration and responsible entrepreneurship have been key to the company's technological and scientific advances. To this day, the founding family remains the majority owner of the publicly listed company.