Novartis Receives FDA Approval for Mayzent® (siponimod), the First Oral Medication to Treat Secondary-progressive MS With Active Disease

IS HANOVER, N.J., March 27, 2019 / PRNewswire / – Novartis announced today that Mayzent has been approved by the US Food and Drug Administration (FDA).^® (siponimod) for the treatment of relapsing forms of multiple sclerosis, including clinically isolated syndrome (CIS), is defined as a first episode of neurological symptoms that lasts at least 24 hours and is caused by inflammation or demyelination of the Central nervous system (CNS)³), relapsing remitting disease and active secondary active disease in adults. SPMS is a debilitating form of multiple sclerosis characterized by a progressive and irreversible neurological handicap.⁴. Mayzent is expected to be available in the United States in about a week. * Patients will not need to observe the first dose (FDO, early cardiac monitoring) unless they have some pre-existing cardiac disorders.

"Delaying the progression of disability is an essential goal of multiple sclerosis treatment and, historically, patients with advanced disease had very few options to help them," he said. Fabrice Chouraqui, President of Novartis Pharmaceuticals Corporation. "We have a long-standing mission to improve understanding of MS and help reinvent treatment options, and we are excited to develop our Mayzent heritage for patients with recurrent forms of MS, including SPMS with active disease. "

Most patients move from RRMS to SPMS over time¹. Therefore, it is essential that patients begin their treatment early to help slow the progression of the disability. The progression of disability usually includes, but is not limited to, an impact on ambulation, which could lead patients to need help with walking or walking. ;A wheelchair.⁵.

"We are grateful that there is a new treatment option for adults with active secondary progressive MS," he said. Bruce Bebo, PhD, Executive Vice President, Research, National MS Society. "We hope this approval will stimulate a conversation between patients and healthcare professionals about the progression of disability after recurrent MS and its early treatment."

Mayzent's approval is based on the results of the EXPAND Phase II, randomized, double-blind, placebo-controlled study that compared the efficacy and safety of Mayzent with placebo in people with MSPS. Patients enrolled in EXPAND were representative of a typical population of patients with MSPS: at the start of the study, patients had an average age of 48 years, lived with MS for about 16 years and over 50% had a median score on the Expanded Disability Status Scale (EDSS). of 6.0 and relies on a walking aid². Mayzent significantly reduced the risk of confirmed 3-month disability progression (primary endpoint, 21% reduction over placebo, p = 0.013, 33% reduction compared to placebo in placebo). Relapsed patients in the two years preceding screening, p =0.01)². Mayzent also cut 55% annualized relapse rate².

The most common side effects (incidence greater than 10%) are headache, hypertension and elevated transaminase.

"With Mayzent's approval, we now have an essential therapeutic option for treating SPMS with an active disease," said a member of the EXPAND Steering Committee. Bruce Cree, MD, Ph.D., MAS, Director of Clinical Research and Full Professor George A. Zimmermann in Multiple Sclerosis, University of California, San Francisco, Medicine School. "It's important to note that health professionals now have even more reasons to help patients identify the evolution of symptoms and to detect early signs of progression."

Novartis is committed to bringing Mayzent to patients around the world. Additional regulatory filings are being filed with other health authorities outside the United States. A regulatory action for Mayzent in the European Union is planned for the end of 2019, and further regulatory measures are planned Swiss, Japan, Australia, and Canada this year.

*The availability period may vary as health care providers incorporate Mayzent into their practices.

About the EXPAND study
EXPAND is a randomized, double-blind, placebo-controlled Phase III study that compares the efficacy and safety of Mayzent with placebo in people with MSPS with different levels of disability. EDSS scores of 3 · 0-6 · 5.². It's the biggest randomized, prospective, a controlled study in SPMS to date, including 1,651 people diagnosed with SPMS from 31 countries². Mayzent has demonstrated that its safety profile is broadly consistent with the known effects of S1P receptor modulation. It reduced the risk of CDP at three months by a statistically significant 21% (p = 0.013, primary endpoint)². CDP was defined as a 1-point increase in the EDSS score, if the initial score was 3, 0-5, 0, or an increase of 0.5, if the initial score was 5, 5-6, 5.². No important differences were found in the T25FW, however, Volume of T2 lesion Has been reduced by 79% compared to placebo². Data on additional secondary endpoints included a 55% relative reduction in ADD and, compared to placebo, more patients were free of gadolinium-enhancing lesions (89%) and new T2 lesions. or enlarged (57%).².

About Mayzent^® (Siponimod)
Mayzent is a selective next generation selective sphingosine 1-phosphate receptor modulator indicated for the treatment of relapsing forms of multiple sclerosis (RMS), including the clinically isolated syndrome (CIS), is defined as a first episode neurological symptoms of a minimum duration of 24 hours. and is caused by inflammation or demyelination of the central nervous system (CNS)³), relapsing remitting disease and active secondary active disease in adults. Mayzent selectively binds to S1P1 and S1P5 receptors. Regarding the S1P1 receptor, it prevents lymphocytes from coming out of the lymph nodes and, therefore, from entering the CNS of patients with MS. This leads to the anti-inflammatory effects of Mayzent². Mayzent also enters the CNS and binds directly to S1P5 and S1P1 sub-receptors of CNS-specific cells (oligodendrocytes and astrocytes).⁶ to prevent inflammation.

About multiple sclerosis
Multiple sclerosis is a chronic disorder of the central nervous system that affects approximately 400,000 people in the United States.⁷. Patients can be diagnosed with the following types of MS: RRMS (the most common form of the condition at the time of diagnosis), SPMS and Primary Progressive SP (PPMS)⁸. MS disrupts the normal functioning of the brain, optic nerves and spinal cord due to inflammation and tissue loss⁹.

SPMS follows an initial form of MS, which accounts for approximately 85% of all MS diagnoses and is characterized by progressive deterioration of neurological function over time³. This leads to a gradual accumulation of neurological disability. There is still a significant need for safe and effective treatments to help delay the progression of disability in the SPMS with active disease (with relapses and / or evidence of a new MRI activity).⁴.

Novartis in neuroscience
Novartis is strongly committed to the field of neuroscience and providing innovative treatments to patients with neurological disorders for whom unmet needs are high. We are committed to helping patients and physicians in many areas including Multiple Sclerosis, Migraine, Alzheimer's Disease, Parkinson's Disease, Epilepsy, and Deficit Hyperactivity Disorder. Beware, and we have a promising pipeline in multiple sclerosis, Alzheimer's disease, spinal muscular atrophy and specialized neurology.

MAYZENT US INDICATION

What are MAYZENT® tablets (siponimod)?
MAYZENT is a prescription medication that is used to treat relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease and progressive active secondary progressive disease, in adults.
It is not known if MAYZENT is safe and effective in children.

IMPORTANT SAFETY INFORMATION:

Do not take MAYZENT if you:

• have a CYP2C9 * 3 / * 3 genotype. Before starting treatment with MAYZENT, your CYP2C9 genotype must be determined by your health care provider. Ask your health care provider if you are unsure.
• you have had a heart attack, a chest pain called unstable angina, a mini-stroke (transient ischemic stroke or TIA) or certain types of heart failure in the last 6 months
• have certain types of heart block or irregular or abnormal heart rhythm (arrhythmia), unless you have a pacemaker

MAYZENT can cause serious side effects, including:

1. Slow heart rate (bradycardia or bradyarrhythmia) when you start taking MAYZENT. MAYZENT may slow your heart rate, especially after the first dose. Before taking your first dose of MAYZENT, you must pbad an electrocardiogram (ECG) test to check the electrical activity of your heart. During the initial update period (4 days for the daily dose of 1 mg or 5 days for the 2 mg daily dose), if you miss one or more doses of MAYZENT, you must restart the update. Call your health care provider if you miss a dose of MAYZENT.
2. Infections MAYZENT may increase the risk of serious infections that can be life threatening and lead to death. MAYZENT reduces the number of white blood cells (lymphocytes) in your blood. This usually returns to normal within 3 to 4 weeks of stopping treatment. Your health care provider should review a recent blood test on your white blood cells before you start taking MAYZENT. If you have any of these symptoms of infection during treatment with MAYZENT and 3 to 4 weeks after your last dose of MAYZENT, call your health care provider immediately: • fever • fatigue • body aches • chills • nausea • vomiting • headache with fever, stiffness of the neck, sensitivity to light, nausea, confusion (it can be symptoms of meningitis, infection of the brain lining and the spine)
3. A vision problem called macular edema. Macular edema can cause the same visual symptoms as a multiple sclerosis (MS) attack (optic neuritis). You may not notice any symptoms of macular edema. If macular edema occurs, it usually starts within 1 to 4 months of starting your MAYZENT treatment. Your health care provider should test your eyesight before you start taking MAYZENT and every time you notice vision changes during MAYZENT treatment. Your risk of macular edema is higher if you are diabetic or have had inflammation of the eye called uveitis. Call your health care provider right away if you have the following symptoms: blur or shadows in the center of your vision, blind spots in the center of your vision, sensitivity to light, or vision with abnormal (tinted) color.

Before taking MAYZENT, tell your health care provider about all your medical conditions, including if you:
• an irregular or abnormal heart rhythm
• have a history of stroke or other blood vessel-related diseases in the brain
• have breathing problems, even while you sleep
• have a fever or infection, you can not fight off infections due to illness, or take medications that weaken your immune system. Tell your health care provider if you have had chicken pox or received the chickenpox vaccine. Your health care provider may have a blood test for the chickenpox virus. You may need to get full treatment for chicken pox and then wait a month before you start taking MAYZENT.
• have a slow heart rate
• have liver problems
• have diabetes
• suffer from eye problems, especially an inflammation of the eye called uveitis
• have high blood pressure
• Are pregnant or planning to become pregnant. MAYZENT can harm your unborn baby. If you become pregnant with MAYZENT treatment or if you become pregnant within 10 days of stopping treatment with MAYZENT, talk to your health care provider immediately.
o If you are a woman who may become pregnant, you should use an effective method of contraception while you are taking MAYZENT and at least 10 days after you stop taking MAYZENT.
• badfeed or plan to badfeed. It is not known if MAYZENT pbades into bad milk. Ask your health care provider what is the best way to feed your baby if you are taking MAYZENT.

Tell your doctor about all the medicines you take, including: prescription drugs, over-the-counter medications, vitamins and herbal supplements. In particular, tell your health care provider if you are taking medicines to control your heart rate (antiarrhythmics), your blood pressure (antihypertensives), or your heartbeat (such as calcium channel blockers or beta-blockers). ; take medications that affect your immune system, such as beta-interferon or glatiramer acetate, or any of those medications that you have taken in the past.

Tell your doctor if you have recently received a live vaccine. You should avoid receiving live vaccines while taking MAYZENT. MAYZENT should be stopped 1 week before and for 4 weeks after vaccination. If you get a live vaccine, you can get the infection it was supposed to prevent. Vaccines may not work as well when administered during treatment with MAYZENT.

MAYZENT may cause side effects, including:

• increase in blood pressure. Your health care provider should check your blood pressure while you are taking MAYZENT.
• liver problems. MAYZENT can cause liver problems. Your health care provider should do blood tests to check your liver before you start taking MAYZENT. Call your health care provider immediately if you have any of the following symptoms of liver problems: nausea o vomiting o stomach ache o tiredness o loss of appetite o your skin or white your eyes turn yellow o dark urine
• breathing problems. Some people who take MAYZENT are short of breath. Call your health care provider immediately if you have new or worsening breathing problems.
• swelling and narrowing of the blood vessels in your brain. A condition called PRES (posterior reversible encephalopathy syndrome) has occurred with drugs of the same clbad. PRES symptoms usually worsen when you stop taking MAYZENT. However, if it is not treated, this can lead to a stroke. Call your health care provider right away if you have any of the following symptoms: sudden and severe headache, sudden confusion, sudden loss of vision or other changes in vision, seizures.
• Serious aggravation of multiple sclerosis after stopping MAYZENT. When MAYZENT is stopped, the symptoms of MS may reappear and worsen compared to before or during treatment. Always consult your doctor before stopping MAYZENT for any reason. If you experience worsening symptoms of MS after stopping MAYZENT, talk to your health care provider.

The most common side effects of MAYZENT are: headaches, high blood pressure and abnormal liver tests.

These are not all the possible side effects of MAYZENT. Call your doctor for medical advice on side effects.

We encourage you to report side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

Please refer to the complete prescribing information, including the Medication Guide.

Warning
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act, 1995. These statements can usually be identified by words such as "potential," "may," "will," "plan," "expect," "anticipate," "anticipate," "believe," " "Experimental", "pipeline", "launch", or similar terms, or through explicit or implicit discussions about potential marketing approvals indications or labeling for the experimental or approved products described in this press release, or regarding the potential future income of these products.You should not place undue reliance on these statements.These forward-looking statements are based on our current beliefs and expectations regarding future events and are subject to important risks and uncertainties, known and unknown. If one or more of these risks or uncertainties materialize, or if the underlying badumptions prove to be incorrect, the actual results could be materially different from those indicated in the forward-looking statements. There can be no guarantee that the experimental or approved products described in this press release will be submitted or approved for sale or for any additional indication or labeling in any market, or at any given time. There is no guarantee that these products will be commercially successful in the future. In particular, uncertainties in research and development, including clinical trial results and additional badysis of existing clinical data, could affect our expectations for these products. regulatory measures or delays or government regulation in general; global trends in health care cost control, including pressure from governments, payers and the general public on prices and reimbursements; our ability to obtain or maintain exclusive intellectual property protection; the particular preferences of doctors and patients in prescribing; general political and economic conditions; safety, quality or manufacturing issues; potential or actual breaches of data security and data confidentiality, or disruption of our computer systems, as well as other risks and factors mentioned in Novartis AG's current Form 20-F, archived by the Securities and Exchange Commission of the United States. Novartis provides the information contained in this press release as of such date and badumes no obligation to update the forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Novartis
Novartis reinvents drugs to improve and extend people's lives. As the world's leading drug company, we use innovative scientific and digital technologies to create transformational therapies in areas of high medical need. In our quest for new medicines, we regularly rank among the world's largest companies investing in research and development. Novartis products reach more than 800 million people around the world and we are finding innovative ways to expand access to our latest treatments. About 130,000 people of nearly 150 nationalities work at Novartis worldwide. Novartis Pharmaceuticals Corporation, a US subsidiary of Novartis, is located in East Hanover, NJ. More information on www.novartis.com.

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References
¹ International Multiple Sclerosis Federation. Atlas of MS 2013. http://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf. Accessed March 21, 2019.
² Kappos L, Cree B, Fox R, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): Phase III double-blind, randomized study. The lancet. Posted online March 22, 2018. http://dx.doi.org/10.1016/S0140-6736(18)30475-6.
³ National Society of Multiple Sclerosis. Clinically Isolated Syndrome (CIS). https://www.nationalmssociety.org/Symptoms-Diagnosis/Clinically-Isolated-Syndrome-(CIS). Accessed March 21, 2019.
⁴ National Society of Multiple Sclerosis. Secondary Progressive MS (SPMS). https://www.nationalmssociety.org/What-is-MS/Types-of-MS/Secondary-progressive-MS. Accessed March 21, 2019.
⁵ Gross H, et al. Characteristics, burden of disease, and physical functioning of patients with progressive or secondary progressive multiple sclerosis: a cross-sectional study conducted in the United States. Neuropsychiatric disease and treatment. 2017 13: 1349-1357.
⁶ Tavares A et al. Brain distribution of MS565, an imaging badogue of siponimod (BAF312), in nonhuman primates. Neurology. 2014; 82 (10): suppl. P1.168.
⁷ Tullman M. Overview of Epidemiology, Diagnosis and Progression of Multiple Sclerosis-Related Disease. Am J Managed Care. 2013 February; 19 (2 Suppl): S15-20.
⁸ Society of Multiple Sclerosis. Types of MS. https://www.mssociety.org.uk/about-ms/types-of-ms. Accessed March 21, 2019.
⁹ PubMed Health. Multiple sclerosis (MS). https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024311/. Accessed March 21, 2019.

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