In its earliest stages, multiple sclerosis (MS) can be difficult to diagnose, with many people having symptoms such as unexplained fatigue, urgent need to urinate, depression, and short-term memory loss for years prior to their diagnosis.1 And in most cases, the disease continues to evolve in unpredictable and often subtle ways — making treatment a perpetual challenge.
MS is an autoimmune disease in which the immune system attacks myelin, the protective coating that surrounds neurons in the brain, spinal cord, and optic nerves. Around 85 percent of people living with MS develop recurrent immune attacks, called relapses. Relapse symptoms range from visual loss out of one eye to numbness and weakness in extremities to spinning sensations and double vision. These unpredictable neurological attacks can worsen rapidly over a few days to several weeks, and recovery may not be complete, which means people living with MS may experience vastly different symptoms.
As people living with MS age, some may start to develop progressively worsening impairment, which is thought to be caused by the accumulation of permanent nerve damage in the central nervous system (neurodegeneration). This disability progression can be assessed by a measurement scale called the Expanded Disability Status Scale (EDSS), which can detect changes over time like muscle weakness, balance problems, and difficulty with multitasking or short-term memory.2 This increasing disability progression that many people with the disease eventually experience may signal a shift from the inflammatory stage of relapsing MS (RMS) to the progressive stage.3
“Evidence supports that injury to the brain and spinal cord can occur early in the disease, which leaves people living with MS at risk for future disability,” says Barry Singer, M.D., Director of The MS Center for Innovations in Care at Missouri Baptist Medical Center, St. Louis. “A major goal for MS treatment is trying to protect the nervous system as much as possible, as soon as possible, in order to slow down disease progression.”
According to Dr. Singer, a comprehensive, holistic approach can be used to address the many components of a person’s life that are impacted by the disease. “Alleviating key symptoms such as fatigue, nerve pain, cramping, and bladder issues has helped many of my patients continue their passions. Great care requires a tailored, collaborative team approach including MS nurses, therapists and subspecialists. A focus on overall wellness is highly important including diet, exercise, mental health, cognitive health, and social connections.”
Traditional approaches to detecting this transition from relapsing MS to early disease progression—such as tracking changes in physical strength and coordination over time—often miss its onset. Evidence of disease progression can include extremely subtle broader symptoms from the EDSS such as mild cognitive decline, trouble with memory or concentration, and other neurologic changes related to MS that are not as easy to measure as changes in physical function.4 As a result, until recently, minimal clinical trial research had specifically focused on patients transitioning to a progressive stage of RMS called active secondary progressive MS (SPMS).5 Recognizing the need to better treat this transition, Novartis researchers concluded that it was crucial to investigate this pivotal moment in the MS disease journey.
“Patients at this stage of RMS are difficult to identify, and there has not been a lot of research in this patient population. Novartis recognized it was time to change the conversation around disease progression by focusing on this critical transition period,” says Dharmesh Patel, M.D., Vice President, Neuroscience Medical Unit Head, Novartis.
Recent diagnostic innovations have enabled scientists to detect and measure subtle signs of disability progression among patients with RMS.6 Novartis used some of these new approaches to identify and follow RMS patients in the earlier stages of disability progression in the EXPAND clinical trial, the largest Phase 3 study of SPMS patients to date,7 which eventually led to the U.S. Food and Drug Administration’s 2019 approval of the oral drug Mayzent® (siponimod). Mayzent is the first and only pill studied and proven to delay disability progression in people with RMS whose disease was more progressed.*
“The EXPAND trial looked at a patient population that’s reflective of a large group of my own MS patients, and those for whom we haven’t had a lot of treatment options historically,” says Dr. Singer. “When discussing therapies to slow down disability progression, it’s important to have evidence from a large clinical trial that supports what we are trying to do in real-world clinical practice.”
The EXPAND trial zeroed in on disability progression by including only those patients who had experienced consistent symptom worsening for three months or more, but not the return to baseline that characterizes the earlier stages of the disease. It assessed disability progression by measuring eight key areas of the EDSS, reflecting changes in cognitive and physical function.
“This trial showed, for the first time, that these transitional or progressive patients do benefit from a specific therapy,” says Dr. Patel. “Mayzent showed consistent benefits in this patient population.”
Physicians, people with RMS, and researchers have always known that the disease does not proceed in a strictly stepwise way.8 The EXPAND trial confirmed that the transition to SPMS is gradual, and that inflammation overlaps with nerve damage. We still need additional rigorous research and disease monitoring methods that detect subtle and gradual changes, especially in cognitive functions, which can be difficult to track in daily life. This will allow physicians to further hone in on the right medicines or combinations of medicines to use—including traditional MS disease-modifying treatments—at the right time.
We also need to better understand the biological mechanisms that underlie RMS progression, so researchers can develop new treatments that slow it. According to both Dr. Singer and Dr. Patel, an emerging research path is around brain cells called microglia, which may have the potential to address both inflammatory and neurodegenerative components to fight MS,9 and on finding ways to restore the protective nerve cell coating that is steadily lost in progressive forms of the disease.
“At Novartis, we constantly strive to address unmet needs in every disease area that we study,” says Dr. Patel. “By better understanding the drivers of nerve damage in MS, we have the potential to give patients who confront advancing disability even more possibilities and hope for a healthier future.”
*Mean EDSS score of 5.4
What is MAYZENT® (siponimod) tablets?
MAYZENT is a prescription medicine that is used to treat relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and 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 should be determined by your health care provider. Ask your health care provider if you are not sure.
- have had a heart attack, chest pain called unstable angina, stroke or mini-stroke (transient ischemic attack or TIA), or certain types of heart failure in the last 6 months
- have certain types of heart block or irregular or abnormal heartbeat (arrhythmia), unless you have a pacemaker
MAYZENT may cause serious side effects, including:
During the initial updosing period (4 days for the 1-mg daily dose or 5 days for the 2-mg daily dose), if you miss 1 or more doses of MAYZENT, you need to restart the updosing. Call your health care provider if you miss a dose of MAYZENT.
Call your health care provider right away if you have any of these symptoms of an infection during treatment with MAYZENT and for 3 to 4 weeks after your last dose of MAYZENT:
- fever
- tiredness
- body aches
- chills
- nausea
- vomiting
- headache with fever, neck stiffness, sensitivity to light, nausea, confusion (these may be symptoms of meningitis, an infection of the lining around your brain and spine)
Call your health care provider right away if you have any of the following: blurriness or shadows in the center of your vision, a blind spot in the center of your vision, sensitivity to light, or unusually colored (tinted) vision.
Before taking MAYZENT, tell your health care provider about all of your medical conditions, including if you:
- have an irregular or abnormal heartbeat
- have a history of stroke or other diseases related to blood vessels in the brain
- have breathing problems, including during your sleep
- have a fever or infection, or you are unable to fight infections due to a disease or are taking medicines that lower your immune system. Tell your health care provider if you have had chickenpox or have received the vaccine for chickenpox. Your health care provider may do a blood test for chickenpox virus. You may need to get the full course of vaccine for chickenpox and then wait 1 month before you start taking MAYZENT.
- have slow heart rate
- have liver problems
- have diabetes
- have eye problems, especially an inflammation of the eye called uveitis
- had or now have a type of skin cancer called basal cell carcinoma (BCC), melanoma, or squamous cell carcinoma
- have high blood pressure
- are pregnant or plan to become pregnant. MAYZENT may harm your unborn baby. Talk to your health care provider right away if you become pregnant while taking MAYZENT or if you become pregnant within 10 days after you stop taking MAYZENT.
- If you are a woman who can become pregnant, you should use effective birth control during your treatment with MAYZENT and for at least 10 days after you stop taking MAYZENT.
- Pregnancy Registry: There is a registry for women who become pregnant during treatment with MAYZENT. If you become pregnant while taking MAYZENT, talk to your health care provider. For more information or to register, contact MotherToBaby by calling 1-877-311-8972, by sending an email to MotherToBaby@health.ucsd.edu, or go to www.mothertobaby.org/join-study.
- are breastfeeding or plan to breastfeed. It is not known if MAYZENT passes into your breast milk. Talk to your health care provider about the best way to feed your baby if you take MAYZENT.
Tell your health care provider about all the medicines you take, including prescription medicines, over-the-counter medicines, vitamins, and herbal supplements. Especially tell your health care provider if you take medicines to control your heart rhythm (anti-arrhythmics), or blood pressure (antihypertensives), or heart beat (such as calcium channel blockers or beta-blockers); take medicines that affect your immune system, such as beta-interferon or glatiramer acetate, or any of these medicines that you took in the past.
Tell your health care provider if you have recently received a live vaccine. You should avoid receiving live vaccines during treatment with MAYZENT. MAYZENT should be stopped 1 week before and for 4 weeks after receiving a live vaccine. If you receive a live vaccine, you may get the infection the vaccine was meant to prevent. Vaccines may not work as well when given during treatment with MAYZENT.
MAYZENT may cause possible side effects, including:
- increased blood pressure. Your health care provider should check your blood pressure during treatment with MAYZENT.
- liver problems. MAYZENT may 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 right away if you have any of the following symptoms of liver problems:
- nausea
- vomiting
- stomach pain
- tiredness
- loss of appetite
- your skin or the whites of your eyes turn yellow
- dark urine
- breathing problems. Some people who take MAYZENT have shortness of breath. Call your health care provider right away 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 happened with drugs in the same class. Symptoms of PRES usually get better when you stop taking MAYZENT. However, if left untreated, it may lead to a stroke. Call your health care provider right away if you have any of the following symptoms: sudden severe headache, sudden confusion, sudden loss of vision or other changes in vision, or seizure.
- severe worsening of multiple sclerosis after stopping MAYZENT. When MAYZENT is stopped, symptoms of MS may return and become worse compared to before or during treatment. Always talk to your doctor before you stop taking MAYZENT for any reason. Tell your health care provider if you have worsening symptoms of MS after stopping MAYZENT.
- a type of skin cancer called basal cell carcinoma (BCC), melanoma, and squamous cell carcinoma. Tell your doctor if you have any changes in the appearance of your skin, including changes in a mole, a new darkened area on your skin, a sore that does not heal, or growths on your skin, such as a bump that may be shiny, pearly white, skin-colored, or pink. Your doctor should check your skin for any changes at the start of and during treatment with MAYZENT. Limit the amount of time you spend in sunlight and ultraviolet (UV) light. Wear protective clothing and use a sunscreen with a high sun protection factor.
The most common side effects of MAYZENT include: headache, high blood pressure (hypertension), and abnormal liver tests.
These are not all of the possible side effects of MAYZENT. Call your doctor for medical advice about side effects.
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.
Please see full Prescribing Information, including Medication Guide.
Dr. Singer is a consultant for Novartis.
References
- National Multiple Sclerosis Society. Multiple Sclerosis FAQs. Accessed April 9, 2021. https://www.nationalmssociety.org/What-is-MS/MS-FAQ-s#question-Why-is-MS-so-difficult-to-diagnose
- Hauser SL, Oksenberg JR. The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron. 2006;52(1):61-76.
- National Multiple Sclerosis Society. MS Symptoms. Accessed April 9, 2021. https://www.nationalmssociety.org/Symptoms-Diagnosis/MS-Symptoms
- O’Loughlin E, Hourihan S, Chataway J, et al. The experience of transitioning from relapsing remitting to secondary progressive multiple sclerosis: views of patients and health professionals. Disabil Rehabil. 2017;39(18):1821-1828.
- National Multiple Sclerosis Society. Secondary Progressive MS (SPMS). Accessed April 9, 2021. https://www.nationalmssociety.org/What-is-MS/Types-of-MS/Secondary-progressive-MS
- Inojosa H, Proschmann U, Akgün K, Ziemssen T. A focus on secondary progressive multiple sclerosis (SPMS): challenges in diagnosis and definition.
J Neurol. 2021;268(4):1210-1221. - Kappos L, Bar-Or A, Cree BAC, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomized, phase 3 study. Lancet. 2018;(10127):1263-1273. Doi: 10.1016/S0140-6736(18)30475-6.
- Guthrie E. Multiple sclerosis: a primer and update. Adv Studies Pharm. 2007;4(11):313-317.
- Fatoba O, Itokazu T, Yamashita T, et al. Microglia as therapeutic target in central nervous system disorders. J Pharmacol Sci 2020; 144:102-118.
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