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Relapsing-remitting Multiple Sclerosis (RRMS)

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What is relapsing-remitting multiple sclerosis (RRMS)?

Multiple sclerosis is an unpredictable disease of the central nervous system that disrupts the flow of information within the brain, and between the brain and body. Relapsing-remitting multiple sclerosis (RRMS) is the most common course of MS.

If you have RRMS, you will experience clearly defined attacks of new or increasing neurologic symptoms. These attacks — also called “ relapses” or “exacerbations ” — are followed by periods of partial or complete recovery (remissions). During remissions, all symptoms may disappear, or some symptoms may continue and become permanent. However, there is no apparent progression of the disease during the periods of remission.

RRMS can be further characterized as either  active  (with relapses and/or evidence of new MRI activity over a specified period of time) or  not active , as well as  worsening  (a confirmed increase in disability following a relapse) or  not worsening .

Approximately 85 percent of people with MS are initially diagnosed with RRMS.

This graphic shows the kinds of disease activity that can occur in RRMS though each person's experience with RRMS will be unique. Following a relapse, the new symptoms may disappear without causing any increase in level of disability, or the new symptoms may only partially disappear, resulting in an increase in disability. New lesions on MRI, as shown by the arrows, often occur as part of a relapse. However, new MRI lesions indicating MS activity may also occur without symptoms of which the person is aware.

What happens in RRMS?

RRMS is defined by inflammatory attacks on myelin — the fatty substance that surrounds and insulates nerve fibers (axons) — as well as the nerve fibers themselves. During these inflammatory attacks, activated immune cells cause small, localized areas of damage that produce the symptoms of MS . Because the location of the damage is so variable, no two people have exactly the same symptoms.

How do I know if my disease course is stable?

Disease activity and worsening should be evaluated at regular intervals by neurologic examination and MRI. Being able to characterize the course of your disease at different points in time helps you and your MS care provider discuss your treatment options and expected outcomes. For example:

• If you have RRMS that is active and worsening, you and your MS care provider may want to discuss a different treatment approach than if there were no evidence of activity or worsening. Together, you can weigh the potential risks and benefits of other treatment options.
• If your symptoms have not worsened while on your current treatment, but you have evidence of new disease activity on your MRI, you and your healthcare provider may discuss switching to another treatment with a different mechanism of action in order to control the disease activity more effectively and help prevent worsening.

If your RRMS is stable without evidence of MRI activity or worsening, you and your healthcare provider can feel confident that the current treatment regimen is working effectively.

How does RRMS differ from progressive types of MS?

While RRMS is defined by attacks or relapses of new MS symptoms, progressive forms of MS involve fewer attacks and are characterized by gradual accumulation of disability.

• People with RRMS tend to develop more new brain lesions — also called “plaques” or “scars” — on magnetic resonance imaging (MRI) scans.
• People with RRMS tend to have more inflammatory lesions on MRI (seen when gadolinium dye is used during the MRI).
• People with  primary progressive MS (PPMS)  tend to have more spinal cord lesions.
• In RRMS, women are affected two to three times as often as men. In PPMS, the number of women and men are approximately equal.

RRMS is generally diagnosed earlier than the progressive disease courses.

• Most people with RRMS are diagnosed in their 20s and 30s (although it can occur in childhood or later adulthood) while PPMS is typically diagnosed during the 40s or 50s.
• The transition from RRMS to SPMS generally occurs in people who have been living with RRMS for at least 10 years.

RRMS symptoms

The most common  symptoms  reported in RRMS include episodic bouts of:

• Bowel and bladder problems
• Problems with cognition (learning and memory or information processing)
• Spasticity or stiffness
• Vision problems

People with progressive forms of MS are also more likely to experience  problems with walking and mobility that gradually worsen over time, along with whatever other symptoms they may have.

Managing MS relapses

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Stories and advice from people living with relapsing-remitting MS

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5 Fun Things to Do During an MS Flare-Up

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Drive-By Criticism: Handicapped Parking and Relapsing-Remitting MS

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INTRODUCTION

The onset and phenotypes of MS will be reviewed here. Other aspects of MS are discussed separately:

● Pathogenesis and epidemiology of multiple sclerosis

● Management of clinically and radiologically isolated syndromes suggestive of multiple sclerosis

● Manifestations of multiple sclerosis in adults

AARON SAGUIL, MD, MPH, EDWIN A. FARNELL, IV, MD, AND TENEISHA S. JORDAN, MD

Am Fam Physician. 2022;106(2):173-183

Author disclosure: No relevant financial relationships.

Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system and the most common cause of nontraumatic neurologic disability in young adults. Types of MS include relapsing-remitting (most common), secondary progressive, and primary progressive. Clinically isolated syndrome and radiologically isolated syndrome are additional categories for patients with findings concerning for MS who do not yet meet the diagnostic criteria for the disease. Symptoms of MS depend on the areas of neuronal involvement. Common symptoms include sensory disturbances, motor weakness, impaired gait, incoordination, optic neuritis, and Lhermitte sign. A patient history, neurologic examination, and application of the 2017 McDonald Criteria are needed to diagnose MS accurately. Patients with MS should be treated by a multidisciplinary team that may include physical and occupational therapists, speech and language therapists, mental health professionals, pharmacists, dietitians, neurologists, and family physicians. Steroids are the mainstay of treatment for the initial presentation of MS and relapses. Patients who do not adequately respond to steroids may benefit from plasmapheresis. Patients with MS who smoke tobacco should be strongly encouraged to quit. Disease-modifying therapy has been shown to slow disease progression and disability; options include injectable agents, infusions, and oral medications targeting different sites in the inflammatory pathway. Symptom-based care is important to address the bowel and bladder dysfunction, depression, fatigue, movement disorders, and pain that often complicate MS.

Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system and the most common cause of nontraumatic neurologic disability in young adults. 1 Prevalence differs by latitude, with higher rates among those living further from the equator. The prevalence of MS is 40 per 100,000 people in Lubbock, Tex., compared with 191 per 100,000 people in Olmstead County, Minn. 2 An estimated 1 million people in the United States live with MS. 1 Risk factors include smoking and a history of infectious mononucleosis. Women are twice as likely as men to have MS, and there is a modest genetic influence. 3 , 4

A woman with MS diagnosed at 35 years of age has an average life expectancy of seven to eight years less than that of the general population. Because MS has a relatively high prevalence and patients have a long life span after diagnosis, many family physicians care for patients with the disease. 5

Pathophysiology

Types of MS include relapsing-remitting (RRMS; most common), secondary progressive, and primary progressive ( Table 1 6 – 13 ) . There are also classifications for people with first episodes concerning for MS who do not meet the diagnostic criteria for MS (clinically isolated syndrome) and those with incidental radiologic findings concerning for MS in the absence of clinical symptoms (radiologically isolated syndrome). 13

MS is characterized by focal areas of inflammation, demyelination, gliosis (proliferation and activation of glial cells), and degeneration (axonal loss) secondary to immune-mediated attacks. 10 There is debate about whether the inflammation leading to MS is initiated within or outside the central nervous system; however, T cells, B cells, macrophages (including central nervous system microglia), astrocytes, inflammatory mediators, and blood-brain barrier permeability are all involved in a response that is associated with myelin sheath destruction, axonal injury, and clinical symptoms. 4 , 10 , 14 – 16 In RRMS, clinical lesions may resolve through mechanisms such as axonal changes, neuroplasticity, and remyelination. 13 Progressive forms of MS are associated with cumulative axonal loss and increasing neurologic deficits. 10

Clinical Presentation

Symptoms and signs of MS depend on the areas of neuronal involvement 17 ( Table 2 1 , 18 – 22 ) . Common presenting symptoms include sensory disturbances, motor weakness, impaired gait, incoordination, optic neuritis (unilateral vision loss with pain worsened by extraocular movements), and Lhermitte sign (an electric shock–like sensation down the spine on neck flexion). 18 – 20 Other symptoms include urinary, bowel, and sexual dysfunction.

In RRMS, relapse symptoms evolve over days before partially or fully resolving, and patients are typically stable between acute exacerbations. Some symptoms, such as fatigue, can be persistent. 20 , 23

Multiple diseases may mimic MS clinically and radiologically ( Table 3 ) . 13 , 18 , 23 , 24 The differential diagnosis includes genetic, infectious, inflammatory, metabolic, and neoplastic processes. Psychiatric diseases, ingestions, and nutritional deficiencies may also be mistaken for MS. 13 , 18 , 23 , 24 Table 4 lists tests that may help differentiate MS from other diseases. 18

A patient history, neurologic examination, and application of the 2017 McDonald Criteria are needed to accurately diagnose MS ( Table 5 ) . 25 Diagnosis relies on the acute exacerbations of MS being disseminated in space and time ( Figure 1 18 ) . In cases where only part of the diagnostic criteria are met, magnetic resonance imaging (MRI) of the brain and spine may be used to confirm the presence of lesions consistent with MS ( Figure 2 , Figure 3 , and  Figure 4 ) . 18 Cerebrospinal fluid assays demonstrating oligoclonal bands may also aid in meeting diagnostic criteria. 25

The diagnosis should be questioned if the patient has a family history of neurologic disorders other than MS, an abrupt or transient (less than 24 hours) presentation, progressive ataxia, cognitive dysfunction, other organ involvement, or nonspecific neurologic symptoms that are difficult to localize. 13 , 20 , 26

Patients with MS should be treated by a multidisciplinary team that may include physical and occupational therapists, speech and language therapists, mental health professionals, pharmacists, dietitians, neurologists, and family physicians. 27

INITIAL PRESENTATION AND ACUTE RELAPSES

Steroids are the mainstay of treatment for the initial presentation of MS and MS relapses. A Cochrane review and another systematic review and meta-analysis found no difference in effectiveness between intravenous and oral steroids for relapse recovery or MRI activity. 28 , 29 A higher dosage of steroids, such as 1,000 mg per day of methylprednisolone (intravenously or orally) for three days, is recommended. 30 , 31 Patients who do not have an adequate response to treatment with steroids may benefit from plasmapheresis. 30 , 32 A randomized controlled trial involving six plasmapheresis treatments in patients unresponsive to steroids found higher rates of complete recovery at one month than in those treated with placebo. 33

SMOKING CESSATION

Patients with MS who smoke tobacco should be strongly encouraged to quit. A cohort study found that each smoke-free year was associated with a decrease in disability progression. 34 A cross-sectional study found that each additional year of smoking accelerated the development of secondary progressive MS by 4.7% (95% CI, 2.3 to 7.2). 35

DISEASE-MODIFYING THERAPY

In patients with active MS, long-term disease-modifying therapy should be initiated to decrease new clinical attacks and radiographic lesions and delay disability progression. 36 , 37 There is disagreement about whether to use disease-modifying therapy in patients with clinically isolated syndrome. 36 – 38

Interferon beta-1b (Betaseron, Extavia) was the first disease-modifying therapy approved for use in 1993. Since then, multiple injectable agents, infusions, and oral medications such as monoclonal antibodies and other immunomodulatory medications targeting multiple steps in the MS inflammatory pathway have been approved by the U.S. Food and Drug Administration ( Table 6 ) . 13 , 37 – 39

The choice of initial disease-modifying therapy is dependent on patient preference, disease activity, potential adverse effects, and specialist input. All approved agents help prevent disease progression, with a relative risk of progression from 0.47 for mitoxantrone to 0.87 for interferon beta-1a (Avonex, Rebif). 40 For patients with less active disease, agents with a lower risk of adverse effects (e.g., cardiac arrhythmia, increased risk of malignancy, progressive multifocal leukoencephalopathy) are preferred at the cost of effectiveness. For patients with more active disease, effectiveness may be considered more important than avoiding adverse effects. Shared decision-making conversations should consider the availability of the medication options, route and frequency of administration, patient preferences regarding effectiveness vs. adverse effects, and the patient's ability to tolerate and comply with monitoring regimens. 36 , 37

For patients who have newly diagnosed RRMS with minimal symptoms and MRI burden of disease, an appropriate regimen may include a moderately effective agent such as interferon or glatiramer (Copaxone, Glatopa) to control disease activity while minimizing adverse effects. In patients with newly diagnosed, rapidly evolving RRMS, a highly effective agent such as alemtuzumab (Lemtrada), cladribine (Mavenclad), natalizumab (Tysabri), or ocrelizumab (Ocrevus) may be considered. A greater risk of debilitating adverse effects is weighed against a greater chance of controlling disease activity in this strategy. 38 Ocrelizumab is the only disease-modifying therapy currently approved by the U.S. Food and Drug Administration for primary progressive MS. 39

Medications should be continued for at least six months to allow time for benefits to occur. If the disease is not controlled by initial therapy, the patient should be offered a more effective medication, recognizing the increased potential for adverse effects. 37 , 38 It is appropriate to consider switching medications if adverse effects develop. 37

Once started, disease-modifying therapy is generally continued for the patient's lifetime; however, guidelines allow for exceptions. Discontinuation can be considered for patients with secondar y progressive MS who have a higher level of disability, are nonambulatory, and have not had a relapse in two years. Discontinuation can also be considered before conception for patients who want to become pregnant and have well-controlled MS. 37 , 38 During pregnancy, patients tend to have a lower risk of flare-ups, with overall better-controlled disease. 41

In addition to disease-modifying therapy, preliminary research suggests that hematopoietic stem cell transplantation may be a more effective alternative in preventing relapses and disability accumulation. 42

SYMPTOM-BASED CARE

In addition to treatment directed at acute relapses and disease progression, patients with MS require a comprehensive program that addresses overall wellness, symptom management, and comorbid mental health and physical conditions ( Table 7 ) . 13 , 22 , 38 , 43 – 85 A multidisciplinary approach is most effective for many symptoms. Physical activity has good evidence for improving walking ability (increased distance on six-minute walking test, faster times on 10-minute walking test), balance (as measured by the Berg Balance Scale), and depression (decreased scores on depression scales). 43 – 45 Pharmacotherapy used for symptoms associated with MS is often off-label and supported by low-quality evidence. A notable exception is dalfampridine extended-release (Ampyra), which has been approved by the U.S. Food and Drug Administration to improve walking in patients with MS. 86 Pain is treated with analgesics, neuromodulators, hydrotherapy, and sometimes cannabinoids. 49 , 82 , 84

More than one-half of patients with untreated RRMS transition to secondary progressive disease. 36 Greater disability and brain atrophy at the time of diagnosis, male sex, and older age are risk factors for progression to more significant functional limitations. 13 Disease-modifying therapy has been shown to alter the course of MS, decreasing the rate at which disability progresses, and is also associated with a lower likelihood of transitioning to progressive disease. 37 , 87

Many governments, nonprofit organizations, and websites provide information and support for individuals and families affected by MS ( eTable A ) .

This article updates previous articles on this topic by Saguil, et al. , 18  and Calabresi . 88

Data Sources: PubMed, the Cochrane Database of Systematic Reviews, Essential Evidence Plus, the National Institute for Health and Care Excellence (UK), and the European Committee for Treatment and Research in Multiple Sclerosis were searched for relevant articles and clinical practice guidelines. Key words included multiple sclerosis, demyelinating disorders, disease-modifying treatment, and others as directed by the search. Search dates: August 2021 and May 2022.

Editor's Note: Dr. Saguil is a contributing editor for AFP .

The views expressed in this article are those of the authors and do not reflect the official policy of the U.S. Army or the Uniformed Services University of the Health Sciences.

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• Patient Care & Health Information
• Diseases & Conditions
• Multiple sclerosis
• What is multiple sclerosis? An expert explains

Learn more from neurologist Oliver Tobin, M.B., B.Ch., B.A.O., Ph.D.

I'm Dr. Oliver Tobin, a neurologist specializing in multiple sclerosis at Mayo Clinic. In this video, we'll be covering the basics of multiple sclerosis. What is it? Who gets it? The symptoms, diagnosis, and treatment. Whether you're looking for answers about your own health or that of someone you love, we're here to provide you with the best information available. Multiple sclerosis is a disorder in which the body's immune system attacks the protective covering of the nerve cells in the brain, optic nerve and spinal cord, called the myelin sheath. And this sheath is often compared to the insulation on an electrical wire. When that covering is damaged, it exposes the actual nerve fiber, which can slow or block the signals being transmitted within it. The nerve fibers themselves might also be damaged. The body can repair damage to the myelin sheath, but it's not perfect. The resulting damage leaves lesions or scars, and this is where the name comes from: multiple sclerosis, multiple scars. Now everyone loses brain cells and spinal cord cells as they get older. But if part of the brain or spinal cord has been damaged by MS, the nerve cells in that area will die off faster than the areas around it that are normal. This happens very slowly, usually over decades and typically shows up as gradual walking difficulty happening over several years. When you read about multiple sclerosis, you may hear about different types -- the most frequent being relapsing-remitting multiple sclerosis. And this is characterized by attacks, or relapses.

We don't know what causes MS, but there are certain factors that may increase the risk or trigger its onset. So while MS can occur at any age, it mostly makes its first appearance in people between the ages of 20 and 40. Low levels of vitamin D and low exposure to sunlight, which enables our body to make vitamin D, are associated with an increased risk of developing MS. As people who have MS who have low vitamin D tend to have more severe disease. So people who are overweight are more likely to develop MS and people who have MS and are overweight tend to have more severe disease and a faster onset of progression. People who have MS and who smoke tend to have more relapses, worse progressive disease, and worse cognitive symptoms. Women are up to three times as likely as men to have relapsing-remitting MS. The risk for MS in the general population is about 0.5%. If a parent or sibling has MS, your risk is about twice that or about 1%. Certain infections are also important. A variety of viruses have been linked to MS, including Epstein-Barr virus, which causes mono. Northern and southern latitudes have a higher prevalence, including Canada, the northern US, New Zealand, southeastern Australia, and Europe. White people, especially of northern European descent, are at the highest risk. People of Asian, African, and Native American ancestry have the lowest risk. A slightly increased risk is seen if a patient already has autoimmune thyroid disease, pernicious anemia, psoriasis, type 1 diabetes, or inflammatory bowel disease.

Symptoms of a relapse usually come on over 24 to 48 hours, last for a few days to a few weeks and then improve in the region of 80 to a 100 percent. Those symptoms include loss of vision in an eye, loss of power in an arm or leg or a rising sense of numbness in the legs. Other common symptoms associated with MS include spasms, fatigue, depression, incontinence issues, sexual dysfunction, and walking difficulties.

There's currently no single test to make a diagnosis of MS. However, there are four key features which help to secure the diagnosis. Firstly, are there typical symptoms of multiple sclerosis? Again, those are loss of vision in an eye, loss of power in an arm or leg, or sensory disturbance in an arm or leg lasting for more than 24 hours. Secondly, do you have any physical examination findings consistent with MS? Next, is the MRI of your brain or spine consistent with MS? Now here it's important to note that 95 percent of people over the age of 40 have an abnormal brain MRI, just the same as many of us have wrinkles on our skin. Lastly, are the results of the spinal fluid analysis consistent with MS? Your doctor may recommend blood tests to check for other diseases that share the same symptoms. They may also recommend an OCT test or optical coherence tomography. This is a short scan of the thickness of the layers at the back of your eye.

So the best thing to do when living with MS is to find a trusted interdisciplinary medical team that can help you monitor and manage your health. Having a multidisciplinary team is essential for addressing the individual symptoms that you're experiencing. If you have an MS attack or relapse, your doctor may prescribe you corticosteroids to reduce or improve your symptoms. And if your attack symptoms do not respond to steroids, another option is plasmapheresis or plasma exchange, which is a treatment similar to dialysis. About 50 percent of people who do not respond to steroids have a significant improvement with a short course of plasma exchange. There are over 20 medications currently approved for prevention of MS attacks and prevention of new MRI lesions.

As learning to function with MS can be challenging, there are medical experts ready to work with you to help you manage it, so you can still live a full life. Consulting with a physiatrist, physical or occupational therapist can help you deal with physical difficulties. Physical activity is strongly recommended for all people with MS. Mental health is also an important consideration. So keeping up personal connections with friends and family and trying to stay involved with your hobbies is important. But also be kind to yourself and realistic about what you're up for. This can change from day to day, so it's okay to give yourself permission if something seems like too much or if you need to cancel plans. You may also find support groups helpful to connect with people who understand what you are going through and discuss your feelings and concerns with a doctor or a counselor. Meanwhile, scientists are hard at work, expanding our understanding of this disease and developing new treatments and medications which are ever more effective. If you want to learn more, watch more of our videos or visit mayoclinic.org. We wish you well.

In multiple sclerosis, the protective coating on the nerve fibers (myelin) is damaged and may eventually be destroyed. Depending on where the nerve damage occurs, MS can affect vision, sensation, coordination, movement, and bladder or bowel control.

Multiple sclerosis (MS) is a potentially disabling disease of the brain and spinal cord (central nervous system).

In MS , the immune system attacks the protective sheath (myelin) that covers nerve fibers and causes communication problems between your brain and the rest of your body. Eventually, the disease can cause permanent damage or deterioration of the nerve fibers.

Signs and symptoms of MS vary widely between patients and depend on the location and severity of nerve fiber damage in the central nevous system. Some people with severe MS may lose the ability to walk independently or ambulate at all. Other individuals may experience long periods of remission without any new symptoms depending on the type of MS they have.

There's no cure for multiple sclerosis. However, there are treatments to help speed the recovery from attacks, modify the course of the disease and manage symptoms.

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• Myelin damage and the nervous system

In multiple sclerosis, the protective coating on nerve fibers (myelin) in the central nervous system is damaged. This creates a lesion that, depending on the location in the central nervous system, may cause symptoms such as numbness, pain or tingling in parts of the body.

Multiple sclerosis signs and symptoms may differ greatly from person to person and over the course of the disease depending on the location of affected nerve fibers.

Common symptoms include:

• Numbness or weakness in one or more limbs that typically occurs on one side of your body at a time
• Electric-shock sensations that occur with certain neck movements, especially bending the neck forward (Lhermitte sign)
• Lack of coordination
• Unsteady gait or inability to walk
• Partial or complete loss of vision, usually in one eye at a time, often with pain during eye movement
• Prolonged double vision
• Blurry vision
• Problems with sexual, bowel and bladder function
• Slurred speech
• Cognitive problems
• Mood disturbances

When to see a doctor

See a doctor if you experience any of the above symptoms for unknown reasons.

Disease course

Most people with MS have a relapsing-remitting disease course. They experience periods of new symptoms or relapses that develop over days or weeks and usually improve partially or completely. These relapses are followed by quiet periods of disease remission that can last months or even years.

Small increases in body temperature can temporarily worsen signs and symptoms of MS . These aren't considered true disease relapses but pseudorelapses.

At least 20% to 40% of those with relapsing-remitting MS can eventually develop a steady progression of symptoms, with or without periods of remission, within 10 to 20 years from disease onset. This is known as secondary-progressive MS .

The worsening of symptoms usually includes problems with mobility and gait. The rate of disease progression varies greatly among people with secondary-progressive MS .

Some people with MS experience a gradual onset and steady progression of signs and symptoms without any relapses, known as primary-progressive MS .

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Multiple sclerosis care at Mayo Clinic

• Multiple sclerosis: Can it cause seizures?

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The cause of multiple sclerosis is unknown. It's considered an immune mediated disease in which the body's immune system attacks its own tissues. In the case of MS , this immune system malfunction destroys the fatty substance that coats and protects nerve fibers in the brain and spinal cord (myelin).

Myelin can be compared to the insulation coating on electrical wires. When the protective myelin is damaged and the nerve fiber is exposed, the messages that travel along that nerve fiber may be slowed or blocked.

It isn't clear why MS develops in some people and not others. A combination of genetics and environmental factors appears to be responsible.

Risk factors

These factors may increase your risk of developing multiple sclerosis:

• Age. MS can occur at any age, but onset usually occurs around 20 and 40 years of age. However, younger and older people can be affected.
• Sex. Women are more than 2 to 3 times as likely as men are to have relapsing-remitting MS .
• Family history. If one of your parents or siblings has had MS , you are at higher risk of developing the disease.
• Certain infections. A variety of viruses have been linked to MS , including Epstein-Barr, the virus that causes infectious mononucleosis.
• Race. White people, particularly those of Northern European descent, are at highest risk of developing MS . People of Asian, African or Native American descent have the lowest risk. A recent study suggests that the number of Black and Hispanic young adults with multiple sclerosis may be greater than previously thought.
• Climate. MS is far more common in countries with temperate climates, including Canada, the northern United States, New Zealand, southeastern Australia and Europe. Your birth month may also affect the chances of developing multiple sclerosis, since exposure to the sun when a mother is pregnant seems to decrease later development of multiple sclerosis in these children.
• Vitamin D. Having low levels of vitamin D and low exposure to sunlight is associated with a greater risk of MS .
• Your genes. A gene on chromosome 6p21 has been found to be associated with multiple sclerosis.
• Obesity. An association with obesity and multiple sclerosis has been found in females. This is especially true for female childhood and adolescent obesity.
• Certain autoimmune diseases. You have a slightly higher risk of developing MS if you have other autoimmune disorders such as thyroid disease, pernicious anemia, psoriasis, type 1 diabetes or inflammatory bowel disease.
• Smoking. Smokers who experience an initial symptom that may signal MS are more likely than nonsmokers to develop a second event that confirms relapsing-remitting MS .

Complications

People with multiple sclerosis may also develop:

• Muscle stiffness or spasms
• Severe weakness or paralysis, typically in the legs
• Problems with bladder, bowel or sexual function
• Cognitive problems, like forgetfulness or word finding difficulties
• Mood problems, such as depression, anxiety or mood swings
• Seizures, though very rare
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• Kappos L, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): A double-blind, randomized, phase 3 study. The Lancet. 2018; doi: 10.1016/S0140-6736(18)30475-6.
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• Pantavou KG, et al. Season of birth and multiple sclerosis: A systematic review and multivariate meta-analysis. Journal of Neurology. 2020; doi:10.1007/s00415019-09346-5.
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• Acetyl-L-carnitine: Can it relieve MS fatigue?
• Demyelinating disease: What can you do about it?
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• Explaining multiple sclerosis
• Infographic: Multiple Sclerosis
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Health Encyclopedia

Relapsing-remitting multiple sclerosis, what is relapsing-remitting multiple sclerosis.

In multiple sclerosis (MS), the central nervous system, which includes the brain and spinal cord, becomes damaged. MS causes the immune system to attack the myelin, which is the insulation protecting the nerves. The nerves themselves can also be damaged. When myelin or the nerves become damaged, nerves can't correctly pass along their signals. The damaging process forms scar tissue called sclerosis, which gives the disease its name of multiple sclerosis.

Different types of MS affect people in different ways. One type is called relapsing-remitting MS. With this type, you have flare-ups of the disease, or relapses. Between these flare-ups, you have periods of recovery, or remissions. During a remission, all symptoms may not improve completely. This leads to symptoms getting worse with each flare-up.

Most people diagnosed with MS start off with the relapsing-remitting type. In most cases, the course of the disease changes after a few decades and is then likely to become steadily worse.

MS most often develops in people in their 20s and 30s. Women are twice as likely to have MS as men.

What causes relapsing-remitting MS?

MS occurs when your body’s immune system attacks the central nervous system, damaging the myelin that protects nerve fibers. Experts believe that environmental factors trigger the disease in people whose genetics make them susceptible to MS.

Who is at risk for relapsing-remitting MS?

Scientists think MS may be caused by an infection that lays dormant in the body, such as Epstein-Barr Virus (the virus that causes infectious mononucleosis).

Scientists also think there may be a genetic susceptibility for some people.

Cigarette smoking appears to increase risk.

What are the symptoms of relapsing-remitting MS?

These are often the earliest symptoms of MS:

Trouble seeing

Sensitivity to heat

Numbness, especially in the feet

Severe tiredness (fatigue)

Trouble thinking clearly

Needing to urinate urgently

Trouble with balance

Lack of coordination

Relapsing-remitting MS is marked by relapses that last at least 24 hours. During a relapse, symptoms get worse. A relapse will be followed by a remission. During a remission, symptoms partly or completely go away.

How is relapsing-remitting MS diagnosed?

Healthcare providers use many tests to help diagnose MS. Your healthcare provider will ask you questions about your symptoms. It's important to rule out other diseases that can cause similar symptoms.

Your healthcare provider will also check to see how well your vision, your sense of balance, and other functions are working. You will need an MRI of your brain and spine. This may find areas of damage in your brain or spinal cord that suggest you may have MS.

Another possible test measures what’s called visual evoked potentials. Painless electrodes placed on your scalp measure how your brain responds to things you see.

Your healthcare provider may want to check your blood for other signs of disease. They may also order a test called a spinal tap (lumbar puncture) to look at a sample of your spinal fluid.

How is relapsing-remitting MS treated?

MS is not considered curable. But different types of medicine are available to decrease inflammation and slow down the progression of the disease. These medicines include: 

Beta-interferon

Glatiramer acetate

Monoclonal antibodies

Dimethyl fumarate

Teriflunomide

Mitoxantrone

Other medicines can be prescribed to treat:

Muscle spasms

Urge to urinate

Erectile dysfunction

Your healthcare provider may also suggest steroids to reduce symptoms during flare-ups. If steroids are not effective, your provider may advise plasmapheresis, a blood-cleansing procedure.

What are possible complications of relapsing-remitting MS?

In most cases, relapsing-remitting MS is mild. But you may need to use a cane or other mobility device. In some cases, the disease is severe and makes you unable to care for yourself. Seldom does it cause death.

Living with relapsing-remitting MS

If you have relapsing-remitting MS, you can take steps to manage your condition.

Physical therapy may help relieve muscle spasms.

Eat a diet low in saturated fat and trans fat. Eat more foods with healthy omega-3 fatty acids because these nutrients are believed to fight inflammation.

Talk with a counselor to help with depression.

Stay away from situations that cause you to become overheated.

Don't smoke.

Get a moderate amount of exercise and enough sleep.

Key points about relapsing-remitting MS

MS most often develops in people in their 20s and 30s.

MS affects the way your muscles and eyes work.

Although there is no cure, medicines can help you manage your symptoms.

Adopting a healthy lifestyle can also help you manage your disease.

Preventing overheating or other triggers can prevent flares of MS.

Tips to help you get the most from a visit to your healthcare provider:

Know the reason for your visit and what you want to happen.

Before your visit, write down questions you want answered.

Bring someone with you to help you ask questions and remember what your provider tells you.

At the visit, write down the name of a new diagnosis, and any new medicines, treatments, or tests. Also write down any new instructions your provider gives you.

Know why a new medicine or treatment is prescribed, and how it will help you. Also know what the side effects are.

Ask if your condition can be treated in other ways.

Know why a test or procedure is recommended and what the results could mean.

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Patient Case #1: 37-Year-Old Female With RRMS

• Gabriel Pardo, MD, FAAN

Expert neurologists review treatment options for a young female with relapsing remitting multiple sclerosis (RRMS).

EP: 1 . Advances in the Management of Relapsing-Remitting Multiple Sclerosis (RRMS)

EP: 2 . Unmet Needs in the RRMS Treatment Landscape

EP: 3 . Generic Disease-Modifying Therapies (DMTs) in RRMS

Ep: 4 . fda approval process for rrms therapies, ep: 5 . treatment selection in rrms.

EP: 6 . Generic DMTs as First-Line Treatment in RRMS

Ep: 7 . patient case #1: 37-year-old female with rrms, ep: 8 . switching dmts in patients with rrms, ep: 9 . patient case #2: 36-year-old female with rrms with lesions in the spine and brain, ep: 10 . treatment options for a patient with rrms and psoriasis, ep: 11 . use of generic dmts in clinical practice in rrms, ep: 12 . challenges in use of generic dmts for treatment of ms, ep: 13 . the future of rrms treatment, ep: 14 . recommendations for rrms management.

Ahmed Zayed Obeidat MD, PhD: The first case we’re going to talk about is a 37-year-old female with 2 young children. We’re going to talk about some factors about what you would select as a treatment. The patient presented to the neurology clinic for first time with fatigue, weakness, tremors in the right hand, so that’s 1 side. And then medical history was significant for previous numbness and tingling in the lower extremity which was both and the result spontaneously about 2 years ago—not an uncommon scenario where people had maybe a pinched disc or something and they didn’t get medical attention because it went away on a physical exam. She had mild right upper extremity weakness and then increased tone in her right hand, already with increased tone, and some mild intention tremor. That’s important to keep in mind. And then gait was stable but had some hyperreflexia on examination. So those are some of the symptoms she presented with.

You did an MRI, and there were some lesions consistent with demyelination, and then spinal fluid showed unique oligoclonal bands. So, the diagnosis was consistent with what appears to be a relapsing remitting MS [multiple sclerosis].I’ll start with you, Dr Dukkipati. What’s your impression of this case and the initial treatment recommendation? How would you treat this patient?

Ravi Dukkipati, MD: Based on the vignette given, this is a relatively young woman, still of childbearing age with 2 young children, who I’m presuming is fairly active, and by all means has relapsing remitting multiple sclerosis based on the clinical presentation. And the brain MRI demonstrates multiple areas of demyelination, which is concerning, and I would characterize this woman as having a moderate disease burden both clinically and radiographically.

This is the type of patient whom I would not hesitate in terms of being aggressive from the beginning because the concern is that time is brain matter. And so, I generally don’t start new patients on platform therapies any longer, so the real decision-making in my mind would be between one of the oral therapies vs monoclonal antibodies with a patient like this or natalizumab.

Ahmed Zayed Obeidat MD, PhD: Dr Pardo?

Gabriel Pardo, MD, FAAN: Yes, I completely agree. I think there are some concerning signs already in this patient. I assume she’s right-hand dominant just by statistics and that’s where she has most of her symptoms. She already has dexterity problems spasticity problems weakness problems, and it’s not harboring good things for the future. The burden of disease seems to be high, and the diagnosis is straightforward. So, I am concerned about this patient. I think that there is no time to waste with platform therapies; there is no doubt about that.

Other elements we were discussing to individualize the decision-making along with the patient will be, as Dr Dukkipati mentioned, as she is still of childbearing age, is she planning on having more children? That will be a very important aspect in the counseling of this patient regarding the selection of the different agents that we have. And each one of them will have different characteristics in that regard. Some of them will allow her to be treated with 4 courses and then be free of treatment if she is able to delay pregnancy for 2 years, for example, maybe 2½ years 1½ years, or 18 months. Or she might imply the decision of having to stop treatment to pursue pregnancy with the risk of a potential rebound if she does not become pregnant promptly. So, a lot of elements again become important in individual patients, and for this patient, we’ll have to get that in the conversation to be able to counsel her in addition. But from the get-go, I am concerned about the patient, and she should definitely be on high-efficacy therapies. There’s no time to beat around the bush.

Ahmed Zayed Obeidat MD, PhD: Yes, and I agree because as you mentioned, there are already signs of incomplete recovery. There are signs of maybe brain stem involvement here, right? There’s a tremor, there is maybe cerebellar involvement. And that’s concerning when we think about her young age and that it was previously untreated for probably over 2 years because the first episode was over 2 years ago with what appears to be transgressed myelitis, which is again another spinal cord involvement which carries a poor prognosis sometimes. So I would do the same. I would start with a highly effective therapy for her. And then maybe, again, considering other factors; when she wants, if she wants more children, when the plan is. And we’ll work around many of these factors.

So I’m going to tell you a little bit of what happened. Maybe she was not started on highly effective therapy. So despite receiving disease-modifying therapy [DMT], she had 2 more relapses in the past year. She reported increased fatigue, difficulty with memory and concentration. And her exam showed right-sided weakness and wrist reflexes are still there, but more weakness. Another MRI of the brain shows multiple new and enhancing lesions while on a disease-modifying therapy, suggestive of ongoing disease activity. Her fatigue and memory issues are interfering with job performance. Now her symptoms are starting to affect her day-to-day and then maybe threatening her job or maybe could result in her losing her job. So this is now even more concerning. So now the patient comes back to you and asks, “How would you monitor? How would you treat me? What else can I do?" Dr Dukkipati, I’ll start with you for this one now, and then we’ll see what Dr Pardo has to say.

Ravi Dukkipati, MD: Well, this is clearly the worst-case scenario, what we had talked about earlier. This woman unfortunately is progressing. Clinically she’s had several relapses. She’s exhibiting signs of progression and her MRI studies clearly demonstrate a very active disease, involving both the brain and the spinal cord. Now, we don’t necessarily know what her initial disease-modifying therapy was, but clearly, she’s failing with that initial therapy. And this patient would need close monitoring both clinically and radiographically and imminent or immediate change or escalation of therapy to a different class.

Ahmed Zayed Obeidat MD, PhD: Dr Pardo, do you agree, and do you have any other additional thoughts?

Gabriel Pardo, MD, FAAN: Absolutely. I agree completely. And just this case highlights the fact that in addition to our selection of the disease-modifying therapy, we need to be always in tune with the patient’s needs and the fact that MS is multifaceted, it has a lot of manifestations, and that it does require comprehensive management of the disease. We need to go beyond the selection of the DMT. We need to explore all these other possibilities.

The threat of potentially losing her job has tremendous social, familial, and personal implications. And it brings then the conversation of the complementary things that we do to the DMTs, which are symptom management and trying to improve function, something that we also need to monitor closely. It is not just the markers that we use for failing a treatment as clearly evident in this case with relapses, and new MRI additions, but all these other ancillary ways of assessing how the patient is functioning and what else should we do, and can we do to improve that function, and to improve the ability of the patient to continue to live their life the best they can?

Ahmed Zayed Obeidat MD, PhD: Yes, and what strikes me in this case is also that she had 2 relapses in the past year, so she was left to relapse again after 1 relapse. So we didn’t have to even wait for that, right? You see 1 relapse, and for me, it’s sufficient to just switch to a different mechanism of action, and in this case, perhaps going higher; something with known higher efficacy.

Transcript edited for clarity

Episode 112: Exploring Dimethyl Fumarate to Treat Friedreich Ataxia

Earlier Initiation of Ublituximab Results In Improved Disease Outcomes in Treatment-Naïve Multiple Sclerosis

Episode 111: Reviewing ACTRIMS 2024

This Week on NeurologyLive® — April 8, 2024

NeurologyLive® Brain Games: April 7, 2024

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Novartis kesimpta® six-year efficacy data show substantial benefits in recently diagnosed treatment- naïve people with relapsing multiple sclerosis.

Continuous Kesimpta ®  treatment for up to six years showed sustained efficacy in recently diagnosed (≤3 years) treatment-naïve people living with relapsing multiple sclerosis (RMS) in an analysis of the ALITHIOS open-label extension study 1

Similar efficacy outcomes were demonstrated in a separate analysis of continuous Kesimpta treatment for up to six years in the overall ALITHIOS study population 2

Switch from teriflunomide to Kesimpta resulted in significant improvements across several efficacy outcomes such as annualized relapse rate and MRI lesion activity in both analyses 1, 2

Treatment with Kesimpta for up to six years continues to be well tolerated with consistent safety outcomes, supporting the favorable benefit-risk profile of Kesimpta in RMS 2

Basel, April 17, 2024 – Novartis today announced data from the ALITHIOS open-label extension study showing sustained efficacy of first-line, continuous Kesimpta ® (ofatumumab) treatment for up to six years in recently diagnosed – defined as starting treatment within three years of initial diagnosis – treatment-naïve people living with relapsing multiple sclerosis (RMS). 1 These efficacy outcomes included 44% fewer relapses; 96.4% and 82.7% reductions in MRI lesions (Gd+ T1 and neT2), respectively; and 24.5% and 21.6% fewer 3- and 6-month confirmed disability worsening (CDW) events, respectively, versus those who switched to Kesimpta from teriflunomide. 1 A separate analysis of the overall ALITHIOS population showed similar efficacy with continuous Kesimpta treatment, which was also well-tolerated with a consistent safety profile up to six years. 2 These data will be presented at the American Academy of Neurology (AAN) 2024 Annual Meeting held in Denver, Colorado and virtually on April 13-18, 2024.

“Our analysis of treatment-naïve people who were recently diagnosed with relapsing multiple sclerosis found that first-line use of Kesimpta for up to six years provided long-term benefits, including fewer relapses, profoundly suppressed MRI lesion activity, and fewer disability worsening events,” said principal investigator Gabriel Pardo, MD, Founding Director of the Multiple Sclerosis Center of Excellence at Oklahoma Medical Research Foundation. “While measurable improvements were also seen in patients switching to Kesimpta later on, the delay in irreversible disability worsening was not fully realized in the switch group compared to those starting on Kesimpta first, reinforcing the value of introducing the treatment to patients earlier.”

“We are extremely pleased to share the new data from ALITHIOS, which adds to the growing body of evidence of Kesimpta as an efficacious and well-tolerated option for people living with RMS,” said Norman Putzki, Development Unit Head, Neuroscience & Gene Therapy, Development, Novartis Pharmaceuticals Corporation. “Novartis is committed to addressing the biggest challenges for people living with MS through relentless discovery, development, and delivery of potentially transformative medicines with the goal of achieving complete disease control.”

Study Results In the first analysis, the low annualized relapse rate (ARR) experienced by recently diagnosed treatment-naïve (RDTN) people living with RMS receiving continuous Kesimpta during the core Phase III trials was further reduced in the ALITHIOS open-label extension study, from 0.104 to 0.050 (52.0% reduction), corresponding to an adjusted ARR of one relapse per 20 years. 1 Rates of 3- and 6-month progression independent of relapse activity (PIRA) with first-line Kesimpta were also lower versus switch. 1 The observed rapid increase in the proportion of participants with no evidence of disease activity (NEDA-3) with continuous first-line Kesimpta treatment was maintained up to six years. 1

In RDTN people living with RMS initially randomized to teriflunomide, improvements across several efficacy outcomes were seen after switching to Kesimpta, including significant reductions in ARR (71.3%) and in MRI lesion activity (Gd+ T1: 98.5% reduction; neT2: 93% reduction), and rapid increase in rates of NEDA-3. 1 However, rates of 3- and 6-month CDW events remained higher compared to patients receiving continuous Kesimpta, indicating that the efficacy benefit of first-line Kesimpta on delaying disability worsening was not fully achieved in the switch group. 1 Across both continuous and switch groups, nine out of 10 participants achieved NEDA-3 at Year 6. 1

Similar results were seen in the second analysis, which looked at the overall ALITHIOS population. 2 Data showed sustained efficacy of continuous Kesimpta up to six years, including low ARR (49.9% reduction between core Phase III trials and extension phase), suppression of MRI lesion activity (Gd+ T1: 56.7% reduction; neT2: 89.3% reduction), sustained reduction of 6-month CDW events (14.1%, relative to the switch group), lower rates of 6-month PIRA, and sustained high rates of NEDA-3. 2 People switching from teriflunomide to Kesimpta experienced reductions in ARR (73.8%) and MRI lesion activity (Gd+ T1: 97.7% reduction; neT2: 91.8% reduction) and a rapid increase in NEDA-3 rates during the extension period. 2 Six-month CDW rates remained higher compared to patients receiving continuous Kesimpta, again highlighting an efficacy benefit of first-line Kesimpta on delaying disability worsening that was not fully achieved in the switch group. 2 At Year 6, NEDA-3 status was achieved in nine out of 10 participants in both the continuous and switch groups. 2

The study also found that treatment with Kesimpta for up to six years was well-tolerated with no unexpected safety signals identified. 2 The rates of adverse events (AEs), serious AEs, serious infections, and malignancies remained stable with no increased risks over six years. 2

The overall rates of AEs and serious AEs up to six years of Kesimpta treatment were consistent between the core Phase III trials and the ALITHIOS extension study. 2 The most common AEs were infections (COVID-19 [34.3%], nasopharyngitis [20.6%], upper respiratory tract infection [14.9%], and urinary tract infection [14.4%]). 2 The incidence of serious infections remained stable over time and did not increase with Kesimpta treatment up to six years. 2

Mean serum immunoglobulin G (IgG) levels remained stable up to six years of treatment and the majority of patients (97.2%) had lgG levels above the lower limit of normal (LLN). 2 Mean serum immunoglobulin M (IgM) levels decreased over time but remained above the LLN for the majority of patients (65.9%). 2 No clinically meaningful association was observed between IgG/IgM levels below the LLN and risk of serious infections. 2

About Multiple Sclerosis Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by myelin destruction and axonal damage in the brain, optic nerves and spinal cord. 3 MS, which affects around 2 million people worldwide, can be characterized into four main types: clinically isolated syndrome (CIS), relapsing-remitting (RRMS), secondary progressive (SPMS) and primary progressive (PPMS). 4,5 The various forms of MS can be distinguished based on whether a patient experiences relapses (clearly defined acute inflammatory attacks of worsening neurological function), and/or whether they experience progression of neurologic damage and disability from the onset of the disease. 3

About Kesimpta ® (ofatumumab) Kesimpta is a targeted, precisely dosed and delivered B-cell therapy that provides the flexibility of self-administration for adults with relapsing forms of multiple sclerosis (RMS). Kesimpta is the first fully human anti-CD20 monoclonal antibody (mAb) self-administered by a once-monthly injection, delivered subcutaneously (SC) in RMS. 6, 7, 8

The treatment regimen was designed and tested to enhance safety and tolerability and minimize the risk of systemic injection-related reactions. 6 Initial doses of Kesimpta are at Weeks 0, 1 and 2, with the first injection performed under the guidance of a healthcare professional. Monthly Kesimpta 20 mg doses are associated with rapid reduction and near-complete peripheral B-cell depletion, with no significant effect on pharmacokinetics due to body weight. 6 As shown in preclinical studies, Kesimpta is thought to work by binding to a distinct epitope on the CD20 molecule inducing potent B-cell lysis and depletion. 9 The selective mechanism of action and SC administration of Kesimpta allows precise delivery to the lymph nodes, where B-cell depletion in MS is needed, and preclinical studies have shown that it may preserve the B-cells in the spleen. 10

Data from the ASCLEPIOS I/II core studies demonstrate Kesimpta’s efficacy and favorable safety and tolerability profile in RMS participants and the ALITHIOS open-label extension study provides additional support with up to 6 years of data. 2, 11 The at-home administration of Kesimpta by monthly doses of 20 mg/0.4mL with an autoinjector (Sensoready ® ) also matches the preferences of many people living with MS due to its ease of use and supports patients to be compliant with, and persistent on the therapy over time. 6 Kesimpta was originally developed by Genmab and licensed to GlaxoSmithKline; Novartis obtained rights for ofatumumab from GlaxoSmithKline in all indications, including RMS, in December 2015. 12

Kesimpta has been approved for the treatment of relapsing forms of multiple sclerosis in over 90 countries worldwide with more than 100,000 patients treated as of March 2024.

Novartis in Neuroscience At Novartis, in Neuroscience, we are committed to understanding and solving some of the most burdensome neurological conditions to improve the quality of life for patients and their caregivers, and to make a positive impact on society. We aim to lead the discovery, development and delivery of innovative medicines to create a transformational impact for people living with severe neurological conditions by changing the course of disease progression.

Through innovation, partnerships and community engagement, we have been tackling neurological conditions for >80 years, launching transformative treatments which have made meaningful differences to millions of people worldwide. We continue to collaborate on the development of industry-leading innovative medicines for multiple sclerosis, and in the areas of neuroimmunology, neurodegeneration, and neuromuscular/rare diseases.

To ensure patients everywhere can benefit from these life-changing therapies, we work closely with key stakeholders across the world to ensure rapid access and sustainable accessibility to our medicines, with the aim of providing the best treatment choices for each person’s unique journey.

Disclaimer This is a legal statement identifying forward-looking statements involving known and unknown risks and uncertainties. You should include the standard disclaimer in your release as outlined in the Global Press Release Approval Guidelines.

This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as “potential,” “can,” “will,” “plan,” “may,” “could,” “would,” “expect,” “anticipate,” “look forward,” “believe,” “committed,” “investigational,” “pipeline,” “launch,” or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Novartis Novartis is an innovative medicines company. Every day, we work to reimagine medicine to improve and extend people’s lives so that patients, healthcare professionals and societies are empowered in the face of serious disease. Our medicines reach more than 250 million people worldwide.

Reimagine medicine with us: Visit us at https://www.novartis.com and connect with us on LinkedIn , Facebook , X/Twitter and Instagram .

Pardo G, Hauser SL, Bar-Or A, et al. Longer-term (up to 6 Years) Efficacy of Ofatumumab in People with Recently Diagnosed and Treatment-Naïve Relapsing Multiple Sclerosis. Oral presentation at the American Academy of Neurology (AAN) 2024 Annual Meeting; April 13-18, 2024; Denver, CO.

Wiendl H, Hauser SL, Nicholas J, et al. Longer-term Safety and Efficacy of Ofatumumab in People With Relapsing Multiple Sclerosis for Up to 6 Years. Poster presentation at the American Academy of Neurology (AAN) 2024 Annual Meeting; April 13-18, 2024; Denver, CO.

Guthrie EW. Multiple sclerosis: A primer and update. Adv Studies Pharm. 2007;4(11):313-317.

Multiple Sclerosis International Federation. Atlas of MS 2013-Mapping Multiple Sclerosis Around the World. Accessed August 12, 2020. http://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf

National MS Society. Types of MS. Accessed January 18, 2023. https://www.nationalmssociety.org/What-is-MS/Types-of-MS

Hauser SL, Kappos L, Bar-Or A, et al. The Development of Ofatumumab, a Fully Human Anti-CD20 Monoclonal Antibody for Practical Use in Relapsing Multiple Sclerosis Treatment. Neurol Ther. 2023;12(5):1491-1515. doi:10.1007/s40120-023-00518-0

Kesimpta Prescribing Information. East Hanover, NJ: Novartis Pharmaceuticals Corp; September 2022.

Bar-Or A, Fox E, Goodyear A, et al. Onset of B-cell depletion with subcutaneous administration of ofatumumab in relapsing multiple sclerosis: results from the APLIOS bioequivalence study. Poster presentation at: ACTRIMS; February 2020; West Palm Beach, FL.

Smith P, Kakarieka A, Wallstroem E. Ofatumumab is a fully human anti-CD20 antibody achieving potent B-cell depletion through binding a distinct epitope. Poster presentation at: ECTRIMS; September 2016; London, UK.

Smith P, Huck C, Wegert V, et al. Low-dose, subcutaneous anti-CD20 therapy effectively depletes B-cells and ameliorates CNS autoimmunity. Poster presentation at: ECTRIMS; September 2016; London, UK.

Cohen, JA, Hauser SL, Zielman R., et al. Effect of Longer-term Ofatumumab Treatment on Disability Progression and Brain Volume Change. Poster presentation at: AAN; April 2023; Boston, US.

Genmab Press Release: Genmab announces completion of agreement to transfer remaining ofatumumab rights. December 21, 2015. Accessed January 18, 2023. https://ir.genmab.com/static-files/9d491b72-bb0b-4e46-a792-dee6c29aaf7d

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Dysregulated Lipid Metabolism Networks Modulate T-cell Function in People with Relapsing Remitting Multiple Sclerosis

Affiliations.

• 1 Centre for Rheumatology, Division of Medicine, University College London, United Kingdom.
• 2 Department of Neurology and Centre of Clinical, Neuroscience, First Faculty of Medicine, General University Hospital and First Faculty of Medicine, Charles University in Prague, Czech Republic.
• 3 Department of Neuroinflammation, University College London and Institute of Neurology and National Hospital of Neurology and Neurosurgery, United Kingdom.
• 4 Centre for Experimental & Translational Medicine, Division of Medicine, University College London, United Kingdom.
• PMID: 38625017
• DOI: 10.1093/cei/uxae032

Altered cholesterol, oxysterol, sphingolipid, and fatty acid concentrations are reported in blood, cerebrospinal fluid, and brain tissue of people with relapsing remitting multiple sclerosis (RRMS) and are linked to disease progression and treatment responses. CD4+ T cells are pathogenic in RRMS, and defective T cell function could be mediated in part by liver X receptors (LXRs) - nuclear receptors that regulate lipid homeostasis and immunity. RNA-sequencing and pathway analysis identified that genes within the 'lipid metabolism' and 'signalling of nuclear receptors' pathways were dysregulated in CD4+ T cells isolated from RRMS patients compared with healthy donors. While LXRB and genes associated with cholesterol metabolism were upregulated, other T cell LXR-target genes, including genes involved in cellular lipid uptake (inducible degrader of the LDL receptor, IDOL), and the rate-limiting enzyme for glycosphingolipid biosynthesis (UDP-glucosylceramide synthase, UGCG) were downregulated in T cells from patients with RRMS compared to healthy donors. Correspondingly, plasma membrane glycosphingolipids were reduced, and cholesterol levels increased in RRMS CD4+ T cells, an effect partially recapitulated in healthy T cells by in vitro culture with T cell receptor stimulation in the presence of serum from RRMS patients. Notably, stimulation with LXR-agonist GW3965 normalised membrane cholesterol levels, and reduced proliferation and IL17 cytokine production in RRMS CD4+ T-cells. Thus, LXR-mediated lipid metabolism pathways were dysregulated in T cells from patients with RRMS and could contribute to RRMS pathogenesis. Therapies that modify lipid metabolism could help restore immune cell function.

Keywords: CD4+ T cells; Lipid metabolism; Lipid rafts; Liver X Receptor; Multiple Sclerosis.

© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology.

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Risk Factors for Relapsing Remitting Multiple Sclerosis

1 Synthesis Economic Evaluation and Decision Science (SEEDS) group, University of Central Lancashire

2 Lancashire and South Cumbria NHS Foundation Trust

Background to the reviews

Multiple sclerosis (MS) is a central nervous system disease and is classified by inflammation and demyelination of central nerve cells that leads to axon degeneration and physical disability ( Reich et al, 2018 ). MS affects an estimated 2.2 million people globally ( Collaborators, 2019 ), and is the most common neurological disability ( Ghasemi et al, 2017 ). MS can be classified into several main types, which are progressive relapsing MS (PRMS), relapsing remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS) ( Loma and Heyman, 2011 ). RRMS is the most common type, affecting approximately 85% of all MS patients ( Loma and Heyman, 2011 ). The cause of MS is unclear, but it is suggested that it is multi-factorial ( McKay et al, 2015 ). Similarly, the cause of relapse has been attributed to multiple factors ( McKay et al, 2017 ). However, despite this multifactorial relationship, previous systematic reviews have only assessed single factors at a time ( McKay et al, 2017 ; Xie et al, 2020 ). Subsequently, the systematic review by Xie et al (2020) aimed to assess multiple factors associated with relapses in RRMS.

Aim of commentary

This commentary aims to critically appraise the methods used within the review by Xie et al (2020) and expand upon the findings in context to clinical practice.

A robust multi-database search was undertaken from January 1983 to December 2018. A broad inclusion criterion was used: only cohort and case control studies that included adults (over 18 years of age) with a RRMS diagnosis at the time of the study ( Poser et al, 1983 ), or McDonald criteria ( Polman et al, 2011 ). Initial screening of abstract and title was undertaken by a single reviewer. Secondary title, abstract and full paper screening were undertaken by two reviewers independently, with arbitration by a third reviewer. The exact process of data extraction and assessment of included study quality (Newcastle-Ottawa Scale) was unclear. An appropriate meta-analysis was undertaken using a random effects meta-analysis (DerSimonian and Laird method) to produce a summary estimate risk ratio (RR) and 95% confidence interval (95% CI). A range of subgroup analyses were planned for cohort studies versus case control studies; corrected immunomodulatory therapy versus non-corrected immunomodulatory therapy; and length of follow-up.

This systematic review included 43 studies, of which 40 were cohort studies and three were case control design. Out of these 43 included studies, when using the Newcastle-Ottawa Scale, 16 were graded to be of good quality; 25 were fair quality; and two were deemed to be of poor quality. The included studies had a varying follow-up period ranging from 2 months to 5 years.

The findings of the systematic review identified that there was a statistical and clinically significant increase in risk of relapse between a period of infection compared to non-infection for adults with RRMS (RR 2.07, 95% CI: 1.64-2.60) (see Table 1 for all factors). There was a small amount of heterogeneity observed (I2 30.6%), and it was suggested that this small degree of variance in studies may be due to study design. Only seven studies out of the 12 included in this analysis reported any type of infection. These included adenovirus, chlamydia pneumoniae, Human Herpes Virus-6 (HHV-6), Epstein–Barr virus and influenza virus. Due to the limited number of studies for each of these viruses, it was not possible to undertake a subgroup analysis.

The summary estimate from eight studies demonstrated a statistical and clinical increase in risk of relapse for women in the postpartum period compared to before pregnancy (RR, 1.43 95% CI:, 1.19 to 1.72) and pregnancy period (RR, 2.07, 95% CI: 1.49-2.88). For the period of pregnancy, there was a statistical and clinically significant reduction in the risk of relapse compared to women before pregnancy (RR, 0.56 95% CI: 0.37-0.84). There was no notable heterogeneity for all pregnancy-related comparisons.

There was some evidence that the presence of genetic markers is positively associated with an increased risk of relapse; however, this was based on only three studies with statistically significant moderate heterogeneity. It was indicated that this variation in the study effects may be explained by the varying quality of the included three studies. There was no clear association in change of risk of relapse for factors such as smoking status, obesity and breastfeeding. For the remaining factors of vaccination status, stress, vitamin D levels and age, there was substantial unexplained heterogeneity and wide confidence intervals, which resulted in these associations being questionable. For the variables of vaccination status and age, the study size was noted as a significant component of heterogeneity.

Using the Joanna Briggs Institute Critical Appraisal tool for systematic reviews, seven out of the 11 criteria were deemed satisfactory (Joanna Briggs Institute, 2017): review question, inclusion criteria, critical appraisal tool, data extraction, data synthesis, assessment of publication bias and directives for future research. There were four criteria of quality within the review that remained unclear. First, despite the use of an appropriate critical appraisal tool, it was uncertain whether this was applied in an independent manner by two reviewers. Second, within the search strategy, it was not made evident why the date limit for publication was applied (1983 onwards). This may have had an impact on identifying relevant evidence. The search strategy may also be subject to language bias, due to only including studies that were reported in English or Chinese. Third, the sources used to search for evidence were deemed insufficient, as attempts were not made to undertake hand searching or identify unpublished studies. Finally, although it was stated that clinicians and policymakers could benefit from the review findings, no specific recommendations for practice were made.

Based on this quality assessment, it was deemed that the systematic review may not have identified all the relevant evidence for associated risk factors in RRMS. However, based on the evidence included within the review, it may provide an accurate summary of the results available.

Due to the limited evidence, wide confidence intervals and substantial heterogeneity, the factors of infection and post-partum pregnancy period are the only valid factors with a positive association for increased risk of relapse in adults with RRMS. These findings concur with previous systematic reviews ( D’Hooghe et al, 2010 ; McKay et al, 2017 ). Investigation of these factors should be considered as a method for identifying patients who are at greater risk of relapse. There is also evidence to indicate that there is a negative association with the pregnancy period, which results in a reduced risk of relapse. This negative association is also supported by previous systematic review findings ( McKay et al, 2017 ).

The association of vaccination status, stress, vitamin D levels and genetic risk factors is unclear, due to the wide variation of study findings. It is important that future research explores the possible causes of this heterogeneity, as there was some evidence to suggest that these are important moderators for increased risk of relapse for adults with RRMS. Future research should also ensure that standardised definitions are used for these moderating factors, as the variation of use may be causing additional heterogeneity. Moreover, further research should explore the different infection types, as there was some indication that the type of infection may influence the level of increased risk. Finally, there is the need for larger robust cohort studies as, for some of these factors, there was limited evidence; in many cases, these studies had small sample sizes.

CPD reflective questions

• - What are the main strengths and weaknesses of the systematic review?
• - What advice can be given to patients who may be at increased risk of relapse?
• - How can we gain a greater understanding of the connection between infection during the post-partum period and the onset of RRMS?
• ▪ Acquired infection and the period post-partum may both be risk factors for relapse in relapsing remitting multiple sclerosis
• ▪ The period of pregnancy may be a protective factor in risk of relapse in relapsing remitting multiple sclerosis
• ▪ For the factors of vaccinations, stress, vitamin D and age, there was substantial unexplained heterogeneity
• ▪ Future research should focus on developing standardised definitions of risk factors for relapse in relapsing remitting multiple sclerosis

Acknowledgement

This report is independent research funded by the National Institute for Health Research Applied Research Collaboration North West Coast (ARC NWC). The views expressed in this publication are those of the author(s) and not necessarily those of the National Institute for Health Research, the NHS, or the Department of Health and Social Care.

• Collaborators GBDMS. Global, regional, and national burden of multiple sclerosis 1990-2016: A systematic analysis for the global burden of disease study 2016. Lancet Neurol. 2019; 18 (3):269–285. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• D’Hooghe MB, Nagels G, Bissay V, De Keyser J. Modifiable factors influencing relapses and disability in multiple sclerosis. Multiple Sclerosis Journal. 2010; 16 (7):773–785. [ PubMed ] [ Google Scholar ]
• Ghasemi N, Razavi S, Nikzad E. Multiple sclerosis: Pathogenesis, symptoms, diagnoses and cell-based therapy. Cell journal. 2017; 19 (1):1–10. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Loma I, Heyman R. Multiple sclerosis: Pathogenesis and treatment. Curr Neuropharmacol. 2011; 9 (3):409–416. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• McKay KA, Jahanfar S, Duggan T, Tkachuk S, Tremlett H. Factors associated with onset, relapses or progression in multiple sclerosis: A systematic review. Neurotoxicology. 2017; 61 :189–212. [ PubMed ] [ Google Scholar ]
• McKay KA, Kwan V, Duggan T, Tremlett H. Risk factors associated with the onset of relapsing-remitting and primary progressive multiple sclerosis: A systematic review. Biomed Res Int. 2015; 2015 :817238. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the mcdonald criteria. Annals of neurology. 2011; 69 (2):292–302. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, Johnson KP, Sibley WA, Silberberg DH, Tourtellotte WW. New diagnostic criteria for multiple sclerosis: Guidelines for research protocols. Annals of neurology. 1983; 13 (3):227–231. [ PubMed ] [ Google Scholar ]
• Reich DS, Lucchinetti CF, Calabresi PA. Multiple sclerosis. N Engl J Med. 2018; 378 (2):169–180. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Xie Y, Tian Z, Han F, Liang S, Gao Y, Wu D. Factors associated with relapses in relapsing-remitting multiple sclerosis: A systematic review and meta-analysis. Medicine (Baltimore) 2020; 99 (27):e20885. [ PMC free article ] [ PubMed ] [ Google Scholar ]

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Novartis Kesimpta® six-year efficacy data show substantial benefits in recently diagnosed treatment- naïve people with relapsing multiple sclerosis

• Continuous Kesimpta ®  treatment for up to six years showed sustained efficacy in recently diagnosed (=3 years) treatment-naïve people living with relapsing multiple sclerosis (RMS) in an analysis of the ALITHIOS open-label extension study 1
• Similar efficacy outcomes were demonstrated in a separate analysis of continuous Kesimpta treatment for up to six years in the overall ALITHIOS study population 2
• Switch from teriflunomide to Kesimpta resulted in significant improvements across several efficacy outcomes such as annualized relapse rate and MRI lesion activity in both analyses 1, 2
• Treatment with Kesimpta for up to six years continues to be well tolerated with consistent safety outcomes, supporting the favorable benefit-risk profile of Kesimpta in RMS 2

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"Our analysis of treatment-naïve people who were recently diagnosed with relapsing multiple sclerosis found that first-line use of Kesimpta for up to six years provided long-term benefits, including fewer relapses, profoundly suppressed MRI lesion activity, and fewer disability worsening events,” said principal investigator Gabriel Pardo, MD, Founding Director of the Multiple Sclerosis Center of Excellence at Oklahoma Medical Research Foundation. "While measurable improvements were also seen in patients switching to Kesimpta later on, the delay in irreversible disability worsening was not fully realized in the switch group compared to those starting on Kesimpta first, reinforcing the value of introducing the treatment to patients earlier.”

"We are extremely pleased to share the new data from ALITHIOS, which adds to the growing body of evidence of Kesimpta as an efficacious and well-tolerated option for people living with RMS,” said Norman Putzki, Development Unit Head, Neuroscience & Gene Therapy, Development, Novartis Pharmaceuticals Corporation. "Novartis is committed to addressing the biggest challenges for people living with MS through relentless discovery, development, and delivery of potentially transformative medicines with the goal of achieving complete disease control.”

Study Results In the first analysis, the low annualized relapse rate (ARR) experienced by recently diagnosed treatment-naïve (RDTN) people living with RMS receiving continuous Kesimpta during the core Phase III trials was further reduced in the ALITHIOS open-label extension study, from 0.104 to 0.050 (52.0% reduction), corresponding to an adjusted ARR of one relapse per 20 years. 1 Rates of 3- and 6-month progression independent of relapse activity (PIRA) with first-line Kesimpta were also lower versus switch. 1 The observed rapid increase in the proportion of participants with no evidence of disease activity (NEDA-3) with continuous first-line Kesimpta treatment was maintained up to six years. 1

In RDTN people living with RMS initially randomized to teriflunomide, improvements across several efficacy outcomes were seen after switching to Kesimpta, including significant reductions in ARR (71.3%) and in MRI lesion activity (Gd+ T1: 98.5% reduction; neT2: 93% reduction), and rapid increase in rates of NEDA-3. 1 However, rates of 3- and 6-month CDW events remained higher compared to patients receiving continuous Kesimpta, indicating that the efficacy benefit of first-line Kesimpta on delaying disability worsening was not fully achieved in the switch group. 1 Across both continuous and switch groups, nine out of 10 participants achieved NEDA-3 at Year 6. 1   

Similar results were seen in the second analysis, which looked at the overall ALITHIOS population. 2 Data showed sustained efficacy of continuous Kesimpta up to six years, including low ARR (49.9% reduction between core Phase III trials and extension phase), suppression of MRI lesion activity (Gd+ T1: 56.7% reduction; neT2: 89.3% reduction), sustained reduction of 6-month CDW events (14.1%, relative to the switch group), lower rates of 6-month PIRA, and sustained high rates of NEDA-3. 2 People switching from teriflunomide to Kesimpta experienced reductions in ARR (73.8%) and MRI lesion activity (Gd+ T1: 97.7% reduction; neT2: 91.8% reduction) and a rapid increase in NEDA-3 rates during the extension period. 2 Six-month CDW rates remained higher compared to patients receiving continuous Kesimpta, again highlighting an efficacy benefit of first-line Kesimpta on delaying disability worsening that was not fully achieved in the switch group. 2 At Year 6, NEDA-3 status was achieved in nine out of 10 participants in both the continuous and switch groups. 2

The study also found that treatment with Kesimpta for up to six years was well-tolerated with no unexpected safety signals identified. 2 The rates of adverse events (AEs), serious AEs, serious infections, and malignancies remained stable with no increased risks over six years. 2

The overall rates of AEs and serious AEs up to six years of Kesimpta treatment were consistent between the core Phase III trials and the ALITHIOS extension study. 2 The most common AEs were infections (COVID-19 [34.3%], nasopharyngitis [20.6%], upper respiratory tract infection [14.9%], and urinary tract infection [14.4%]). 2 The incidence of serious infections remained stable over time and did not increase with Kesimpta treatment up to six years. 2

Mean serum immunoglobulin G (IgG) levels remained stable up to six years of treatment and the majority of patients (97.2%) had lgG levels above the lower limit of normal (LLN). 2 Mean serum immunoglobulin M (IgM) levels decreased over time but remained above the LLN for the majority of patients (65.9%). 2 No clinically meaningful association was observed between IgG/IgM levels below the LLN and risk of serious infections. 2

About Multiple Sclerosis Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by myelin destruction and axonal damage in the brain, optic nerves and spinal cord. 3 MS, which affects around 2 million people worldwide, can be characterized into four main types: clinically isolated syndrome (CIS), relapsing-remitting (RRMS), secondary progressive (SPMS) and primary progressive (PPMS). 4,5 The various forms of MS can be distinguished based on whether a patient experiences relapses (clearly defined acute inflammatory attacks of worsening neurological function), and/or whether they experience progression of neurologic damage and disability from the onset of the disease. 3

About Kesimpta ® (ofatumumab) Kesimpta is a targeted, precisely dosed and delivered B-cell therapy that provides the flexibility of self-administration for adults with relapsing forms of multiple sclerosis (RMS). Kesimpta is the first fully human anti-CD20 monoclonal antibody (mAb) self-administered by a once-monthly injection, delivered subcutaneously (SC) in RMS. 6, 7, 8

The treatment regimen was designed and tested to enhance safety and tolerability and minimize the risk of systemic injection-related reactions. 6 Initial doses of Kesimpta are at Weeks 0, 1 and 2, with the first injection performed under the guidance of a healthcare professional. Monthly Kesimpta 20 mg doses are associated with rapid reduction and near-complete peripheral B-cell depletion, with no significant effect on pharmacokinetics due to body weight. 6 As shown in preclinical studies, Kesimpta is thought to work by binding to a distinct epitope on the CD20 molecule inducing potent B-cell lysis and depletion. 9 The selective mechanism of action and SC administration of Kesimpta allows precise delivery to the lymph nodes, where B-cell depletion in MS is needed, and preclinical studies have shown that it may preserve the B-cells in the spleen. 10

Data from the ASCLEPIOS I/II core studies demonstrate Kesimpta’s efficacy and favorable safety and tolerability profile in RMS participants and the ALITHIOS open-label extension study provides additional support with up to 6 years of data. 2, 11 The at-home administration of Kesimpta by monthly doses of 20 mg/0.4mL with an autoinjector (Sensoready ® ) also matches the preferences of many people living with MS due to its ease of use and supports patients to be compliant with, and persistent on the therapy over time. 6 Kesimpta was originally developed by Genmab and licensed to GlaxoSmithKline; Novartis obtained rights for ofatumumab from GlaxoSmithKline in all indications, including RMS, in December 2015. 12

Kesimpta has been approved for the treatment of relapsing forms of multiple sclerosis in over 90 countries worldwide with more than 100,000 patients treated as of March 2024.

Novartis in Neuroscience At Novartis, in Neuroscience, we are committed to understanding and solving some of the most burdensome neurological conditions to improve the quality of life for patients and their caregivers, and to make a positive impact on society. We aim to lead the discovery, development and delivery of innovative medicines to create a transformational impact for people living with severe neurological conditions by changing the course of disease progression.

Through innovation, partnerships and community engagement, we have been tackling neurological conditions for >80 years, launching transformative treatments which have made meaningful differences to millions of people worldwide. We continue to collaborate on the development of industry-leading innovative medicines for multiple sclerosis, and in the areas of neuroimmunology, neurodegeneration, and neuromuscular/rare diseases.

To ensure patients everywhere can benefit from these life-changing therapies, we work closely with key stakeholders across the world to ensure rapid access and sustainable accessibility to our medicines, with the aim of providing the best treatment choices for each person’s unique journey.

Disclaimer This is a legal statement identifying forward-looking statements involving known and unknown risks and uncertainties. You should include the standard disclaimer in your release as outlined in the Global Press Release Approval Guidelines.

This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "potential,” "can,” "will,” "plan,” "may,” "could,” "would,” "expect,” "anticipate,” "look forward,” "believe,” "committed,” "investigational,” "pipeline,” "launch,” or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Novartis Novartis is an innovative medicines company. Every day, we work to reimagine medicine to improve and extend people’s lives so that patients, healthcare professionals and societies are empowered in the face of serious disease. Our medicines reach more than 250 million people worldwide.

Reimagine medicine with us: Visit us at https://www.novartis.com and connect with us on LinkedIn , Facebook , X/Twitter and Instagram .

• Pardo G, Hauser SL, Bar-Or A, et al. Longer-term (up to 6 Years) Efficacy of Ofatumumab in People with Recently Diagnosed and Treatment-Naïve Relapsing Multiple Sclerosis. Oral presentation at the American Academy of Neurology (AAN) 2024 Annual Meeting; April 13-18, 2024; Denver, CO.
• Wiendl H, Hauser SL, Nicholas J, et al. Longer-term Safety and Efficacy of Ofatumumab in People With Relapsing Multiple Sclerosis for Up to 6 Years. Poster presentation at the American Academy of Neurology (AAN) 2024 Annual Meeting; April 13-18, 2024; Denver, CO.
• Guthrie EW. Multiple sclerosis: A primer and update. Adv Studies Pharm. 2007;4(11):313-317.
• Multiple Sclerosis International Federation. Atlas of MS 2013-Mapping Multiple Sclerosis Around the World. Accessed August 12, 2020. http://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf
• National MS Society. Types of MS. Accessed January 18, 2023. https://www.nationalmssociety.org/What-is-MS/Types-of-MS
• Hauser SL, Kappos L, Bar-Or A, et al. The Development of Ofatumumab, a Fully Human Anti-CD20 Monoclonal Antibody for Practical Use in Relapsing Multiple Sclerosis Treatment. Neurol Ther. 2023;12(5):1491-1515. doi:10.1007/s40120-023-00518-0
• Kesimpta Prescribing Information. East Hanover, NJ: Novartis Pharmaceuticals Corp; September 2022.
• Bar-Or A, Fox E, Goodyear A, et al. Onset of B-cell depletion with subcutaneous administration of ofatumumab in relapsing multiple sclerosis: results from the APLIOS bioequivalence study. Poster presentation at: ACTRIMS; February 2020; West Palm Beach, FL.
• Smith P, Kakarieka A, Wallstroem E. Ofatumumab is a fully human anti-CD20 antibody achieving potent B-cell depletion through binding a distinct epitope. Poster presentation at: ECTRIMS; September 2016; London, UK.
• Smith P, Huck C, Wegert V, et al. Low-dose, subcutaneous anti-CD20 therapy effectively depletes B-cells and ameliorates CNS autoimmunity. Poster presentation at: ECTRIMS; September 2016; London, UK.
• Cohen, JA, Hauser SL, Zielman R., et al. Effect of Longer-term Ofatumumab Treatment on Disability Progression and Brain Volume Change. Poster presentation at: AAN; April 2023; Boston, US.
• Genmab Press Release: Genmab announces completion of agreement to transfer remaining ofatumumab rights. December 21, 2015. Accessed January 18, 2023. https://ir.genmab.com/static-files/9d491b72-bb0b-4e46-a792-dee6c29aaf7d

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Novartis Kesimpta® six-year efficacy data show substantial benefits in recently diagnosed treatment- naïve people with relapsing multiple sclerosis

• Continuous Kesimpta® treatment for up to six years showed sustained efficacy in recently diagnosed (≤3 years) treatment-naïve people living with relapsing multiple sclerosis (RMS) in an analysis of the ALITHIOS open-label extension study 1
• Similar efficacy outcomes were demonstrated in a separate analysis of continuous Kesimpta treatment for up to six years in the overall ALITHIOS study population 2
• Switch from teriflunomide to Kesimpta resulted in significant improvements across several efficacy outcomes such as annualized relapse rate and MRI lesion activity in both analyses 1, 2
• Treatment with Kesimpta for up to six years continues to be well tolerated with consistent safety outcomes, supporting the favorable benefit-risk profile of Kesimpta in RMS 2

Basel, April 17, 2024 – Novartis today announced data from the ALITHIOS open-label extension study showing sustained efficacy of first-line, continuous Kesimpta® (ofatumumab) treatment for up to six years in recently diagnosed – defined as starting treatment within three years of initial diagnosis – treatment-naïve people living with relapsing multiple sclerosis (RMS).1 These efficacy outcomes included 44% fewer relapses; 96.4% and 82.7% reductions in MRI lesions (Gd+ T1 and neT2), respectively; and 24.5% and 21.6% fewer 3- and 6-month confirmed disability worsening (CDW) events, respectively, versus those who switched to Kesimpta from teriflunomide.1 A separate analysis of the overall ALITHIOS population showed similar efficacy with continuous Kesimpta treatment, which was also well-tolerated with a consistent safety profile up to six years.2 These data will be presented at the American Academy of Neurology (AAN) 2024 Annual Meeting held in Denver, Colorado and virtually on April 13-18, 2024.

“Our analysis of treatment-naïve people who were recently diagnosed with relapsing multiple sclerosis found that first-line use of Kesimpta for up to six years provided long-term benefits, including fewer relapses, profoundly suppressed MRI lesion activity, and fewer disability worsening events,” said principal investigator Gabriel Pardo, MD, Founding Director of the Multiple Sclerosis Center of Excellence at Oklahoma Medical Research Foundation. “While measurable improvements were also seen in patients switching to Kesimpta later on, the delay in irreversible disability worsening was not fully realized in the switch group compared to those starting on Kesimpta first, reinforcing the value of introducing the treatment to patients earlier.”

“We are extremely pleased to share the new data from ALITHIOS, which adds to the growing body of evidence of Kesimpta as an efficacious and well-tolerated option for people living with RMS,” said Norman Putzki, Development Unit Head, Neuroscience & Gene Therapy, Development, Novartis Pharmaceuticals Corporation. “Novartis is committed to addressing the biggest challenges for people living with MS through relentless discovery, development, and delivery of potentially transformative medicines with the goal of achieving complete disease control.”

Study Results

In the first analysis, the low annualized relapse rate (ARR) experienced by recently diagnosed treatment-naïve (RDTN) people living with RMS receiving continuous Kesimpta during the core Phase III trials was further reduced in the ALITHIOS open-label extension study, from 0.104 to 0.050 (52.0% reduction), corresponding to an adjusted ARR of one relapse per 20 years.1 Rates of 3- and 6-month progression independent of relapse activity (PIRA) with first-line Kesimpta were also lower versus switch.1 The observed rapid increase in the proportion of participants with no evidence of disease activity (NEDA-3) with continuous first-line Kesimpta treatment was maintained up to six years.1

In RDTN people living with RMS initially randomized to teriflunomide, improvements across several efficacy outcomes were seen after switching to Kesimpta, including significant reductions in ARR (71.3%) and in MRI lesion activity (Gd+ T1: 98.5% reduction; neT2: 93% reduction), and rapid increase in rates of NEDA-3.1 However, rates of 3- and 6-month CDW events remained higher compared to patients receiving continuous Kesimpta, indicating that the efficacy benefit of first-line Kesimpta on delaying disability worsening was not fully achieved in the switch group.1 Across both continuous and switch groups, nine out of 10 participants achieved NEDA-3 at Year 6.1  

Similar results were seen in the second analysis, which looked at the overall ALITHIOS population.2 Data showed sustained efficacy of continuous Kesimpta up to six years, including low ARR (49.9% reduction between core Phase III trials and extension phase), suppression of MRI lesion activity (Gd+ T1: 56.7% reduction; neT2: 89.3% reduction), sustained reduction of 6-month CDW events (14.1%, relative to the switch group), lower rates of 6-month PIRA, and sustained high rates of NEDA-3.2 People switching from teriflunomide to Kesimpta experienced reductions in ARR (73.8%) and MRI lesion activity (Gd+ T1: 97.7% reduction; neT2: 91.8% reduction) and a rapid increase in NEDA-3 rates during the extension period.2 Six-month CDW rates remained higher compared to patients receiving continuous Kesimpta, again highlighting an efficacy benefit of first-line Kesimpta on delaying disability worsening that was not fully achieved in the switch group.2 At Year 6, NEDA-3 status was achieved in nine out of 10 participants in both the continuous and switch groups.2

The study also found that treatment with Kesimpta for up to six years was well-tolerated with no unexpected safety signals identified.2 The rates of adverse events (AEs), serious AEs, serious infections, and malignancies remained stable with no increased risks over six years.2

The overall rates of AEs and serious AEs up to six years of Kesimpta treatment were consistent between the core Phase III trials and the ALITHIOS extension study.2 The most common AEs were infections (COVID-19 [34.3%], nasopharyngitis [20.6%], upper respiratory tract infection [14.9%], and urinary tract infection [14.4%]).2 The incidence of serious infections remained stable over time and did not increase with Kesimpta treatment up to six years.2

Mean serum immunoglobulin G (IgG) levels remained stable up to six years of treatment and the majority of patients (97.2%) had lgG levels above the lower limit of normal (LLN).2 Mean serum immunoglobulin M (IgM) levels decreased over time but remained above the LLN for the majority of patients (65.9%).2 No clinically meaningful association was observed between IgG/IgM levels below the LLN and risk of serious infections.2

About Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by myelin destruction and axonal damage in the brain, optic nerves and spinal cord.3 MS, which affects around 2 million people worldwide, can be characterized into four main types: clinically isolated syndrome (CIS), relapsing-remitting (RRMS), secondary progressive (SPMS) and primary progressive (PPMS).4,5 The various forms of MS can be distinguished based on whether a patient experiences relapses (clearly defined acute inflammatory attacks of worsening neurological function), and/or whether they experience progression of neurologic damage and disability from the onset of the disease.3

About Kesimpta® (ofatumumab)

Kesimpta is a targeted, precisely dosed and delivered B-cell therapy that provides the flexibility of self-administration for adults with relapsing forms of multiple sclerosis (RMS). Kesimpta is the first fully human anti-CD20 monoclonal antibody (mAb) self-administered by a once-monthly injection, delivered subcutaneously (SC) in RMS.6, 7, 8

The treatment regimen was designed and tested to enhance safety and tolerability and minimize the risk of systemic injection-related reactions.6 Initial doses of Kesimpta are at Weeks 0, 1 and 2, with the first injection performed under the guidance of a healthcare professional. Monthly Kesimpta 20 mg doses are associated with rapid reduction and near-complete peripheral B-cell depletion, with no significant effect on pharmacokinetics due to body weight.6 As shown in preclinical studies, Kesimpta is thought to work by binding to a distinct epitope on the CD20 molecule inducing potent B-cell lysis and depletion.9 The selective mechanism of action and SC administration of Kesimpta allows precise delivery to the lymph nodes, where B-cell depletion in MS is needed, and preclinical studies have shown that it may preserve the B-cells in the spleen.10

Data from the ASCLEPIOS I/II core studies demonstrate Kesimpta’s efficacy and favorable safety and tolerability profile in RMS participants and the ALITHIOS open-label extension study provides additional support with up to 6 years of data.2,11 The at-home administration of Kesimpta by monthly doses of 20 mg/0.4mL with an autoinjector (Sensoready®) also matches the preferences of many people living with MS due to its ease of use and supports patients to be compliant with, and persistent on the therapy over time.6 Kesimpta was originally developed by Genmab and licensed to GlaxoSmithKline; Novartis obtained rights for ofatumumab from GlaxoSmithKline in all indications, including RMS, in December 2015.12

Kesimpta has been approved for the treatment of relapsing forms of multiple sclerosis in over 90 countries worldwide with more than 100,000 patients treated as of March 2024.

Novartis in Neuroscience

At Novartis, in Neuroscience, we are committed to understanding and solving some of the most burdensome neurological conditions to improve the quality of life for patients and their caregivers, and to make a positive impact on society. We aim to lead the discovery, development and delivery of innovative medicines to create a transformational impact for people living with severe neurological conditions by changing the course of disease progression.

Through innovation, partnerships and community engagement, we have been tackling neurological conditions for >80 years, launching transformative treatments which have made meaningful differences to millions of people worldwide. We continue to collaborate on the development of industry-leading innovative medicines for multiple sclerosis, and in the areas of neuroimmunology, neurodegeneration, and neuromuscular/rare diseases.

To ensure patients everywhere can benefit from these life-changing therapies, we work closely with key stakeholders across the world to ensure rapid access and sustainable accessibility to our medicines, with the aim of providing the best treatment choices for each person’s unique journey.

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This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as “potential,” “can,” “will,” “plan,” “may,” “could,” “would,” “expect,” “anticipate,” “look forward,” “believe,” “committed,” “investigational,” “pipeline,” “launch,” or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Novartis

Novartis is an innovative medicines company. Every day, we work to reimagine medicine to improve and extend people’s lives so that patients, healthcare professionals and societies are empowered in the face of serious disease. Our medicines reach more than 250 million people worldwide.

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• Pardo G, Hauser SL, Bar-Or A, et al. Longer-term (up to 6 Years) Efficacy of Ofatumumab in People with Recently Diagnosed and Treatment-Naïve Relapsing Multiple Sclerosis. Oral presentation at the American Academy of Neurology (AAN) 2024 Annual Meeting; April 13-18, 2024; Denver, CO.
• Wiendl H, Hauser SL, Nicholas J, et al. Longer-term Safety and Efficacy of Ofatumumab in People With Relapsing Multiple Sclerosis for Up to 6 Years. Poster presentation at the American Academy of Neurology (AAN) 2024 Annual Meeting; April 13-18, 2024; Denver, CO.
• Guthrie EW. Multiple sclerosis: A primer and update. Adv Studies Pharm. 2007;4(11):313-317.
• Multiple Sclerosis International Federation. Atlas of MS 2013-Mapping Multiple Sclerosis Around the World. Accessed August 12, 2020. http://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf
• National MS Society. Types of MS. Accessed January 18, 2023. https://www.nationalmssociety.org/What-is-MS/Types-of-MS
• Hauser SL, Kappos L, Bar-Or A, et al. The Development of Ofatumumab, a Fully Human Anti-CD20 Monoclonal Antibody for Practical Use in Relapsing Multiple Sclerosis Treatment. Neurol Ther. 2023;12(5):1491-1515. doi:10.1007/s40120-023-00518-0
• Kesimpta Prescribing Information. East Hanover, NJ: Novartis Pharmaceuticals Corp; September 2022.
• Bar-Or A, Fox E, Goodyear A, et al. Onset of B-cell depletion with subcutaneous administration of ofatumumab in relapsing multiple sclerosis: results from the APLIOS bioequivalence study. Poster presentation at: ACTRIMS; February 2020; West Palm Beach, FL.
• Smith P, Kakarieka A, Wallstroem E. Ofatumumab is a fully human anti-CD20 antibody achieving potent B-cell depletion through binding a distinct epitope. Poster presentation at: ECTRIMS; September 2016; London, UK.
• Smith P, Huck C, Wegert V, et al. Low-dose, subcutaneous anti-CD20 therapy effectively depletes B-cells and ameliorates CNS autoimmunity. Poster presentation at: ECTRIMS; September 2016; London, UK.
• Cohen, JA, Hauser SL, Zielman R., et al. Effect of Longer-term Ofatumumab Treatment on Disability Progression and Brain Volume Change. Poster presentation at: AAN; April 2023; Boston, US.
• Genmab Press Release: Genmab announces completion of agreement to transfer remaining ofatumumab rights. December 21, 2015. Accessed January 18, 2023. https://ir.genmab.com/static-files/9d491b72-bb0b-4e46-a792-dee6c29aaf7d