The Multiple Facets of Multiple Sclerosis Materials

THE MULTIPLE FACETS OF MULTIPLE SCLEROSIS

JENNIFER SALVON, RPH

Jennifer Salvon is a clinical pharmacist and freelance medical writer at Salvon Scientific, based in Massachusetts. During her career, she has practiced in a variety of venues, including the hospital, retail, managed care, teaching, and clinical research settings. As a lifelong learner, Jennifer enjoys researching and writing to educate herself and others.

Topic Overview

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, progressive central nervous system (CNS) disease that leads to irreversible disability. MS affects people of all ages, is commonly diagnosed in early adulthood, and is the leading cause of non-traumatic neurological disability in young adults. An abnormal immune response causes inflammation in MS. As knowledge of the disease has evolved, treatment options and approaches have shifted and improved. Disease-modifying therapies (DMTs) modify disease course by reducing relapse rate and disability progression. Differing mechanisms of action, administration avenues, dosing, and DMT safety concerns offer healthcare providers and patients many treatment options. A knowledgeable, informed pharmacy team is prepared to educate and counsel patients about MS management.

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Universal Activity Number (UAN): The ACPE Universal Activity Number assigned to this activity is 

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Pharmacy Technician  0669-0000-24-059-H01-T

Credits: 2 contact hour(s) (0.2 CEU(s)) of continuing education credit

Type of Activity: Knowledge

Media: Internet/Home study Fee Information: $6.99

Estimated time to complete activity: 2 contact hour(s) (0.2 CEU(s)), including Course Test and course evaluation

Release Date: May 25, 2024 Expiration Date: May 25, 2027

Target Audience: This educational activity is for pharmacists and pharmacy technicians

How to Earn Credit: From May 25, 2024, through May 25, 2027, participants must:

Read the “learning objectives” and “author and planning team disclosures;”

Study the section entitled “Educational Activity;” and

Complete the Course Test and Evaluation form. The Course Test will be graded automatically. Following successful completion of the Course Test with a score of 70% or higher, a statement of participation will be made available immediately. (No partial credit will be given.)

Credit for this course will be uploaded to CPE Monitor®.

Learning Objectives:

Upon completion of this educational activity, participants should be able to:

Describe the different treatment approaches for relapsing-remitting multiple sclerosis

Identify mechanisms of action associated with current and emerging disease-modifying therapies

Recall common safety considerations associated with treatments for multiple sclerosis

Discuss counseling opportunities for people with multiple sclerosis

Disclosures

The following individuals were involved in developing this activity: Jennifer Salvon, RPh, and Pamela Sardo, PharmD, BS. Pamela Sardo and Jennifer Salvon have no conflicts of interest or financial relationships regarding the subject matter. There are no financial relationships or commercial or financial support relevant to this activity to report or disclose by RxCe.com or any of the individuals involved in the development of this activity.

© RxCe.com LLC 2024: All rights reserved. No reproduction of all or part of any content herein is allowed without the prior, written permission of RxCe.com LLC.

Educational Activity

The Multiple Facets of Multiple Sclerosis Introduction

Multiple sclerosis (MS) is a chronic, progressive, immune-mediated inflammatory disease of the central nervous system (CNS). Multiple sclerosis causes damage to the myelin sheaths of neurons and axons, resulting in motor and cognitive impairments.1 Observation of neurodegenerative symptoms suggestive of MS date back to the late 1300s. In 1868, Jean-Martin Charcot, a French neurologist, first described MS. Early treatments included arsenic, mercury, and deadly nightshade.2 Thankfully, current therapy is less dangerous and more effective. Over twenty Food and Drug Administration (FDA)-approved disease-modifying therapies (DMTs) exist for MS treatment. DMTs differ in mechanism of action, route of administration, dosing schedule, efficacy, and side-effect profile.

Prevalence of Multiple Sclerosis

Multiple sclerosis affects approximately 1 million people in the United States and 2.8 million worldwide.3 Prevalence is highest in North America, Western Europe, and Australasia, steadily increasing over the last few decades.4 The average age of MS diagnosis is between 20 and 40 years of age, making MS the most common disabling disease of young adults.1 Disease progression impacts activities of daily living, work productivity, and mental health, resulting in substantial burdens to patients and caregivers.5

The economic impact of MS is considerable, estimated at $85.4 billion.6 Direct medical costs, including retail prescriptions, outpatient care, and clinic- administered medications and care, are the primary contributors to healthcare expenses. DMTs account for the largest proportion of this cost.6 Indirect costs include presenteeism, absenteeism, early retirement, and informal care due to worsening disability.7 Patients with relapses and greater disability incur higher costs, resource use, and work impairment.7

Pathophysiology of Multiple Sclerosis

The cause of MS is unclear. Patient presentation and symptoms vary according to lesion severity and location within the CNS. Both genetic and environmental factors are associated with MS. The following risk factors are associated with MS development:8,9

Vitamin D deficiency

Gender (more common in females)

UVB exposure

Epstein-Barr virus (EBV) infection

Obesity

Smoking

An abnormal immune response causes inflammation in MS. The adaptive and innate immune responses play a role in MS pathogenesis involving T cells, B cells, and antibodies. T cells are activated in the lymph system. In MS, T cells enter the CNS through blood vessels and cause inflammation and damage. This damages nerve fibers, myelin, and the cells that produce it. Both helper and cytotoxic T cells have been found in MS lesions. Helper T cells fail to function correctly in MS, leading to further damage. Cytotoxic T cells directly attack and destroy cells. Drugs limiting T cell CNS access can reduce or eliminate new MS lesions. B cells become activated with the help of T cells and produce antibodies that fight infections or other abnormal substances. The role of B-cells has yet to be fully understood, but early success with B- cell-depleting therapies highlights their importance, generating further investigation.10,11

Presentation

Clinical symptoms of MS may present suddenly or gradually and can be severe or mild, going unnoticed for years.10 MS often starts with a single event called a clinically isolated syndrome (CIS).12 In a CIS, patients experience neurological symptoms lasting at least 24 hours without active infections and may or may not involve a recovery.12

Symptoms of MS include the following:10

Sensory loss or tingling

Painful loss of vision (optic neuritis)

Facial weakness

Limb weakness

Brain fog, difficulty multitasking

Heat sensitivity

Fatigue

Dizziness

Hearing loss

Multiple sclerosis is classified into different types based on clinical presentation. Types are defined by assessing several factors, including disease progression severity, relapses, and the number of demyelinating lesions found via magnetic resonance imaging (MRI).1 The most common type is relapsing- remitting MS (RRMS). RRMS is characterized by periods of neurological dysfunction followed by a partial or complete recovery period.1 As the disease advances, the extent of recovery lessens, leading to increased disability.1 Approximately 20% of patients transition to uninterrupted progression or secondary progressive MS (SPMS).1,10 Patients experiencing progression from the outset have primary progressive MS (PPMS).10 PPMS occurs in 15% of patients.1 This activity will focus on treatment approaches and considerations in RRMS treatment.

Diagnosis

Diagnosing MS is complex, involving a neurological exam, imaging, and laboratory findings. Magnetic resonance imaging (MRI) is a key diagnostic test in MS. Results are evaluated using the McDonald Criteria for Diagnosis of Multiple Sclerosis. The McDonald Criteria considers the number of attacks, MRI lesions, and evidence of dissemination in space and time. Increased size and number of lesions indicate dissemination in space. Dissemination in time is defined as multiple, distinct attacks at different times.1

RRMS Treatment

Many diseases, such as hypertension and diabetes, have clearly defined treatment approaches. The treatment approach to RRMS is not as clear or structured and has evolved. Individualized treatment plans are essential due to the complexity, variable presentation, and progression of MS.13 A comprehensive treatment plan includes DMTs, symptom management, lifestyle modifications, psychological support, and rehabilitation.1

In 2018, the American Academy of Neurology published practice guideline recommendations for DMTs.14 The guideline contains thirty recommendations encompassing DMT initiation, switching, and discontinuation. A full discussion of the guidelines is beyond the scope of this activity. Highlights of the recommendations include:14

Prescribing a DMT in patients with a CIS and two or more brain lesions after discussing DMT’s benefits and risks

Offering DMTs to RRMS patients with recent clinical relapses or new MRI activity

Using alemtuzumab, fingolimod, and natalizumab in patients with highly active MS

Encouraging pharmaceutical support programs for patients on DMTs

Switching DMTs in the following situations:

Suboptimal response to therapy

Medication-related adverse effects

Laboratory abnormalities

Poor patient adherence

There are two main treatment approaches for RRMS: escalation and early treatment with highly effective therapies (HET).1,15,16 Escalation therapy prioritizes safety, starting with a lower-efficacy drug with a more favorable adverse effect profile. If the patient experiences disease progression with a relapse, MRI changes, or disability, therapy is switched to an agent with higher

efficacy. While minimizing risk, this approach may result in disease and disability progression.1,17

Early treatment with HET starts with a high-efficacy drug at diagnosis. Experts believe that early HET initiation may alter the disease progression, preventing irreversible damage and minimizing future disability. The limitation of this approach is that it exposes patients to a higher risk of adverse events. Observational studies suggest that early use of highly effective therapies improves long-term patient outcomes.1,10

There is no clear definition designating a DMT as HET, though several publications discuss HETs. DMTs considered HETs include natalizumab, the S1P receptor modulators, and the anti-CD20 monoclonal antibodies.10,15,16,18

Efficacy Measurements

The efficacy of DMTs is measured by a reduction in annualized relapse rate (ARR).18 In studies, the HETs have an average ARR greater than 50% when compared to placebo or interferon therapy.18

A newer outcome measurement in evaluating DMTs is no evidence of disease activity (NEDA).19 NEDA-3 is the measurement most used. NEDA-3 indicates no relapses, disability progression, or new MRI activity. NEDA-4 adds the finding of no additional brain volume loss. NEDA is currently used in clinical trials and is gaining interest from healthcare providers to assist in making treatment decisions.19

Worsening disability is the primary cause of indirect costs and is the most troublesome aspect of MS for patients. The expanded disability status scale (EDSS) measures disability severity.20 Many functions are evaluated during a neurological examination, including muscle weakness, balance, coordination, tremor, eyesight, speech, and swallowing. The EDSS uses a scale of zero to ten, with zero indicating normal neurological function. A score of five indicates disability affecting the activities of daily living, and ten indicates death due to MS.20

Progressive Multifocal Leukoencephalopathy

Progressive multifocal encephalopathy (PML) is a rare infection caused by the John Cunningham virus (JCV). The virus attacks the myelin sheath in the CNS, leading to demyelination. Up to 90% of healthy adults carry inactive JCV virus. Reactivation of the JC virus can have serious consequences for immunocompromised individuals. Patients with MS taking immunosuppressive therapy are a high-risk group for developing PML.21

Progressive multifocal encephalopathy presents with a wide range of symptoms, including ataxia, gait disturbances, double vision, and altered mental status. It is diagnosed using a combination of clinical and imaging findings. Management of PML involves stopping the causative agent and supportive care. Several DMTs are associated with PML, including natalizumab, fingolimod, dimethyl fumarate, ocrelizumab, and alemtuzumab. The risk of developing PML is an important consideration when initiating and evaluating MS therapy.21

Disease Modifying Therapies (DMTs)

Disease modifying therapies modulate and suppress immune function, decreasing relapse rate, MRI lesion accumulation, delaying disease progression, and worsening disability.10 Over 20 different DMTs are available for MS treatment. They differ in mechanism of action, administration, dosing, efficacy, safety, and adverse effects. The first DMT, interferon β-1b, gained approval in 1993. Before 1993, immunosuppressive drugs such as azathioprine and methotrexate were used with limited success.1 The number of available DMTs offers the opportunity for individualized patient care but can also be overwhelming. Table 1 lists FDA-approved DMTs for RRMS treatment with dosing and administration notes. Table 2 lists monitoring and safety concerns for available DMTs. Below is a brief discussion of each drug class, including its efficacy and treatment considerations.

Table 1

Disease Modifying Therapies for Relapsing-Remitting Multiple Sclerosis22-42

Siponimod	Mayzent (2019)	PO	5 day titration: Day 1 & 2: 0.25 mg Day 3: 0.50 mg Day 4: 0.75 mg Day 5: 1.25 mg	2 mg once daily starting on Day 6	Administer tablets whole, do not split or crush Dosing adjustments required if patient has CYP2C9 *1/*3 or *2/*3 Use is contraindicated CYP2C9 *3/*3
Ozanimod	Zeposia (2020)	PO	Days 1-4: 0.23 mg once daily Days 5-7: 0.46 mg once daily	0.92 mg once daily starting Day 8	Dose adjustment for hepatic impairment and if dose interruption
Ponesimod	Ponvory (2021)	PO	2 mg QD, titrated over 14 day period to 20 mg once daily	20 mg once daily
Fumarates
Dimethyl fumarate	Tecfidera (2013)	PO	120 mg BID for 7 days	240 mg BID	Administer with or without food
Diroximel fumarate	Vumerity (2019)	PO	231 mg BID for 7 days	462 mg BID	Do not crush, chew, or sprinkle Avoid administration with high-fat or high-calorie food or snack Avoid alcohol
Monomethyl fumarate	Bafiertam (2020)	PO	95 mg BID for 7 days	190 mg BID	Do not crush, chew, or sprinkle Administer with or without food

Interferons and Glatiramer

Interferon β therapies and glatiramer were the first approved medications for RRMS treatment. The exact interferon β mechanism of action is unknown, but it likely involves immunomodulation, decreasing T-cell migration and proliferation. This results in an anti-inflammatory effect, reducing relapse rate, lesion formation, and disability progression.10 Currently approved products include interferon β-1b, interferon β-1a, and peginterferon. In clinical trials, interferon β-1b reduced ARR by 29-34% compared to placebo. Long-term safety of the interferons has been established in several trials.18

Sphingosine-1-phosphate Receptor Modulators (S1PRM)

Sphingosine-1 phosphate receptors (S1PR) exist throughout the body and regulate several immunological, cardiovascular, and neurological functions. They are integral in producing immune mediators, affecting local and systemic inflammatory processes. There are five subtypes of S1PRs. The S1RP subtype 1 is expressed on the surface of lymphocytes. Inhibition of S1RP1 results in the sequestering of lymphocytes in lymph nodes, preventing CNS migration.43

Four FDA-approved S1PRMs exist to treat MS: fingolimod, siponimod, ozanimod, and ponesimod. The S1PRMs differ in their affinity for the different S1PR subtypes and offer the advantage of oral administration and improved efficacy over the interferons and glatiramer.18 In clinical trials, fingolimod reduced ARR by 48-55% compared to placebo and interferon β-1a.18

The first dose of fingolimod acts as an S1PR agonist, leading to bradycardia and heart block. Subsequent doses downregulate the receptor, and cardiac effects resolve. For this reason, all patients require first-dose observation with fingolimod for at least 6 hours.1 First-dose observation is not required for siponimod and ozanimod in the absence of cardiac history.1

Siponimod is metabolized through the cytochrome P450 system, primarily through the CYP2C9 enzyme. Siponimod requires CYP2C9 genetic testing before treatment to determine titration and dosing schedule. An ophthalmic assessment is recommended for ozanimod patients with macular edema or uveitis history.1

Fumarates

The fumarates approved for treating MS include dimethyl fumarate, diroximel fumarate, and monomethyl fumarate. The exact mechanism of action of fumarates is unknown, but it is thought to involve activation of the nuclear (erythroid-derived-2)-like 2 pathway. Fumarates have anti- inflammatory and cytoprotective effects. Dimethyl fumarate and diroximel fumarate are metabolized to the active form, monomethyl fumarate.10 Dimethyl fumarate showed a 44-53% reduction in ARR compared to placebo.18

Teriflunomide

Teriflunomide is a once-daily oral immunomodulator. Teriflunomide is the active metabolite of leflunomide and is a pyrimidine synthesis inhibitor. Teriflunomide reduces the number of activated T and B cells available to enter the CNS.10 Considered a modestly effective DMT, teriflunomide produced a 22-36% reduction in ARR compared to placebo.18

Cladribine

A purine nucleoside analog, cladribine, was initially developed to treat hematological malignancies. Cladribine exerts a cytotoxic effect on T-cells and B-cells, resulting in the depletion of lymphocytes.37 Compared to placebo, cladribine reduced ARR by 55-58%, making it a highly effective therapy. Cladribine has a low treatment burden consisting of 2 short courses one year apart, followed by two years of no treatment.37 Serious adverse events limit the use of cladribine.10

Monoclonal Antibodies

Many DMTs used to treat RRMS are monoclonal antibodies (mAb). Most available mAbs are administered by infusion, and all possess a higher efficacy profile than injectable and oral DMTs. Monoclonal antibody therapy commonly causes infusion reactions involving headache, nausea, itching, and flushing. Premedication with corticosteroids, antihistamines, and antipyretics mitigate infusion reaction symptoms.1 Due to the risk of serious adverse effects, two mAbs, natalizumab, and alemtuzumab, require patient registration with a Risk Evaluation and Mitigation Strategy (REMS) program.1 REMS programs are drug safety programs that the FDA requires to ensure the benefits of a drug outweigh the risks.

There are three available mAbs targeting the CD20 antigen on B and T cells: ocrelizumab, ofatumumab, and ublituximab. All are approved to treat CIS, RRMS, and SPMS. Ocrelizumab carries an additional indication to treat PPMS. By selectively depleting CD20 B and T cells, anti-CD20 mAbs disrupt lymphocyte CNS migration, suppressing the inflammatory process.1 Comparative clinical trials demonstrate the high efficacy of mAbs.18 Compared to interferon β-1a, ocrelizumab therapy resulted in a 47% ARR reduction.18 Efficacy trials compared ofatumumab and ublituximab with teriflunomide, resulting in similar ARR reduction: 50-60% for ofatumumab and 49-59% for ublituximab.18

Natalizumab is an mAb that binds to the alpha-4 subunit of integrins found in lymphocytes, limiting their CNS access.38 Efficacy trials compared natalizumab to placebo, resulting in an ARR reduction of 68%.18 Due to the risk of PML, natalizumab is only available through a REMS program, the TOUCH Prescribing Program.38

Alemtuzumab causes cell cytolysis by binding to the CD52 antigen on B and T cells, resulting in a 68% reduction of ARR compared to placebo.18 Alemtuzumab is associated with serious autoimmune effects, including hypo- and hyperthyroidism and immune thrombocytopenia.1 As a result, it is usually reserved for treatment in patients with inadequate responses to two or more DMTs.

Table 2

Safety and Monitoring of DMTs in RRMS1,22-42

Symptom Management, Supportive Care, and Lifestyle Modifications

Various medications and therapies are available to manage MS symptoms such as spasticity and spasms, gait impairment, tremor, bladder dysfunction, depression, and cognitive impairment. Table 3 lists some of the medications used to support symptom management.

Physical, occupational, and speech therapy can help improve mobility and function. Rehabilitation programs focus on maximizing function and independence through exercise, mobility aids, and adaptive techniques. Healthy lifestyle habits such as regular exercise, a balanced diet, stress management, and adequate rest can help manage symptoms and improve overall well-being. Psychosocial support, counseling, and support groups provide emotional support, education, and resources for patients living with MS and their caregivers.1

Table 3

Medications used to support symptom management in MS1,10

Front Line Support from the Pharmacy Team

Pharmacists and pharmacy technicians are among the most accessible healthcare providers. People routinely turn to neighborhood pharmacies for advice on many health topics. The complicated nature of MS creates an environment ripe for patient confusion and treatment adherence issues. MS diagnosis is a stressful event; patients may only remember some of the information given at the time of diagnosis. Patients with MS need extensive education about disease management and possible adverse effects. A knowledgeable pharmacy team can answer questions, allowing patients better to understand the risks and benefits of MS treatments.

The following are important points to consider when counseling patients with MS:

When talking with a patient, it’s important to acknowledge the silent progression and invisibility of MS without making assumptions about how a patient feels.

Showing empathy to someone with MS involves understanding their experiences, challenges, and emotions while offering support and compassion. Remind patients that MS is a progressive disease and treatment adherence is critical to managing the symptoms of the disease and slowing down its progression.

Talk with MS patients when they come in, asking how they are doing and touching base about periodic monitoring.

Discuss the role of individual treatment plans with patients so they know there is more than one approach.

Stay current on the different DMTs, dosage forms, titrations, administration techniques, and potential adverse reactions.

Encourage patients to stop smoking and remain active, engaging in physical and mental activities.

The high cost of DMTs often means higher out-of-pocket costs for patients in the form of copays and deductibles. This could lead to poor adherence, resulting in relapses, hospitalization, and worsening disability. The pharmacy team can assist MS patients with signing up for copay cards or other financial assistance.

Summary

Multiple sclerosis is a progressive and debilitating disease with no clear cause. It presents differently in each patient. Treatment is individualized, multifaceted, and long-term. There is no cure for multiple sclerosis. Patients with MS face lifelong challenges, including disability and cognitive impairment. Newer DMTs offer higher efficacy and easier administration but with potentially severe adverse effects.

The treatment of multiple sclerosis can seem intimidating due to the number of approved disease-modifying therapies. However, the approach to treatment is shifting, and the recent approval of several new highly efficacious therapies provides hope for patients. These drugs are the mainstay of MS treatment and work to reduce the frequency and severity of relapses, slow down the progression of disability, and decrease the number of lesions in the brain.

Course Test

Which of the following is prioritized in the escalation approach to multiple sclerosis (MS) treatment?

Annualized relapse rate reduction

*Safety profile

Route of administration

Cost of therapy

An emerging treatment approach utilizes disease-modifying therapies (DMT), classified as highly effective therapies (HET). DMTs are considered HETs based on what parameter?

Expanded disability status scale (EDSS)

No evidence of disease activity (NEDA)

The McDonald Criteria (TMC)

*Annualized relapse reduction rate (ARR)

Which of the following DMTs requires additional monitoring due to potentially severe cardiovascular adverse effects?

Interferon β-1b

Dimethyl fumarate

*Fingolimod

Ofatumumab

Which of the following DMT acts on sphingosine-1-phosphate receptors?

*Ozanimod

Glatiramer

Dimethyl fumarate

Cladribine

Which of the following DMTs requires patient registration with a Risk Evaluation and Mitigation Strategy (REMS) program?

*Alemtuzumab

Ocrelizumab

Fingolimod

Teriflunomide

When filling a prescription for diroximel fumarate, you notice the patient copay is $500. What advice would you offer the patient?

Explain that this is their insurance coverage, and there is nothing you can do.

Advise the patient to call their provider for a different medication.

Suggest the patient hold off on starting therapy.

*Offer to research available copay assistance programs.

                       is a DMT that is associated with a high risk of progressive multifocal leukoencephalopathy (PML).

Glatiramer

Ofatumumab

*Natalizumab

Ponesimod

Ocrelizumab’s mechanism of action involves

CD52 antigens.

*CD20 antigens.

⍺-4 subunit of integrins.

Pyrimidine synthesis.

A regular pharmacy customer shares their recent MS diagnosis. They are overwhelmed with the treatment plan. How would you advise them?

*Discuss the importance of a comprehensive treatment plan.

Let them know you can only assist with medication-related questions.

Refer them to their provider for questions.

Advise them to read through the treatment plan again.

Which of the following describes the overall treatment recommendations for MS?

The treatment approach to MS is clear-cut, with a defined step-wise approach.

Treatment recommendations only involve therapy with a DMT.

Treatment begins with lifestyle modifications, only starting DMT when the disease progresses.

*Individualized therapy is key, involving lifestyle modifications, DMTs, and symptom management.

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Ponvory [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2023. https://www.janssenlabels.com/package-insert/product- monograph/prescribing-information/PONVORY-pi.pdf. Accessed April 24, 2024.

Tecfidera [package insert]. Cambridge, MA: Biogen, Inc. 2024. https://www.tecfidera.com/content/dam/commercial/tecfidera/pat/en_u s/pdf/full-prescribing-info.pdf. Accessed April 26, 2024.

Vumerity [package insert]. Cambridge, MA: Biogen, Inc. 2024. https://www.vumerity.com/content/dam/commercial/vumerity/pat/en_ us/pdf/vumerity-prescribing-information.pdf. Accessed April 26, 2024.

Bafiertam [package insert]. High Point, NC: Banner Life Sicences, LLC. 2023. https://bafiertam.com/pdf/bafiertam-prescribing-information.pdf.

Accessed April 19, 2024.

Aubagio [package insert]. Cambridge, MA: Sanofi 2021. https://products.sanofi.us/aubagio/aubagio.pdf. Accessed April 26, 2024.

Mavenclad [package insert]. Rockland, MA: EMD Serono, Inc. 2024. https://www.emdserono.com/us-en/pi/mavenclad-pi.pdf. Accessed April 26, 2024.

Tysabri [package insert]. Cambridge, MA: Biogen, Inc. 2023. https://www.tysabri.com/content/dam/commercial/tysabri/pat/en_us/p df/tysabri_prescribing_information.pdf. Accessed April 24, 2024.

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Accessed April 24, 2024.

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