Spinal Muscular Atrophy as a Treatable Disease: Disease-Modifying Therapies Improving Clinical Outcomes and Quality of Life

Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder characterized by progressive skeletal muscle hypotonia affecting voluntary movements.1 A recessive mutation in the survival motor neuron 1 (SMN1) gene, which is required for proper production of the SMN protein, leads to irreversible loss of α motor neurons in the ventral spinal cord and motor nuclei in the lower brainstem. Symmetric, proximal greater than distal, and progressive muscle weakness is the hallmark symptom.
SMA is the second most common autosomal recessive disorder worldwide and the most common cause of infant mortality, with an estimated incidence of 1 in 10,000 live births and estimated prevalence of 1 to 2 per 100,000 persons (Figure 1).3 Approximately 2% of SMA cases are de novo mutations.2  

The pathogenesis of SMA centers around a mutation in the SMN1 gene that causes the absence of exon 7, which encodes 90% of the genetic material for the SMN protein. The other 10% of genetic material is encoded by the survival motor neuron 2 (SMN2) gene.3 SMN2 and SMN1 share 99% of nucleotide identity, except that SMN2 does not transcribe exon 7.4 However, the SMN2 gene copy number is the most important modifier for SMA disease severity. If an individual has a higher number of SMN2 copies in the absence of SMN1, the prognosis may be better.5 SMA is classified by types 0 to 4 with lower numbers reflecting greater clinical severity (Table 1).1-3

Patients with type 0 typically have 1 SMN2 copy, patients with type 1 have 1 to 2 SMN2 copies, patients with type 2 have 3 SMN2 copies, patients with type 3 have 3 to 4 SMN2 copies, and patients with type 4 have 4 or more SMN2 copies (Figure 2).1,3 Type 1 is the most common type, with approximately 60% of cases worldwide. 3

Multiplex ligation-dependent probe amplification (MLPA) is a convenient, highly sensitive deletion test that can determine the copy numbers of both SMN1 and SMN2. For this reason, it is one of the most popular laboratory tests used for diagnosing SMA.1
There are 2 approaches to treatment once a diagnosis for SMA has been made: SMN2 modulators and SMN1 gene therapy. SMN2 modulators alter SMN2 messenger RNA (mRNA) to transcribe exon 7 and produce a full-length SMN protein, and SMN1 gene therapy delivers the SMN1 gene directly to DNA via a viral vector. Historically, SMA treatment consisted of supportive care only. The arrival of disease-modifying therapies has made a major impact on the prognosis for patients with SMA.
There are currently 3 therapies approved by the US Food and Drug Administration (FDA) for the treatment of SMA, with several others under investigation (Table 2).1-7 Additionally, research is being conducted on the effectiveness of combining the 2 existing types of SMA therapies.1 

SMN2 Modulators

Nusinersen. Nusinersen is an antisense oligonucleotide that modifies pre-mRNA splicing of the SMN2 gene to promote the inclusion of exon 7 in the mRNA resulting in a full-length, functional SMN protein.6
The ENDEAR trial (ClinicalTrials.gov Identifier: NCT02193074) is a phase 3 study that tested the safety of nusinersen in 121 infants with SMA who were randomly assigned in a 2 to 1 ratio to receive nusinersen or placebo over a 10-month period. Investigators found a significantly higher percentage of patients in the nusinersen group (41%) experienced positive motor milestone response compared with patients in the control group (0%). The overall survival rate was significantly higher in the patients in the nusinersen group vs the control group (P =.004).6 Similar positive motor milestone efficacy was seen in CHERISH (ClinicalTrials.gov Identifier: NCT02292537), a phase 3 trial that enrolled 126 children aged 2 to 12 years with experienced symptom onset at 6 months of age and older.7 Children were randomly assigned in a 2 to 1 ratio to received nusinersen or placebo over a 9-month period. Both of these trials were stopped early given their compelling results.6,7
Nusinersen does not cross the blood-brain barrier and is administered intrathecally in 4 doses over 2 months followed by a maintenance dose every 4 months.8 In December 2016, nusinersen became the first FDA-approved pediatric and adult treatment for SMA.9
The most common adverse events linked to nusinersen are upper- and lower-respiratory tract infections, atelectasis, constipation, headache, back pain, and post-lumbar puncture syndrome. Nusinersen has no known drug-drug interactions. Ongoing studies are assessing long-term drug-drug interactions and safety risks since most of the clinical trials investigating nusinersen lasted less than 18 months in duration.10
The steep price, possible non-reimbursement from insurance, and a complicated intrathecal administration, especially in patients with scoliosis, are some of the drawbacks of this drug.10,11
Risdiplam. Risdiplamis a small molecule SMN2 splicing modifier with high specificity for exon 7.12
The safety, efficacy, and tolerability of risdiplam were assessed in the FIREFISH trial (ClinicalTrials.gov Identifier: NCT02913482), a 2-part study that enrolled 21 infants with SMA type 1 and 2 copies of SMN2 aged 1 to 7 months at time of enrollment.13 In part 1 of the trial, 93% of infants showed an increase in their Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score, and 14 infants had an overall increase in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) milestones over the course of 8 months. The Hammersmith Infant Neurological Examination Module 2 milestones include rolling to the side or going from prone to supine, sitting with or without support, horizontal or upward kicking, and full head control. No drug-related adverse events were reported.13 In part 2 of the trial, which included an additional 4 months of treatment, 29% of infants could sit unsupported for at least 5 seconds, which is a major milestone achievement for infants with SMA type 1. After 23 months of treatment, 95% of the surviving infants were able to swallow and 89% were able to orally feed. The trial survival rate was 93% after 12 months of treatment.13
Risdiplam is administered daily as an oral liquid. After receiving FDA-approval in patients aged 2 months and older, risdiplam became the first orally deliverable small molecule therapy for the treatment of SMA.14
The most common adverse events associated with risdiplam were fever, rash, oral ulcers, joint pain, diarrhea, and urinary tract infections. Infants treated with risdiplam also had upper respiratory tract infections, pneumonia, vomiting, and constipation. Pregnancy testing is recommended in women of reproductive age before beginning treatment.12
Risdiplam is suitable for patients with SMA who have tolerability or immune response concerns regarding gene therapy. The treatment is easy to administer and works systemically.10

SMN1 Gene Therapy

Onasemnogene abeparvovec. Onasemnogene abeparvovecis an adeno-associated virus 9 (AAV9) vector that delivers wild-type SMN1 to motor neurons, muscle, and other peripheral tissues where SMN1 is expressed.8
In a 2019 study, 12 infants with SMA type 1 who received a one-time dose of onasemnogene abeparvovec had a survival rate of 100% at 24 months compared with a rate of 38% in a historical cohort.15 The infants who were treated with onasemnogene abeparvovec also had improved Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores compared with a historical cohort whose scores decreased by 24 months of age. The infants who received onasemnogene abeparvovec achieved several motor milestones, including sitting unassisted and walking.15
Onasemnogene abeparvovec needs to be monitored closely for safety and tolerability. High doses of AAV vectors expressing human SMN may cause acute hepatotoxicity and sensory neuron toxicity.8
Onasemnogene abeparvovec can cross the blood-brain barrier and only requires a one-time injection to produce a sustained systemic expression of SMN protein.8 It was approved by the FDA for the treatment of SMA in patients aged 2 years and younger.16
A potential issue with the effectiveness of onasemnogene abeparvovec is the presence of anti-AAV9 antibodies in patients with SMA.17 Individuals who become naturally infected with AAVs can mount adaptive immune responses driven partly by innate immune responses to a helper virus such as adenovirus.18 The neutralizing antibodies could block gene transfer to cellular targets. However, humans typically have low titers of AAV9.17

What is the greatest determinant of SMA severity?
The SMN2 gene copy number.

Newborn Screening

One of the ways to maximize normal functioning in infants with SMA before the irreversible loss of motor neurons is to start treatment in the pre-symptomatic period. A newborn screening can identify such infants.19 Treatment before symptoms surface leads to the greatest benefits for survival prognosis, motor development, and reduced need for permanent ventilation.20 Newborn screening is especially helpful for patients with SMA type 1 because rapid motor unit loss can occur within the first 3 months of life and more than 95% of motor units are lost within 6 months of life.1
An Australian study screened dried blood spots of 103,903 newborns using polymerase chain reaction to diagnose infants with SMA.20 Investigators followed up with the infants for several months. One infant who started nusinersen therapy while symptomatic on day 33 of life had a normal neurological exam aside from mild head-lag on pull to sit when the infant was 5 months of age. Another infant who started nusinersen therapy while symptomatic on day 21 of life had restored truncal tone and improved functional motor scores at 4 months of age. Both infants remain free of permanent ventilation and are fully orally fed.20
The NURTURE trial (ClinicalTrials.gov Identifier: NCT02386553), a phase 2, open-label, single-arm, multinational study, examined clinical outcomes in 25 infants with SMA who underwent a 5-year treatment period with nusinersen before SMA symptoms were present. The interim analysis reported no infant deaths or permanent respiratory ventilation requirements after approximately 4 years of treatment and 100% of infants achieved the ability to sit without support. Of these patients, 84% reached the milestone set by the World Health Organization’s timeframe for healthy children. There were 4 infants who needed respiratory support for extended periods of time.21

Lifestyle Modifications

Metabolic dysfunction, such as hyperlipidemia and glucose intolerance, has been reported in SMA mouse models and patient groups.22 Lifestyle modifications may benefit the clinical severity of patients with SMA. A study published in 2019 assessed the effect of 10 months of low-intensity running and high-intensity swimming on mice with mild SMA-like characteristics. Investigators found that both exercises improved the mice’s lipid metabolism and glucose homeostasis. They recommended long-term physical exercise as a “therapeutic intervention for [patients with SMA], in complement to pharmacological or gene-therapies.”23 

Managing Multiorgan System Effects

The absence of SMN protein can affect multiple organ systems, including the heart, kidney, liver, pancreas, spleen, and immune system (Table 3). 2 This can manifest as congenital heart defects, cardiac rhythm abnormalities, sleep disturbances, impaired kidney function, and pancreatic defects.2 As patients live longer due to the advent of new therapies, multisystem comorbidities become more prevalent for this patient population.1 In 2018, the SMA Care Group — a panel of experts including geneticists, orthopedists, pulmonologists, physical therapists, and nutritionists — presented updated and comprehensive guidelines for treating comorbid outgrowths of SMA.24,25 The SMA phenotypic variation, patient preferences, cultural differences, and access to care all factor into decisions about how to best manage comorbidities.19


1. Keinath MC, Prior DE, Prior TW. Spinal muscular atrophy: mutations, testing, and clinical relevance. Appl Clin Genet. 2021;14:11-25. doi:10.2147/TACG.S239603
2. Prior TW, Leach ME, Finanger E. Spinal muscular atrophy. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle: University of Washington, Seattle; February 24, 2000.
3. Verhaart IEC, Robertson A, Wilson IJ, et al. Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy – a literature review. Orphanet J Rare Dis. 2017;12(1):124. doi:10.1186/s13023-017-0671-8
4. McKusick VA. Online Mendelian Inheritance in Man. Survival of motor neuron 1; SMN1. January 27, 1995. Updated June 8, 2018. Accessed on March 10, 2022. https://www.omim.org/entry/600354
5. Kolb SJ, Kissel JT. Spinal muscular atrophy. Neurol Clin. 2015;33(4):831-846. doi:10.1016/j.ncl.2015.07.004
6. Finkel RS, Mercuri E, Darras BT, et al; for the ENDEAR Study Group. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med. 2017;377(18):1723-1732. doi:10.1056/NEJMoa1702752
7. Mercuri E, Darras BT, Chiriboga CA, et al; for the CHERISH Study Group. Nusinersen versus sham control in later-onset spinal muscular atrophy. N Engl J Med. 2018;378(7):625-635. doi:10.1056/NEJMoa1710504
8. Messina S, Sframeli M. New treatments in spinal muscular atrophy: positive results and new challenges. J Clin Med. 2020;9(7):2222. doi:10.3390/jcm9072222
9. FDA approves first drug for spinal muscular atrophy. US Food and Drug Administration. December 23, 2016. Updated March 28, 2018. Accessed on March 23, 2022. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-spinal-muscular-atrophy
10. Claborn MK, Stevens DL, Walker CK, Gildon BL. Nusinersen: a treatment for spinal muscular atrophy. Ann Pharmacother. 2019;53(1):61-69. doi:10.1177/1060028018789956
11. Kakazu J, Walker NL, Babin KC, et al. Risdiplam for the use of spinal muscular atrophy. Orthop Rev (Pavia). 2021;13(2):25579. doi:10.52965/001c.25579
12. Singh RN, Ottesen EW, Sing NN. The first orally deliverable small molecule for the treatment of spinal muscular atrophy. Nuerosci Insights. 2020;15:1-11. doi:10.1177/2633105520973985
13. Baranello G, Darras BT, Day JW, et al; for the FIREFISH Working Group. Risdiplam in type 1 spinal muscular atrophy. N Engl J Med. 2021;384(10):915-923. doi:10.1056/NEJMoa2009965
14. FDA approves oral treatment for spinal muscular atrophy. US Food and Drug Administration. August 7, 2020. Accessed on March 23, 2022. https://www.fda.gov/news-events/press-announcements/fda-approves-oral-treatment-spinal-muscular-atrophy
15. Al-Zaidy SA, Kolb SJ, Lowes L, et al. AVXS-101 (onasemnogene abeparvovec) for SMA1: comparative study with a prospective natural history cohort. J Neuromuscul Dis. 2019;6(3):307-317. doi:10.3233/JND-190403
16. FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality. US Food and Drug Administration. May 24, 2019. Accessed on March 23, 2022. https://www.fda.gov/news-events/press-announcements/fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease
17. Day JW, Finkel RS, Mercuri E, et al. Adeno-associated virus serotype 9 antibodies in patients screened for treatment with onasemnogene abeparvovecMol Ther Methods Clin Dev. 2021;21:76-82. doi:10.1016/j.omtm.2021.02.014
18. Ertl HCJ. T cell-mediated immune responses to AAV and AAV vectors. Front Immunol. Published online April 13, 2021. doi:10.3389/fimmu.2021.666666
19. Schorling DC, Pechmann A, Kirschner J. Advances in treatment of spinal muscular atrophy – new phenotypes, new challenges, new implications for care. J Neuromuscul Dis. 2020;7(1):1-13. doi:10.3233/JND-190424
20. Kariyawasam DST, Russell JS, Wiley V, Alexander IE, Farrar MA. The implementation of newborn screening for spinal muscular atrophy: the Australian experience. Genet Med. 2020;22(3):557-565. doi:10.1038/s41436-019-0673-0
21. De Vivo DC, Bertini E, Swoboda KJ, et al. Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: interim efficacy and safety results from the Phase 2 NURTURE study. Neuromuscul Disord. 2019;29(11):842-856. doi:10.1016/j.nmd.2019.09.007
22. Chaytow H, Faller KME, Huang YT, Gillingwater TH. Spinal muscular atrophy: from approved therapies to future therapeutic targets for personalized medicine. Rep Med. 2021;2(7):100346. doi:10.1016/j.xcrm.2021.100346
23. Houdebine L, D’Amico D, Bastin J, et al. Low-intensity running and high-intensity swimming exercises differentially improve energy metabolism in mice with mild spinal muscular atrophy. Front Physiol. 2019;10:1258. doi:10.3389/fphys.2019.01258
24. Mercuri E, Finkel RS, Muntoni F, et al; for the SMA Care group. Diagnosis and management of spinal muscular atrophy: part 1: recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018;28(2):103-115. doi:10.1016/j.nmd.2017.11.005
25. Finkel RS, Mercuri E, Meyer OH, et al; for the SMA Care group. Diagnosis and management of spinal muscular atrophy: part 2: pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018;28(3):197-207. doi:10.1016/j.nmd.2017.11.004
Posted by Haymarket’s Clinical Content Hub. The editorial staff of Neurology Advisor had no role in this content’s preparation.
                                                                                                                                       Reviewed April 2022

Re-evaluating Old and New Therapies for Narcolepsy

Recent research indicates that narcolepsy is a growing problem in the United States.1,2


Research into Type 1 narcolepsy with cataplexy has revealed that many patients have a deficiency in hypocretin, also known as orexin or Hcrt, a neuropeptide hormone produced in the lateral hypothalamus that stabilizes the sleep/wake cycle and promotes wakefulness.3,5,6 In patients with Type 1 narcolepsy associated with cataplexy, the number of Hcrt neurons in the hypothalamus are severely reduced thereby suppressing excitation of certain neurons that support differentiation of sleep/wake states.6 Decreased secretion of hypocretin not only reduces daytime alertness but also interferes with REM sleep, allowing for a blending of the sleep/wake states. This explains the appearance of sleep paralysis in conjunction with hallucinations and cataplexy, all at the point of waking or falling asleep.3

A second pathophysiologic mechanism in Type 1 narcolepsy is autoimmune with a genetic component. Up to 95% of patients with Type 1 narcolepsy have at least 1 HLA-DQB1*0602 allele. However, this allele is also present in 12% to 38% of the unaffected general population, limiting the current clinical utility of HLA typing.3

Clinical Signs of Narcolepsy1,3,7

Narcolepsy is characterized primarily by excessive daytime sleepiness (EDS) and dysregulation of rapid eye movement (REM) sleep. The disruption of REM sleep can result in symptoms of cataplexy during the day. This affects nighttime sleep quality and often manifests as sleep paralysis or hypnagogic and hypnopompic hallucinations. Although these latter symptoms are common, they are not required for a diagnosis of narcolepsy. Only EDS is required for diagnosis.

Primary Symptoms of Narcolepsy1,3,7

EDS: The inability to maintain a wakeful state throughout the day, with involuntary lapses into sleep during waking hours. Patients may refer to their EDS symptoms as fatigue, tiredness, or lack of energy, which are features of many conditions. Clinicians should evaluate patients to uncover possible causes of their reported inability to stay awake during the day.7

Cataplexy: This involuntary sudden loss of muscle tone while awake occurs in approximately three quarters of patients with narcolepsy. Cataplexy is transitory, often beginning in facial muscles as slackening of the jaw and drooping of the head. More pronounced episodes may involve the lower limbs and trunk, causing the individual to collapse while remaining conscious. These symptoms usually occur in parallel with the emergence of EDS but may also appear later in the disease course. An estimated 60% of patients with Type 1 narcolepsy1 and 10% of patients with Type 2 narcolepsy6  experience cataplectic episodes, which are triggered by expressions of emotion.6

Hallucinations: Visual distortions or false perceptions occurring either upon awakening or just before sleep and usually with the patient’s comprehension that they are not real.1,3

Sleep paralysis: An inability to move or speak, lasting for seconds to minutes and most often occurring upon waking or just before falling asleep.1,3

What differentiates Type 1 from Type 2 narcolepsy?
Type 1 has the additional symptom of cataplexy or cerebrospinal fluid hypocretin 1 levels less than 110 pg/mL.

Diagnostic Criteria

Two types of narcolepsy have been identified. Both Type 1 and Type 2 require the presence of the following symptoms and signs:

•       EDS for 3 months or longer that is not explained by other potential causes such as medical and/or psychological conditions, substance overuse, or effects of prescribed medications.
•       Mean sleep latency (MSL) of 8 minutes with 2 or more sleep-onset REM periods shown by results of the MSL Test (MSLT; described below in Assessment Tools for Diagnosis).

These symptoms alone are sufficient for a diagnosis of Type 2 narcolepsy. Cataplexy is only present in Type 1 narcolepsy. Alternatively, cerebrospinal fluid hypocretin-1 levels of 110 pg/mL or lower may substitute for cataplexy in the diagnosis of Type 1 narcolepsy.3

Differential Diagnosis

Idiopathic hypersomnia: A condition that is also characterized by significant daytime sleepiness. The main diagnostic measurement differentiating it from narcolepsy is up to 2 sleep-onset REM sleep periods shown on the MSLT. Unlike patients with narcolepsy, patients with idiopathic hypersomnia usually do not experience fragmented sleep, nocturnal arousals occur less frequently, and daytime naps do not help to restore alertness.3

Kleine-Levin syndrome: A hypersomnia disorder that is less common than narcolepsy. It is characterized by intermittent bouts of sleepiness lasting days to weeks. It is accompanied by cognitive changes and behavioral symptoms such as hyperphagia and hypersexuality.3

Assessment Tools for Diagnosis3,7

Several tools can be used to evaluate and diagnose narcolepsy:

•        Epworth Sleepiness Scale: Administered in the office, this self-rating tool scores the patient’s perception (from 0 to 3) of the chances of falling asleep in 8 different situations. A rating of 0 indicates the patient would never doze and 3 indicates a high change of dozing. Scores below 10 are normal, whereas scores of 10 and above indicate EDS.
•        Pediatric Daytime Sleepiness Scale: Similar to Epworth Sleepiness Scale, this instrument is tailored for the evaluation of children.
•        Actigraphy: A monitoring bracelet that the patient wears for a period of 1 to 2 weeks to measure sleep/wake patterns, sleep duration, bedtimes, and wake times. The patient is asked to complete a sleep log for the duration of the monitoring period to measure subjective observations of these parameters. In order for clinicians to obtain accurate results from actigraphy, all medications with alerting or sedating properties (including antidepressants) should be tapered off 2 to 4 weeks prior to testing.
•        Polysomnography: An overnight test conducted at a monitored sleep study lab. It employs electroencephalogram and electromyography testing to monitor sleep parameters and body movements throughout a single night of sleep. This full-measure test is used to rule out causes of EDS other than narcolepsy.
•        MSLT: Administered subsequent to polysomnography, the MSLT measures sleep and REM latency during 4 to 5 nap opportunities (each 2 hours apart) over the course of a full day. The MSLT is administered 2 hours after waking from an overnight polysomnogram. An average sleep latency of less than 8 minutes is diagnostic for narcolepsy.
•        Maintenance of Wakefulness Test: A test given over 4 periods and lasts 40 minutes each. During the test, the patient is asked to sit without being exposed to any stimulating activity. This test may be used with medication to measure the effects of selected treatments on wakefulness. Notably, the Maintenance of Wakefulness Test is used by the Federal Aviation Administration and other organizations to ensure that its employees are able to remain awake when necessary.
• A cerebrospinal fluid hypocretin-1 level at or below 110 pg/mL is occasionally used instead of the MSLT to diagnose Type 1 narcolepsy.

Current Approved Therapies

Only a few therapies are currently approved by the US Food and Drug Administration (FDA) for the treatment of narcolepsy. Multiple classes of drugs may be used to target either EDS or cataplexy (see Table).

•     Modafinil and armodafinil are first-line choices for the treatment of EDS.1,3 These wakefulness-promoting agents carry a low potential for abuse and are associated with relatively mild adverse effects.3
•       Methylphenidate and amphetamines are often prescribed to manage daytime sleepiness, but they are associated with cardiovascular effects and, rarely, abuse.3
•       Sodium oxybate and antidepressants such as venlafaxine and fluoxetine are commonly prescribed for cataplexy.3
•       Pitolisant was recently approved by the FDA for the treatment of narcolepsy. Meta-analyses showed that pitolisant was superior to modafinil for the treatment of cataplexy in patients who had a high burden of narcolepsy symptoms and was noninferior for the treatment of EDS in Type 1 narcolepsy. 5,8 Both drugs were equally effective treatments for Type 2 narcolepsy.8
•       Solriamfetol, another agent newly approved by the FDA, has shown efficacy for EDS and has acceptable tolerability. Indirect comparisons indicate that improvements in wakefulness seen with solriamfetol may be greater than those achieved with modafinil or armodafinil.1

Nonpharmacologic Treatments

In addition to medications, nonpharmacologic approaches such as counseling and psychosocial guidance are recommended. Scheduled naps lasting 15 to 20 minutes have been shown to improve daytime alertness, and good sleep hygiene improves the quality of nighttime sleep.3 Patients should also be counseled on the effects of caffeine, alcohol, and other substances on sleep and wakefulness. 


1. Thorpy MJ. Recently approved and upcoming treatments for narcolepsy. CNS Drugs. 2020;34(1):9-27. doi:10.1007/s40263-019-00689-1
2. Acquavella J, Mehra R, Bron M, Suomi JM-H, Hess GP. Prevalence of narcolepsy and other sleep disorders and frequency of diagnostic tests from 2013-2016 in insured patients actively seeking care. J Clin Sleep Med. 2020;16(8):1255-1263. doi:10.5664/jcsm.8482
3. Golden EC, Lipford MC. Narcolepsy: diagnosis and management. Cleve Clin J Med. 2018;85(12):959-969. doi:10.3949/ccjm.85a.17086
4. Thorpy MJ, Krieger AC. Delayed diagnosis of narcolepsy: characterization and impact. Sleep Med. 2014;15(5):502-507. doi:10.1016/j.sleep.2014.01.015
5. Monderer R, Ahmed IM, Thorpy M. Evaluation of the sleepy patient: differential diagnosis. Sleep Med Clin. 2020;15(2):155-166. doi:10.1016/j.jsmc.2020.02.004
6. Fabara SP, Ortiz JF, Anas Sohail A, et al. Efficacy of pitolisant on the treatment of narcolepsy: a systematic review. Cureus. 2021;13(7):e16095. doi: 10.7759/cureus.16095
7. Szabo ST, Thorpy MJ, Mayer G, Peever JH, Kilduff TS. Neurobiological and immunogenetic aspects of narcolepsy: implications for pharmacotherapy. Sleep Med Rev. 2019;43:23-36. doi:10.1016/j.smrv.2018.09.006
8. Lehert P, Szoeke C. Comparison of modafinil and pitolisant in narcolepsy: a non-inferiority meta-analytical approach. Drugs Context. 2020;9:2020-6-2. doi:10.7573/dic.2020-6-2
9. Mignot EJ. A practical guide to the therapy of narcolepsy and hypersomnia syndromes. Neurotherapeutics. 2012;9(4):739-52. doi: 10.1007/s13311-012-0150-9

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Neurology Advisor had no role in this content’s preparation.

Reviewed March 2022

Relapsing-Remitting Multiple Sclerosis Treatment: B Cell-Depletion Therapy Shows Promise

Emerging evidence suggests that B lymphocyte (B cell)-depletion therapy represents a breakthrough in slowing the progression of disability in relapsing–remitting multiple sclerosis (RRMS).1 The overall goal in multiple sclerosis (MS) treatment is to modify disease progression and disability and to prevent new lesions on magnetic resonance imaging (MRI).2 The primary pathogenesis of MS comprises focal inflammatory demyelination and degeneration; disease-modifying therapies (DMT) address the inflammatory component.3 In the United States, approximately 1 million people have MS, and many of these people reside in the northern region of the country, a pattern that is seen in the rest of the world.4,5

Neuroimmunology of B Cells in MS

Previously, T lymphocytes (T cells) were thought to be the primary driver of disease in MS.6 Recent clinical trials of the anti-CD20 monoclonal antibody ocrelizumab for RRMS, and subsequent US Food and Drug Administration approval of the drug, have led researchers to investigate more possibilities for disease modification with other CD20 monoclonal antibodies.6 Recognition that B cells produce antibodies against immunoglobulin G (IgG) oligoclonal bands found in the cerebrospinal fluid of most patients with MS further supports targeting B cells in RRMS.1

B-cell Depletion Therapies in Later-Phase Trials

Ocrelizumab, a humanized monoclonal antibody, was compared with interferon β-1a (IFN beta-1a) in the double phase 3 trials OPERA I (N=821) and OPERA II (N=835) in patients with RRMS (ClinicalTrials.gov Identifiers: NCT01247324 and NCT01412333, respectively).7 In these 96-week identical trials, the primary end point was the annualized relapse rate (ARR)7:

• 0.16 for ocrelizumab and 0.29 for IFNB-1a in OPERA I; a 46% lower ARR for ocrelizumab (P <.001)
• 0.16 for ocrelizumab and 0.29 for IFNB-1a in OPERA II; a 47% lower ARR for ocrelizumab in OPERA II (P <.001).  

Compared with IFNB-1a, ocrelizumab was associated with better outcomes as measured by ARR, suppression of new inflammatory lesions, progression of disability, and new formation of enlarged plaque.8
Neoplasms occurred in 0.5% of patients who received ocrelizumab compared with 0.2% of those who received IFNB-1a. Serious infection was more common in patients who received IFNB-1a (2.9%) than in those who received ocrelizumab (1.3%).7
Ofatumumab,a human antibody initially indicated for chronic lymphocytic leukemia, has shown promise in double phase 3 trials in patients with RRMS. The ASCLEPIOS I (N=927) and ASCLEPIOS II (N=955) trials9 (ClinicalTrials.gov Identifiers: NCT02792218 and NCT02792231, respectively) compared ofatumumab with teriflunomide, an oral inhibitor of pyrimidine synthesis that reduces T- and B-cell activation in patients with RRMS or secondary progressive MS.
The primary end point in these trials was the ARR, which was lower with ofatumumab (0.11) than with teriflunomide (0.22; P <.001) in ASCLEPIOS I and, comparably, 0.10 and 0.25 (P <.001), respectively, in ASCLEPIOS II.7
For 3 secondary end points — deteriorating disability at 3 months and at 6 months and disability improvement at 6 months — ofatumumab compared favorably with teriflunomide (10.9% and 15.0% [P =.002], 8.1% and 12.0% [P =.01], and 11.0% and 8.1% [P =.09], respectively).9
The adverse event profile in the ASCLEPIOS trials included occurrences at least 100 days after final administration of the trial drug.9 Events that occurred in at least 10% of patients receiving ofatumumab included injection reactions, nasopharyngitis, headache, upper respiratory tract infection, and urinary tract infection. Events that occurred in at least 10% of patients receiving teriflunomide included nasopharyngitis, injection reactions, alopecia, and upper respiratory tract infection.9
Rituximab,an IgG1 subclass of IgG chimeric-human monoclonal antibody against CD20, was initially approved for treating non-Hodgkin lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis.1 Rituximab was among the first B cell-depleting therapies used off-label to treat RRMS, for which the drug’s anti-CD20 depletion ability was revealed to have a lasting effect on T cells.10
Researchers foresee not only a DMT in B-cell depletion but also a way to reduce the number of reinfusions that reduce disease activity.11 Such was the case in an uncontrolled, open-label study of 102 patients treated with rituximab for a mean of 2.4 years.11 In the dual-site study by Novi and colleagues, patients were reinfused with rituximab 375 mg/m2 based on a prespecified percentage of memory B cells and not on an every-6-month schedule, as had been the standard approach.11 A year before the start of rituximab therapy, the ARR was 0.67; 3 years after initiating rituximab therapy, the ARR decreased to 0.01.11
Because the Novi study did not have a comparator, adverse events could not be compared. However, the researchers conjectured that, after initial induction therapy, reinfusing patients based on the peripheral blood mononuclear cell level, rather than on a 6-month schedule, might reduce the number of treatment-related adverse events and thus provide a template for personalized medicine.11
Although no phase 3 trials of rituximab for RRMS have been published, the RIDOSE-MS study (ClinicalTrials.gov Identifier: NCT03979456), based on a Swedish registry of patients with RRMS, is underway.12,13 This prospective, randomized study will compare 2 regimens of rituximab: 500 mg dosed at 6- and at 12-month intervals. The primary end point is no evidence of disease activity. Results of the 3-year RIDOSE-MS study should be available in 2025.12
Ublituximab, which also demonstrated promise in a phase 2 trial as a B cell-depleting therapy for RRMS, is undergoing phase 3 trials (ULTIMATE 1 and ULTIMATE 2 [ClinicalTrials.gov Identifiers: NCT03277261 and NCT03277248, respectively]).14-16

B Cell-Depletion Therapies in Later-Phase Trials

Therapeutic Approaches for Targeting B Cells

No one treatment algorithm governs B cell-depletion therapy for RRMS due to its heterogeneity and the difficulty in pinpointing the underlying process of disease progression.3 Because MS therapies have varying levels of toxicity, neurologists attempt to minimize long-term safety risks by initiating treatment with the safest but least effective agents.3 The problem with this approach is that the therapeutic window for some patients might close before they receive the most effective therapy.3

Management Challenges and Risk Assessment

While B cell-depletion therapy might be a breakthrough treatment for some patients with RRMS, it does come with caveats. Because B cell-depletion therapy can cause infection, as reported in 57% to 60% of patients with RRMS treated with ocrelizumab compared with 53% to 54% of patients who received IFNB-1a, patients need to be screened carefully before starting therapy.20 They should be tested for tuberculosis,  hepatitis B and C virus infection, and HIV infection.20 During treatment with B cell-depletion therapy, patients need to avoid live vaccines.20
Progressive multifocal leukoencephalopathy (PML) has been reported in patients treated with ocrelizumab. However, most of these patients had been treated previously with fingolimod or natalizumab. In trials with rituximab and ocrelizumab monotherapy, no patients were reported to have developed PML.20
In the phase 3 trials OPERA (I and II) and ORATORIO (ClinicalTrials.gov Identifier: NCT01194570), malignancies occurred in, respectively, 0.5% and 2.3% of patients who received ocrelizumab compared with 0.2% and 0.8% of patients taking interferon and placebo.20 Rituximab, for which there is longer-term data than for ocrelizumab, does not appear to increase the risk of cancer in patients with MS.18

Ocrelizumab adverse effects
Ocrelizumab adverse effects
Adverse effects most commonly reported include upper respiratory tract infection and infusion reactions.

Rituximab adverse effects
Rituximab adverse effects
Adverse effects most commonly reported include urinary tract infection, sinusitis, and infusion reactions.

B Cell-Depletion Therapy in Specific Populations

To determine the benefit of B cell-depletion therapy among subgroups of patients with RRMS (defined by age, sex, body mass index, and disability status measured by the Expanded Disability Status Scale score), Turner and colleagues analyzed data from the OPERA I and OPERA II phase 3 trials that compared ocrelizumab and IFNB-1a.8 They found that the treatment effect of ocrelizumab was consistent in most subgroups for all end points, including ARR, progression of disability, and MRI findings.8
The evidence base is small regarding the safety of B cell-depletion therapy during pregnancy,1 which represents a challenge when treating women during reproductive years, who constitute much of the MS population.1 Although the literature is scant, peripheral lymphocytopenia has been reported in infants born to mothers who received B cell-depletion therapy.1 Primate studies have reported renal toxicity, testicular toxicity, lymphoid follicle formation in the bone marrow, and perinatal death in offspring with severe B-cell reduction.1
One possible strategy is to provide B cell-depleting therapy before pregnancy, which would still offer protection to the mother but not risk harm to a fetus.1 Women of childbearing potential are advised to use contraception during B cell-depletion treatment and for as long as 6 months after the last infusion.1
Lactation studies among B cell-depleting therapies are lacking; more definitive evidence is needed to guide treatment for nursing mothers.16 In one of the few studies of B cell-depleting therapies, a rituximab case study revealed the level of rituximab in breast milk to be 240 times lower than in maternal serum, signaling that B-cell therapies might have potential to be used safely in lactating patients.21
Refer to the full Prescribing Information for additional details about Ocrevus®, Kesimpta®, and Rituxan®.


1. Gelfand JM, Cree BAC, Hauser SL. Ocrelizumab and other CD20+ B-cell-depleting therapies in multiple sclerosis. Neurotherapeutics. 2017;14(4):835-841. doi:10.1007/s13311-017-0557-4
2. Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline recommendations summary: disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology [published correction appears in Neurology. 2019;92(2):112. doi: 10.1212/WNL.0000000000006722]. Neurology. 2018;90(17):777-788. doi:10.1212/WNL.0000000000005347
3. Smith AL, Cohen JA, Hua LH. Therapeutic targets for multiple sclerosis: current treatment goals and future directionsNeurotherapeutics. 2017;14(4):952-960. doi:10.1007/s13311-017-0548-5
4. Patz A. Strength in numbers. Momentum. National Multiple Sclerosis Society.
https://momentummagazineonline.com/strength-in-numbers/. Accessed November 12, 2020.
5. The Multiple Sclerosis International Federation, Atlas of MS. 3rd ed. https://www.msif.org/wp-content/uploads/2020/10/Atlas-3rd-Edition-Epidemiology-report-EN-updated-30-9-20.pdf Accessed November 12, 2020.
6. Greenfield AL, Hauser SL. B‐cell therapy for multiple sclerosis: entering an eraAnn Neurol. 2018;83(1):13-26. doi:10.1002/ana.25119
7. Hauser SL, Bar-Or A, Comi G, et al; OPERA I and OPERA II Clinical Investigators. . Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017;376(3):221-234. doi:10.1056/NEJMoa1601277
8. Turner B, Cree BAC, Kappos L, et al. Ocrelizumab efficacy in subgroups of patients with relapsing multiple sclerosisJ Neurol. 2019;266(5):1182-1193. doi:10.1007/s00415-019-09248-6
9. Hauser SL, Bar-Or A, Cohen JA, et al; ASCLEPIOS I and ASCLEPIOS II Trial Groups. Ofatumumab versus teriflunomide in multiple sclerosisN Engl J Med. 2020;383(6):546-557. doi:10.1056/NEJMoa1917246
10. Nissimov N, Hajiyeva Z, Torke S, et al. B cells reappear less mature and more activated after their anti-CD20-mediated depletion in multiple sclerosis. Proc Natl Acad Sci U S A. 2020;117(41):25690-25699. doi:10.1073/pnas.2012249117
11. Novi G, Bovis F, Fabbri S, et al. Tailoring B cell depletion therapy in MS according to memory B cell monitoring. Neurol Neuroimmunol Neuroinflamm. 2020;7(5):e845. doi:10.1212/NXI.0000000000000845
12. ClinicalTrials.gov. RItuximab long-term DOSE trial in multiple sclerosis – RIDOSE-MS (RIDOSE-MS) [ClinicalTrials.gov Identifier: NCT03979456]. https://clinicaltrials.gov/ct2/show/study/NCT03979456. Accessed November 17, 2020.
13. Wood H. Targeting B cells leads to breakthrough therapy. Nature Research website. https://www.nature.com/articles/d42859-018-00030-8. December 10, 2018. Accessed November 17, 2020.
14. Fox E, Lovett-Racke AE, Gormley M, et al. A phase 2 multicenter study of ublituximab, a novel glycoengineered anti-CD20 monoclonal antibody, in patients with relapsing forms of multiple sclerosisMult Scler. Published online April 30, 2020. doi:10.1177/1352458520918375
15. ClinicalTrials.gov. A phase 3, randomized, multi-center, double-blinded, active-controlled study to assess the efficacy and safety/tolerability of ublituximab (TG-1101; UTX) as compared to teriflunomide in subjects with relapsing multiple sclerosis (RMS) (ULTIMATE 1). https://clinicaltrials.gov/ct2/show/NCT03277261. Accessed November 12, 2020.
16. ClinicalTrials.gov. A phase 3, randomized, multi-center, double-blinded, active-controlled study to assess the efficacy and safety/tolerability of ublituximab (TG-1101; UTX) as compares to teriflunomide in subjects with relapsing multiple sclerosis (RMS) (ULTIMATE 2). https://clinicaltrials.gov/ct2/show/NCT03277248. Accessed November 12, 2020.
17. Ocrevus. Prescribing Information. Genentech, Inc; November 2020. Accessed November 16, 2020. https://www.gene.com/download/pdf/ocrevus_prescribing.pdf
18. Kesimpta. Prescribing Information. Novartis AG; August 2020. Accessed November 16, 2020. https://www.novartis.us/sites/www.novartis.us/files/kesimpta.pdf
19. Rituxan. Prescribing Information. Genentech, Inc; August 2020. Accessed November 16, 2020. https://www.gene.com/download/pdf/rituxan_prescribing.pdf
20. Milo R. Therapies for multiple sclerosis targeting B cellsCroat Med J. 2019;60(2):87-98. doi:10.3325/cmj.2019.60.87
21. Myhr KM, Torkildsen Ø, Lossius A, Bø L, Holmøy T. B cell depletion in the treatment of multiple sclerosisExpert Opin Biol Ther. 2019;19(3):261-271. doi:10.1080/14712598.2019.1568407

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Reviewed February 2021

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