ALS, SMA & Motor Neuron Disease Pharm

Amyotrophic lateral sclerosis (ALS) and other motor neuron diseases have entered a new therapeutic era. Riluzole has been available since 1995 with modest survival benefit; edaravone followed in 2017; sodium phenylbutyrate-taurursodiol (AMX0035) was approved in 2022 and subsequently withdrawn; tofersen was approved in 2023 for SOD1-ALS — the first gene-targeted therapy. Beyond ALS, spinal muscular atrophy treatment has been revolutionized by nusinersen, onasemnogene abeparvovec, and risdiplam. This page covers motor neuron disease pharmacotherapy and symptomatic management.

Amyotrophic Lateral Sclerosis

Disease-Modifying Therapies

Riluzole

  • Mechanism: glutamate antagonism; modulation of Na⁺ channels.
  • 50 mg PO BID.
  • Modest survival benefit (2-3 months in randomized trials; possibly more in real-world).
  • FDA-approved 1995; still standard of care.
  • Side effects: nausea, fatigue, weakness, hepatic enzyme elevation.
  • Monitor LFTs.
  • Oral suspension also available.

Edaravone (Radicava)

  • Mechanism: free radical scavenger; reduces oxidative stress.
  • IV: cyclic dosing — 14 days on, 14 days off (initial); then 10 of 14 days/cycle.
  • Oral suspension (Radicava ORS) FDA-approved 2022.
  • Approved benefit in selected patients (early disease, preserved function).
  • Side effects: bruising, gait disturbance, contact dermatitis.

Tofersen (Qalsody)

  • Antisense oligonucleotide; reduces SOD1 mRNA expression.
  • Intrathecal administration via lumbar puncture.
  • FDA-approved 2023 for SOD1-ALS (accelerated approval based on neurofilament).
  • Only ~2% of ALS patients have SOD1 mutations.
  • Side effects: spinal pain, fatigue, increased intracranial pressure, post-LP headache.
  • Cost very high.
  • Represents proof of concept for gene-targeted therapy.

Sodium Phenylbutyrate-Taurursodiol (AMX0035/Relyvrio)

  • Approved 2022, withdrawn 2024 after confirmatory trial failed to confirm benefit.
  • Historical significance.

Symptomatic Management of ALS

Bulbar Symptoms

  • Sialorrhea: glycopyrrolate (peripheral antimuscarinic), botulinum toxin to salivary glands (FDA-approved), scopolamine patch, sublingual atropine.
  • Dysphagia: dietary modification; gastrostomy tube (PEG) when needed.
  • Pseudobulbar affect: dextromethorphan/quinidine (Nuedexta) FDA-approved.
  • Speech: SLP support; augmentative communication.

Respiratory

  • BiPAP for nocturnal hypoventilation.
  • Diaphragmatic pacing: emerging.
  • Cough assist devices.
  • Tracheostomy and invasive ventilation: individualized decision.

Spasticity

  • Baclofen, tizanidine.
  • Botulinum toxin for focal.
  • Intrathecal baclofen in selected cases.

Cramps and Fasciculations

  • Mexiletine: emerging evidence for ALS cramps.
  • Quinine: traditional but black box for cardiac toxicity; rarely used.
  • Magnesium, gabapentin: try empirically.

Pain

  • NSAIDs, acetaminophen first-line.
  • Gabapentinoids for neuropathic.
  • Opioids for severe pain (late disease).

Mood and Cognition

  • Depression: SSRIs, mirtazapine.
  • Anxiety: SSRIs.
  • FTD spectrum: behavioral; SSRIs for behavioral symptoms.

Constipation

  • Polyethylene glycol, lubiprostone.
  • Address contributing factors (medications, immobility).

Insomnia

  • Trazodone, mirtazapine.
  • Address respiratory distress (BiPAP).
  • Address mood.

End-of-Life Care

  • Hospice referral.
  • Morphine for dyspnea.
  • Lorazepam for terminal anxiety.
  • Discussion of artificial ventilation, feeding.

Spinal Muscular Atrophy (SMA)

Pathophysiology

  • Mutations in SMN1 gene; reduced survival motor neuron (SMN) protein.
  • SMN2 gene provides backup; copy number determines disease severity.
  • Without treatment: SMA1 (severe infantile) → death/severe disability by 2 years; SMA2 → never walk; SMA3 → adult onset with milder course; SMA4 (adult).

Disease-Modifying Therapies

Nusinersen (Spinraza)

  • Antisense oligonucleotide.
  • Modifies SMN2 splicing to produce more functional SMN protein.
  • Intrathecal administration (loading then every 4 months).
  • FDA-approved 2016 for all SMA types.
  • Most successful in early treatment, especially pre-symptomatic.

Onasemnogene Abeparvovec (Zolgensma)

  • AAV9-based gene therapy delivering functional SMN1.
  • One-time IV infusion.
  • FDA-approved 2019 for SMA <2 years.
  • Most effective in pre-symptomatic infants (newborn screening identification).
  • Severe side effects: hepatotoxicity, thrombocytopenia (premedicate with steroid).
  • Very high cost (~$2.1 million per dose).

Risdiplam (Evrysdi)

  • Small-molecule SMN2 splicing modifier.
  • Daily oral; ALL ages.
  • FDA-approved 2020.
  • Convenience advantage over nusinersen and Zolgensma.
  • Side effects: GI, rash.

Newborn Screening

  • Now in most states.
  • Pre-symptomatic treatment dramatically improves outcomes.

Symptomatic Management

  • Respiratory support.
  • Nutrition.
  • Orthopedic management of scoliosis, contractures.
  • PT/OT.

Primary Lateral Sclerosis (PLS)

  • Pure upper motor neuron disease.
  • Symptomatic: spasticity (baclofen), pain, mood.
  • No disease-modifying therapy.
  • Slower course than ALS.

Progressive Muscular Atrophy (PMA)

  • Pure lower motor neuron disease.
  • Considered ALS variant.
  • Similar management.

Kennedy Disease (Spinal-Bulbar Muscular Atrophy)

  • X-linked; androgen receptor mutation.
  • Slower course than ALS.
  • No disease-modifying therapy.

Hereditary Spastic Paraplegia (HSP)

  • Multiple genetic forms.
  • Symptomatic management: baclofen, tizanidine, botulinum toxin.
  • PT mainstay.

Post-Polio Syndrome

  • Late sequelae of polio.
  • Pyridostigmine: limited benefit in some.
  • Energy conservation; assistive devices.
  • Treat associated pain, sleep apnea.

Sodium Phenylbutyrate-Taurursodiol Story

  • FDA approved 2022 based on CENTAUR trial.
  • PHOENIX confirmatory trial in 2023: no benefit demonstrated.
  • Manufacturer voluntarily withdrew in 2024.
  • Lesson about accelerated approval vs confirmatory trial.

Emerging ALS Therapies

  • Other ASOs in development for specific ALS subtypes (FUS, C9ORF72).
  • Gene therapy approaches in development.
  • Inflammation-modulating approaches.
  • Stem cell-based therapies (largely investigational).
  • Edaravone next-generation formulations.

ALS Multidisciplinary Care

  • Multidisciplinary clinics (neurology, pulmonology, GI, nutrition, PT/OT/SLP, social work, palliative care): improve survival.
  • Communication aids, mobility aids, environmental modifications.
  • Caregiver support.
  • Advance care planning.

🔍 Did You Know?

The FDA approval of tofersen (Qalsody) for SOD1-ALS in 2023 represents one of the most consequential advances in neurodegenerative disease therapy — and provides a template for gene-targeted therapy in other neurologic conditions. SOD1 mutations cause approximately 2% of ALS, often with autosomal dominant inheritance. Tofersen is an antisense oligonucleotide (ASO) that binds SOD1 mRNA and triggers its degradation, reducing toxic SOD1 protein production. The approval was based on reduction in neurofilament levels — a biomarker of neuronal injury — under FDA’s accelerated approval pathway, with confirmatory trial requirement. The clinical implication is profound: genetic testing for SOD1 should be performed in any ALS patient with family history, opening a treatment door for those with the mutation. Beyond SOD1, the same approach is being applied to C9ORF72 (the most common ALS gene mutation), FUS, and others. The lesson generalizes: identifying genetic causes of “idiopathic” diseases opens targeted therapeutic approaches, and gene-targeted ASOs (a.k.a. RNA-based medicines) are emerging as a major class of CNS-active therapeutics. SMA — the prior major ASO success story (nusinersen) — exemplifies this principle. For practicing neurologists, the take-home: genetic testing in ALS, SMA, Huntington, and other neurodegenerative conditions is no longer just for prognosis but increasingly for therapeutic eligibility. The era of “one-size-fits-all” neurodegenerative therapy is ending; targeted, personalized approaches are emerging.

Pitfalls and Pearls

  • Riluzole: glutamate modulator; modest survival benefit; standard of care.
  • Edaravone: free radical scavenger; cyclic dosing.
  • Tofersen: SOD1-ALS specific; intrathecal ASO; FDA 2023.
  • AMX0035 (Relyvrio): withdrawn 2024 after failed confirmatory trial.
  • Sialorrhea: glycopyrrolate, botulinum toxin to salivary glands.
  • Pseudobulbar affect: dextromethorphan/quinidine (Nuedexta).
  • Cramps: mexiletine emerging evidence.
  • BiPAP: for nocturnal hypoventilation; survival benefit.
  • Multidisciplinary clinics: improve ALS survival.
  • SMA: nusinersen, onasemnogene abeparvovec, risdiplam.
  • Newborn screening for SMA: pre-symptomatic treatment dramatically improves outcomes.
  • Onasemnogene abeparvovec: one-time IV gene therapy; <2 years; hepatotoxicity.
  • Risdiplam: oral; all ages; convenience.
  • Genetic testing: increasingly important for therapeutic eligibility.
  • Quinine: cardiac toxicity warning; rarely used.
  • End-of-life: hospice; morphine for dyspnea; lorazepam for anxiety.

References

  1. Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev. 2012;(3):CD001447.
  2. Writing Group; Edaravone (MCI-186) ALS 19 Study Group. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis (MCI-186-19). Lancet Neurol. 2017;16(7):505-512.
  3. Miller TM, Cudkowicz ME, Genge A, et al. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2022;387(12):1099-1110.
  4. Mendell JR, Al-Zaidy S, Shell R, et al. Single-dose gene-replacement therapy for spinal muscular atrophy (STR1VE). N Engl J Med. 2017;377(18):1713-1722.
  5. Finkel RS, Mercuri E, Darras BT, et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy (ENDEAR). N Engl J Med. 2017;377(18):1723-1732.
  6. Brown RH, Al-Chalabi A. Amyotrophic lateral sclerosis. N Engl J Med. 2017;377(2):162-172.