What are the newer drugs for treating amyotrophic lateral sclerosis (ALS)?

Newer Drugs for Treating Amyotrophic Lateral Sclerosis (ALS)

Edaravone is the most recent FDA-approved medication for ALS treatment, which has been shown to slow the progression of functional decline in patients with ALS. 1

Currently Approved Medications for ALS

• Riluzole was the first drug approved by the FDA for ALS in 1995, and remained the only approved treatment for 22 years until edaravone's approval 2
• Edaravone (Radicava) was approved by the FDA in 2017 for the treatment of ALS, representing the newest addition to the ALS treatment arsenal 1, 2

Edaravone: Mechanism and Efficacy

• Edaravone functions as a potent free radical scavenger and antioxidant that prevents oxidative stress from inducing motor neuron death in ALS patients 2
• In clinical trials, edaravone demonstrated the ability to slow the loss of physical function in ALS patients by 33% compared to placebo 2
• The drug has been shown to significantly reduce the decline in ALSFRS-R scores (ALS Functional Rating Scale-Revised) compared to placebo, with a treatment difference of 2.49 points (p=0.0013) 1

Administration of Edaravone

• Edaravone is administered as an intravenous infusion over 60 minutes at a dose of 60 mg 1
• The treatment follows a specific cycle pattern:
  • Initial treatment cycle: daily dosing for 14 days followed by a 14-day drug-free period 1
  • Subsequent treatment cycles: daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods 1
• A new oral suspension formulation of edaravone has been developed and studied, which may reduce the burden of intravenous administration for patients with ALS 3

Special Considerations for ALS Patients

• For patients with bulbar dysfunction, proper administration techniques should be considered as they may experience difficulty swallowing medication 4
• Regular monitoring for dysphagia progression is essential, as nearly all ALS patients eventually develop bulbar involvement 4
• Nutritional status should be closely monitored in ALS patients with bulbar dysfunction, as weight loss is detrimental to survival 4

Clinical Evidence and Limitations

• The FDA approval of edaravone was based on clinical evidence from three clinical trials conducted in 368 ALS patients in Japan 2
• A phase II study showed that edaravone significantly reduced the decline in ALSFRS-R scores compared to the pre-treatment period (2.3±3.6 points vs 4.7±2.1 points, p=0.039) 5
• However, a more recent cohort study using propensity score matching found that long-term intravenous edaravone therapy, while mainly well tolerated, was not associated with any disease-modifying benefit compared to standard therapy alone 6

Adverse Effects

• The most common adverse reactions (occurring in at least 10% of patients treated with edaravone and greater than placebo) are contusion, gait disturbance, and headache 1
• Potential serious adverse effects include:
  • Hypersensitivity reactions requiring immediate medical care 1
  • Sulfite allergic reactions, as edaravone contains sodium bisulfite, which may cause allergic-type reactions including anaphylactic symptoms and asthmatic episodes in susceptible individuals 1

Future Directions in ALS Treatment

• Despite the approval of riluzole and edaravone, there remains a significant unmet need for more effective treatments for ALS 7
• Ongoing research is exploring various therapeutic approaches including protein kinase inhibitors, epigenetic modulators, new cytotoxic agents, mitochondrial inhibitors, targeted therapies, therapeutic antibodies, and cellular immunotherapies 8