In a recent press release, RNA-targeted therapeutics company Ionis Pharmaceuticals, Inc. (“Ionis”) shared the initiation of a Phase 2/3 clinical trial evaluating ION373 for patients with Alexander disease (AxD). Currently, treatments are centered around symptom reduction. If ION373 is successful, it could start the move towards disease-modifying therapies for patients with AxD, filling an unmet need in this patient population.

Alexander Disease (AxD)

GFAP gene mutations cause Alexander disease, a form of leukodystrophy, in about 90% of all diagnoses. In the other 10% of cases, the cause of Alexander disease is unknown. Leukodystrophies are progressive central nervous system (CNS) disorders affecting the myelin sheath, or the protective coating of nerves. In this case, Alexander disease causes both myelin sheath damage and an accumulation of Rosenthal fibers.

Altogether, there are four forms of Alexander disease:

• Neonatal
  • Overall, this is the most severe form of Alexander disease. Unfortunately, for most patients with neonatal Alexander disease, the condition will be fatal within 2 years. Symptoms include:
    • Seizures
    • Hydrocephalus (excess fluid in the brain)
    • Severe motor and intellectual disabilities
    • Failure to thrive
    • Vomiting
    • Difficulty swallowing, speaking, or breathing
• Infantile (symptom onset occurs within ~2 years of birth)
  • This is the most common form of Alexander disease. Typically, symptoms appear within 2 years of birth. These include:
    • Seizures
    • Limb and joint stiffness
    • Intellectual and developmental delays
    • Enlarged head and brain
• Juvenile (symptom onset occurs between ages 2-13)
  • In this form, symptoms include:
    • Difficulty swallowing
    • Speech issues
    • Excessive vomiting
    • Poor coordination
    • Loss of motor control
• Adult (symptom onset occurs in late teens or beyond)
  • While adult Alexander disease shares some symptoms with the juvenile form, many patients with adult-onset Alexander disease experience symptoms similar to those found in multiple sclerosis (MS) or Parkinson’s disease (PD).

ION373

On the company’s website, Ionis describes ION373 as:

an investigational antisense medicine targeting glial fibrillary acidic protein (GFAP) messenger ribonucleic acid (mRNA). Nearly all cases of [Alexander disease] are caused by gain-of-function mutations in GFAP that lead to spontaneous overproduction and toxic accumulation of GFAP into abnormal protein deposits called Rosenthal fibers in the brain [so] ION373 is designed to inhibit the production of GFAP and is being developed as a potential therapy for Alexander disease.

During the trial, patients will receive either ION373 or a placebo for 60 weeks (approximately 13.8 months). This study will evaluate multiple-ascending doses of ION373. Altogether, 58 patients with Alexander disease will enroll. In the follow-up period, all 58 patients will receive ION373 for an additional 60 weeks.

Thus far, ION373 has been granted Orphan Drug designation in both the United States and Europe, as well as Rare Pediatric Disease designation within the United States.

To get involved with AxD advocacy, check out the website for the patient advocacy organization End AxD here.