FDA Grants Orphan Drug Designation to Exidavnemab for Multiple System Atrophy

Exidavnemab (BioArctic) was granted orphan drug designation (ODD) by the FDA for treatment of multiple system atrophy (MSA), a rare, rapidly progressing, and fatal disease. The decision provides hope for patients in the form of a novel agent with disease-modifying potential in MSA, a disease with no cure and no available treatments for slowing progression.

Close-up of elder man's hands with Parkinson disease, multiple system atrophy | mage Credit: © ipopba - stock.adobe.com

MSA is a rare condition of the central and autonomic nervous systems that affects balance and movement, as well as basic bodily functions including breathing, digestion, and bladder or bowel control. It can share symptoms with Parkinson disease (PD), which is referred to as the Parkinsonian type—the most common type of MSA. Patients with Parkinsonian-type MSA may present with symptoms such as stiff muscles, trouble bending the arms and legs, tremors, slurred or slow speech, and trouble with posture and balance. The other type of MSA is cerebellar type, which primarily involves poor muscle coordination, vision changes, and dysphagia.^1,2

There is no cure for MSA, and treatment is restricted to symptom management. This can include the use of blood pressure medications or medicines used to treat PD-like symptoms. In more serious cases, patients may need to have catheters inserted for bladder drainage, or a gastrostomy tube delivers food directly into the stomach for those with swallowing difficulties.²

MSA is caused by the misfolding and accumulation of α-synuclein in oligodendrocytes that form glial cytoplasmic inclusions, impairing oligodendrocyte function, disrupting myelin integrity, and triggering neuroinflammation. This leads to the progressive motor, autonomic, and cognitive symptoms that are characteristic of MSA.^1,3

Exidavnemab is a novel, investigational, monoclonal antibody that selectively targets soluble alpha-synuclein (α-synuclein) aggregates, which play a key role in MSA pathology. It promotes clearance of aggregated α-synuclein to preserve neuronal function and reduce the progression of the disease. Exidavnemab is being investigated in the phase 2a, randomized, double-blind, placebo-controlled, multicenter, multinational, multiple ascending doses EXIST trial (NCT06671938). The investigators aim to determine the safety, tolerability, and pharmacokinetics of exidavnemab in patients with mild to moderate PD on stable symptomatic PD medication.^1,4

The patients are randomized 2:1 to receive either exidavnemab—administered intravenously—or placebo, of which 12 will be evaluable of the total population (n = 24). The primary end point is the number of participants with adverse events (AEs), serious AEs, and withdrawals due to AEs from the first dose to day 176. Secondary end points include PK parameters following a single dose, as calculated by the linear trapezoidal method on days 1 and 85; establishment of dose range from first dose to day 176; and an assessment of systemic immunogenicity effects of exidavnemab from first dose to day 176.⁴

The FDA’s ODD for exidavnemab marks a significant milestone in the search for an effective treatment for MSA. As the EXIST trial progresses, exidavnemab offers a potential breakthrough in slowing disease progression and improving quality of life for those affected by MSA.

REFERENCES

1. BioArctic receives orphan drug designation for exidavnemab the US. BioArctic. March 17, 2025. Accessed March 19, 2025. https://www.bioarctic.com/en/bioarctic-receives-orphan-drug-designation-for-exidavnemab-the-us/

2. Multiple system atrophy. Mayo Clinic. August 2, 2024. Accessed March 19, 2025. https://www.mayoclinic.org/diseases-conditions/multiple-system-atrophy/symptoms-causes/syc-20356153

3. Woerman AL, Watts JC, Aoyagi A, Giles K, Middleton LT, Prusiner SB. α-Synuclein: Multiple System Atrophy Prions. Cold Spring Harb Perspect Med. July 2, 2018. doi: 10.1101/cshperspect.a024588

4. Safety, tolerability, and pharmacokinetics of exidavnemab in patients with Parkinson's disease (EXIST). Updated December 12, 2024. Accessed March 19, 2025. https://clinicaltrials.gov/study/NCT06671938