First Brain-Delivered Gene Therapy Approved for AADC Deficiency

The FDA granted accelerated approval to eladocagene exuparvovec (Kebilidi) to treat children and adults with aromatic L-amino acid decarboxylase (AADC) deficiency, the agency announced Thursday.

The treatment is the first approved gene therapy for AADC deficiency, the FDA said. People with this rare disorder have decreased AADC activity that causes severe disability, including gross motor function deficits, weak muscle tone, and developmental and cognitive delays.

AADC is an enzyme involved in dopamine and serotonin synthesis. Eladocagene exuparvovec is a recombinant adeno-associated virus serotype 2-based therapy that delivers a functioning human DDC gene directly into the putamen, increasing the AADC enzyme and restoring dopamine production.

The treatment is the first-ever gene therapy approved in the U.S. directly administered to the brain, maker PTC Therapeutics said. It’s indicated for children and adults who have the full spectrum of AADC deficiency severity.

“AADC deficiency can cause a range of debilitating symptoms, including life-threatening complications,” said Nicole Verdun, MD, director of the FDA’s Office of Therapeutic Products in the Center for Biologics Evaluation and Research. “Today’s approval represents important progress in the advancement and availability of safe and effective treatments for debilitating genetic disorders.”

The FDA based its decision on an open-label, single-arm trial of 13 pediatric patients with confirmed AADC deficiency who were compared with a natural history cohort. At baseline, trial participants had no gross motor function — the most severe presentation of AADC deficiency — and decreased AADC activity in plasma.

Motor assessments were completed for 12 participants. At week 48, eight of 12 treated participants showed an improvement in gross motor function, which had not been reported in untreated patients with severe AADC deficiency.

The most common adverse reactions included dyskinesia, fever, low blood pressure, anemia, increased saliva production, insomnia, and low levels of potassium, phosphate, or magnesium. Procedural complications, including respiratory and cardiac arrest, were reported.

The therapy is contraindicated in patients who have not reached skull maturity assessed by neuroimaging. Its safety and efficacy have not been studied in pediatric patients younger than 16 months, PTC Therapeutics said. Clinical studies also did not include patients ages 65 and older.

A confirmatory trial of the drug’s clinical benefits is ongoing.

Eladocagene exuparvovec was approved in the U.K. and Europe under the brand name Upstaza in 2022.

The FDA said eladocagene exuparvovec is authorized to be administered using the SmartFlow neuro cannula.

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