FDA Approves First Brain-Delivered Gene Therapy for AADC Deficiency

• Eladocagene exuparvovec (Kebilidi) receives accelerated FDA approval as the first gene therapy for Aromatic L-amino acid decarboxylase (AADC) deficiency, a rare genetic disorder.
• The therapy delivers a functioning human DDC gene directly into the brain's putamen to increase AADC enzyme production and restore dopamine synthesis.
• Clinical trials demonstrated improved gross motor function in pediatric patients, a key indicator of therapeutic efficacy, compared to untreated individuals.
• Approved for both children and adults, this marks the first gene therapy administered directly to the brain in the U.S., offering new hope for this debilitating condition.

The FDA has granted accelerated approval to eladocagene exuparvovec (Kebilidi) for the treatment of aromatic L-amino acid decarboxylase (AADC) deficiency in both children and adults. This marks a significant milestone as the first gene therapy approved for this rare and debilitating genetic disorder, and the first to be administered directly into the brain.

AADC deficiency results from decreased AADC activity, leading to severe disability, including gross motor function deficits, weak muscle tone, and developmental and cognitive delays. AADC is an enzyme critical for dopamine and serotonin synthesis. Eladocagene exuparvovec, a recombinant adeno-associated virus serotype 2-based therapy, delivers a functional human DDC gene directly into the putamen, aiming to increase AADC enzyme levels and restore dopamine production.

Clinical Trial Data

The FDA's decision was based on data from an open-label, single-arm trial involving 13 pediatric patients with confirmed AADC deficiency. These patients were compared to a natural history cohort. At baseline, all trial participants exhibited no gross motor function, representing the most severe presentation of AADC deficiency, along with decreased AADC activity in plasma. Motor assessments were completed for 12 participants.

At week 48, eight of the 12 treated participants showed improvement in gross motor function, a development not observed in untreated patients with severe AADC deficiency. This improvement signifies a clinically meaningful benefit, addressing a critical unmet need in this patient population.

Safety and Efficacy Considerations

The most common adverse reactions observed in the clinical trial 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 also reported. The therapy is contraindicated in patients who have not reached skull maturity, as assessed by neuroimaging, and its safety and efficacy have not been established in pediatric patients younger than 16 months or in patients aged 65 and older.

A confirmatory trial to further evaluate the drug's clinical benefits is currently underway. Eladocagene exuparvovec was previously approved in the U.K. and Europe under the brand name Upstaza in 2022.

Administration

The FDA has authorized the administration of eladocagene exuparvovec using the SmartFlow neuro cannula.