The U.S. Food and Drug Administration (FDA) has approved Kebilidi (eladocagene exuparvovec-tneq), a gene therapy for the treatment of aromatic L-amino acid decarboxylase (AADC) deficiency in adult and pediatric patients. This marks a significant milestone as the first FDA-approved gene therapy delivered directly into the brain. The one-time treatment, developed by PTC Therapeutics, addresses the underlying genetic defect of this rare and often fatal disorder.
How Kebilidi Works
AADC deficiency is a rare genetic condition that impairs the production of key neurotransmitters, including dopamine and serotonin. These neurotransmitters are crucial for motor skills, cognitive development, and overall nervous system function. Kebilidi works by delivering a functional copy of the DDC gene, which is mutated in individuals with AADC deficiency, directly into the putamen, a region of the brain involved in motor control and learning. The therapy uses an adeno-associated virus (AAV) vector to ensure stable and effective gene transfer.
Christina Pacak, a molecular biologist from the University of Minnesota, highlighted the safety benefits of surgical delivery, noting, "It keeps the dose relatively low. It doesn’t need to be a systemic thing."
Clinical Trial Results
The FDA's approval was based on data from an open-label study involving 13 pediatric patients with AADC deficiency, ranging in age from 16 months to 10 years. At the start of the study, all patients had no gross motor function. Results showed that Kebilidi improved gross motor function in eight of the 12 treated patients within 48 weeks. Some patients achieved full head control, and others were able to sit with or without assistance. Notably, earlier treatment led to better outcomes, with two patients treated before age 2 able to walk backward by week 48.
The most common adverse reactions associated with Kebilidi include dyskinesia, fever, low blood pressure, anemia, increased saliva production, and insomnia. The therapy is contraindicated in patients who have not achieved skull maturity, as assessed by neuroimaging.
Accelerated Approval and Future Plans
Kebilidi received accelerated approval based on early improvements in gross motor function. Continued approval is contingent upon verification and description of clinical benefit in a confirmatory clinical trial. PTC Therapeutics plans to provide this evidence through long-term follow-up with treated patients.
William Blair analyst Sami Corwin noted the therapy’s effects have shown durability for up to 10 years, adding, "We view the approval of Kebilidi in the U.S. favorably for PTC and think the FDA approval of the first gene therapy that is administered directly to the brain is a positive for the broader gene therapy space, particularly those pursuing similar routes of administration."
Market and Future Prospects
While the prevalence of AADC deficiency is low, estimated at 1 in 30,000 to 90,000 newborns, the approval of Kebilidi represents a significant advancement in the treatment of this debilitating condition. Citi analysts predict that the therapy’s sales will reach between $40 million and $50 million this year. Kebilidi's approval also grants PTC Therapeutics a priority review voucher, potentially valuable for future drug developments.
Guangping Gao, a gene therapy researcher at UMass Chan Medical School, emphasized the broader implications, stating, "Its success or experience we learned from this translation and commercialization will help us to develop other CNS gene therapy products."
