The FDA has granted accelerated approval to Kebilidi (eladocagene exuparvovec-tneq) for the treatment of Aromatic L-Amino Acid Decarboxylase (AADC) deficiency in adult and pediatric patients. Developed by PTC Therapeutics, this marks the first gene therapy approved in the United States that is directly administered to the brain.
AADC deficiency is a rare, genetic disorder that impairs the synthesis of dopamine, a neurotransmitter crucial for motor function. This deficiency leads to metabolic disturbances affecting dopamine, norepinephrine, epinephrine, and serotonin. Children with AADC deficiency often experience severe disabilities, including seizure-like oculogyric crises, frequent vomiting, behavioral problems, and difficulty sleeping. It is estimated that only 350 people have been reported with this condition in the literature.
Clinical Efficacy
The approval of Kebilidi is based on data from a single, open-label trial involving pediatric patients with severe AADC deficiency. In this trial, 13 patients received Kebilidi, and 12 were assessed for efficacy at week 48. Results indicated that eight patients achieved new gross motor milestones. Specifically, three patients attained full head control, two could sit with or without assistance, and two achieved walking backwards. Notably, the two patients who were able to walk backwards had been treated before the age of 2 years. In contrast, none of the 43 untreated patients in the natural history cohort achieved similar milestones.
Administration and Safety
Kebilidi is administered through four infusions in a single surgery via a stereotactic surgical procedure. This method allows for direct delivery of the gene therapy to the brain, utilizing ClearPoint Neuro’s SmartFlow Neuro Cannula. The most common adverse reactions associated with Kebilidi include dyskinesia, fever, low blood pressure, anemia, increased saliva production, insomnia, and low levels of potassium, phosphate, and/or magnesium. Procedural complications such as respiratory and cardiac arrest were also reported.
Expert Commentary
Nicole Verdun, M.D., director of the Office of Therapeutic Products in FDA’s Center for Biologics Evaluation and Research (CBER), stated, "AADC deficiency can cause a range of debilitating symptoms, including life-threatening complications. Today’s approval represents important progress in the advancement and availability of safe and effective treatments for debilitating genetic disorders."
Daniel Curry, M.D., director, Functional Neurosurgery and Epilepsy Surgery at Texas Children’s Hospital and professor, Neurosurgery and Surgery at Baylor College of Medicine, added, "I have witnessed first-hand the positive impact these treatments have had on children with AADC deficiency. Neurosurgeons are leading the way in this promising field to address the underlying genetic cause, and not just the symptoms, of devastating neurological disorders by delivering gene therapy directly to targets in the brain through dedicated platforms."
Market and Availability
PTC Therapeutics has indicated that launch preparations are underway, with centers of excellence already identified and surgeons trained in the procedure to deliver the gene therapy. Kebilidi is also approved in the European Union and the United Kingdom under the name Upstaza. In 2023, sales from Tegsedi, Waylivra, and Upstaza contributed $22.7 million to PTC’s revenue.
