The FDA has granted approval to eladocagene exuparvovec-tneq (Kebilidi; PTC Therapeutics) as the first gene therapy for the treatment of aromatic L-amino acid decarboxylase (AADC) deficiency in both adult and pediatric patients. This landmark decision, announced by the FDA, marks a significant advancement in the treatment of this rare genetic disorder.
AADC deficiency is a rare genetic condition that impairs the production of neurotransmitters, which are essential for communication between cells in the nervous system. This deficiency leads to a range of debilitating symptoms, including delays in motor function, hypotonia, and cognitive delays, significantly impacting the patient's quality of life.
Mechanism of Action and Administration
Kebilidi is administered through four infusions in a single surgical session directly into the putamen, a large structure in the brain responsible for motor control. Post-infusion, the treatment enables the expression of AADC, subsequently boosting dopamine production, a critical neurotransmitter involved in movement, attention, learning, and memory. According to the FDA, the therapy should be administered in specialized medical centers with expertise in pediatric stereotactic neurosurgery.
Nicole Verdun, MD, director of the Office of Therapeutic Products in CBER, emphasized the importance of this approval, stating, "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."
Clinical Trial Data and Efficacy
The approval of Kebilidi was based on data from an open-label, single-arm clinical study involving 13 pediatric patients with confirmed AADC deficiency. At the beginning of the trial, all patients exhibited no gross motor function and had decreased AADC activity in the plasma. When compared to untreated patients, Kebilidi-treated patients showed marked improvements. Motor milestone assessments, completed 48 weeks post-treatment in 12 of the 13 patients, revealed that 8 patients demonstrated gross motor function improvement, a result not observed in untreated patients with severe AADC deficiency.
Adverse Reactions and Contraindications
The most common adverse reactions associated with Kebilidi include dyskinesia (involuntary muscle movements), fever, low blood pressure, anemia (low red blood cell count), increased saliva production, insomnia, and low levels of potassium, phosphate, and/or magnesium. Procedural complications, such as respiratory and cardiac arrest, were also noted. The treatment is contraindicated in patients who have not achieved skull maturity, as assessed by neuroimaging.
Accelerated Approval Pathway
The FDA approved Kebilidi via the Accelerated Approval pathway, which allows for the approval of products for serious conditions based on evidence of a surrogate endpoint or an intermediate clinical endpoint that is reasonably likely to predict clinical benefit. Continued approval for this indication may be contingent upon verification and description of clinical benefit, such as durability of the observed improvements, in a confirmatory clinical trial, which is currently ongoing.
Matthew B. Klein, MD, CEO of PTC Therapeutics, expressed his enthusiasm for the approval, stating, "I am proud of our team's unwavering commitment to achieve this important regulatory milestone. We look forward to bringing this transformational gene therapy to children and adults with AADC deficiency in the United States."
