PTC Therapeutics, Inc. (NASDAQ: PTCT) has received accelerated approval from the U.S. Food and Drug Administration (FDA) for its gene therapy, KEBILIDI™ (eladocagene exuparvovec-tneq), for the treatment of aromatic L-amino acid decarboxylase (AADC) deficiency. This marks the first gene therapy approved in the United States that is directly administered to the brain.
This approval signifies a major advancement in the treatment of AADC deficiency, a rare and life-threatening genetic disorder. KEBILIDI is indicated for both children and adults with AADC deficiency, addressing the full spectrum of disease severity. The therapy is designed to restore dopamine production in patients with this deficiency.
Mechanism of Action
AADC deficiency results from mutations in the DDC gene, leading to a deficiency in the AADC enzyme, which is crucial for dopamine synthesis. KEBILIDI is a recombinant adeno-associated virus serotype 2 (rAAV2)-based gene therapy containing a functional human DDC gene. It is administered directly into the putamen of the brain via a stereotactic neurosurgical procedure. This direct delivery aims to correct the underlying genetic defect by increasing the AADC enzyme levels and restoring dopamine production.
Clinical Trial Data and Accelerated Approval
The FDA's accelerated approval was based on safety and efficacy data from an ongoing global clinical trial (PTC-AADC-GT-002). The trial demonstrated that KEBILIDI leads to de novo synthesis of dopamine, resulting in progressive acquisition of motor development milestones. Continued approval is contingent upon verification and description of clinical benefit in a confirmatory clinical trial.
Safety and Efficacy
Clinical trial results showed notable improvements in motor function and overall well-being in patients treated with KEBILIDI. The most common adverse reactions (≥15%) included dyskinesia (77%), pyrexia (38%), hypotension (31%), and anemia (31%).
AADC Deficiency: Unmet Needs
AADC deficiency is a rare genetic disorder that typically manifests in the first months of life, causing severe disability and suffering. Affected children often experience oculogyric crises, developmental delays, and various life-threatening complications. Current management strategies involve supportive care, including physical, occupational, and speech therapy, but these do not address the underlying genetic defect.
Dosing and Administration
KEBILIDI is administered via a stereotactic surgical procedure by a qualified neurosurgeon in specialized centers. The procedure involves a minimally invasive neurosurgical approach to deliver the gene therapy directly into the putamen.
Priority Review Voucher
Along with the Biologics License Application approval, a Rare Disease Priority Review Voucher was granted, which the company plans to monetize.
Contraindications and Warnings
KEBILIDI is contraindicated in patients who have not achieved skull maturity, as assessed by neuroimaging. Warnings and precautions include potential procedure-related complications such as respiratory and cardiac arrest, CSF leak, intracranial bleeding, and dyskinesia. Patients should be monitored closely for adverse events following administration.
Future Directions
PTC Therapeutics is actively preparing for the commercial launch of KEBILIDI in the United States, with identified centers of excellence and trained surgeons ready to administer the gene therapy. The company aims to provide this transformative therapy to children and adults with AADC deficiency, offering a potential improvement in their quality of life.
Matthew B. Klein, M.D., Chief Executive Officer of PTC Therapeutics, stated, "PTC has once again pioneered a new approach to treating highly morbid neurologic diseases. 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."
