FDA Approves PTC Therapeutics’ Gene Therapy Kebilidi for AADC Deficiency
The gene therapy has been approved in the UK and European Union since 2022 under the brand name Upstaza.
FDA approves Kebilidi
This is a developing story and will be updated with new information as it becomes available.
PTC Therapeutics’ eladocagene exuparvovec, a recombinant adeno-associated virus serotype 2 (AAV2)-based gene therapy, has been approved by the FDA for the treatment of children and adults with aromatic L-amino acid decarboxylase (AADC) deficiency.1 Notably, the indication covers the full spectrum of disease severity and the approval constitutes the first gene therapy for direct administration to the brain to be approved in the United States. The product will be marketed in the US under the name Kebilidi; in the European Union and United Kingdom, it is marketed as Upstaza.
Kebilidi is delivered to the putamen via a 1-time treatment with a stereotactic surgical procedure and provides a functional copy of DDC, the disease-targeted gene. The FDA's approval was made based on data from the global phase 1/2 PTC-AADC-GT-002 clinical trial (NCT04903288). The decision was made under an accelerated approval pathway and PTC noted that long-term follow-up data from patients treated in the study will be provided as confirmatory evidence at a later date. The FDA cited change from baseline in gross motor milestone achievement at 48 weeks posttreatment as an efficacy finding supporting the approval.
"PTC has once again pioneered a new approach to treating highly morbid neurologic diseases," Matthew B. Klein, MD, the chief executive officer of PTC Therapeutics, said in a statement.1 "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."
Data from phase 1/2 clinical trials of eladocagene exuparvovec (NCT01395641; NCT02926066) that demonstrated that treated patients reached clinically meaningful developmental milestones not seen in the natural history of the disease have been previously reported.2-5 Investigators found that treated participants who had not previously reached any developmental motor milestones mastered clinically meaningful motor skills including independent ambulation. Additionally, cognitive and language acquisition was achieved as early as 3 months after administration and clinical benefits were shown to persist up to 10 years after administration.
Furthermore, as early as 12 months after treatment, 44% of patients achieved head control and 20% of subjects could sit unassisted. At 24 months posttreatment, 64% of patients achieved head control, 50% could sit unassisted, and 18% could stand without support. At 60 months posttreatment, 75% of patients achieved head control, 67% of patients could sit unassisted, 25% could stand without support, and 8% of patients could walk with support. By contrast, only 4% of the 49 patients in the Natural History Database achieved key milestones (P <.0001).
The most common adverse events reported in the clinical trials for eladocagene exuparvovec included dyskinesia (77%), pyrexia (38%), hypotension (31%), anemia (31%), salivary hypersecretion (23%), hypokalemia (23%), hypophosphatemia (23%), insomnia (23%), hypomagnesemia (15%), and procedural complications, including respiratory and cardiac arrest (15%).1 PTC notes that additional risks of procedural complications potentially include cerebrospinal fluid leak, intracranial bleeding, neuroinflammation, acute infarction, and infection.
Patients who have not yet reached skull maturity are not eligible to receive eladocagene exuparvovec. Notably, the therapy has not been tested in children younger than 16 months of age or adults 65 years of age or older.
PTC has reported that launch preparations for eladocagene exuparvovec are progressing smoothly, with centers of excellence designated and surgeons already trained to administer the gene therapy. PTC was granted a Rare Disease Priority Review Voucher by the FDA along with eladocagene exuparvovec's approval in the US. PTC stated its intent to sell the voucher. AADC deficiency is a fatal, rare genetic disorder that typically causes severe disability and suffering from the first months of life, leading to decreased muscle tone, movement disorders, and disruption of the autonomic nervous system.
The FDA originally accepted PTC's biologics license application for eladocagene exuparvovec with priority review in May 2024.2 It was previously approved in 2022 in both the United Kingdom and European Union under the name Upstaza for children aged 18 months or older with a severe phenotype of AADC deficiency.3,5
"Before treatment, our daughter had not met any development milestones," Richard Poulin, the founder of Teach RARE, whose daughter was treated as part of a clinical trial, said in a statement at the time of the EU approval.5 "She suffered from oculogyric crises that evolved into hours of pain, and we were told she would be bedridden for life. After receiving Upstaza, she is now speaking, walking, running, and even riding horses. We're thrilled with the EMA approval and the hope that this milestone brings to other children and families impacted by AADC deficiency."
