The FDA has approved PTC Therapeutics' Upstaza (eladocagene exuparvovec), a gene therapy for the treatment of children and adults with aromatic L-amino acid decarboxylase (AADC) deficiency. This marks the first gene therapy approved in the United States for direct administration to the brain. Upstaza delivers a functional copy of the DDC gene and will be marketed in the US under the name Kebilidi.
Mechanism of Action and Clinical Trial Data
Upstaza is administered via a one-time stereotactic surgical procedure to the putamen, delivering a recombinant adeno-associated virus serotype 2 (AAV2)-based vector containing a functional copy of the DDC gene, which is deficient in patients with AADC deficiency. The FDA's approval was 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, with PTC planning to provide long-term follow-up data as confirmatory evidence.
Data from phase 1/2 clinical trials (NCT01395641; NCT02926066) demonstrated that treated patients achieved clinically meaningful developmental milestones not seen in the natural history of the disease. Investigators reported that treated participants, who had not previously reached any developmental motor milestones, mastered clinically meaningful motor skills, including independent ambulation. Cognitive and language acquisition was observed as early as 3 months after administration, with clinical benefits persisting up to 10 years after administration.
Efficacy Outcomes
As early as 12 months after treatment, 44% of patients achieved head control, and 20% 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% could sit unassisted, 25% could stand without support, and 8% could walk with support. In contrast, only 4% of the 49 patients in the Natural History Database achieved key milestones (P < .0001).
Safety Profile
The most common adverse events reported in the clinical trials for Upstaza 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%). 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 Upstaza. The therapy has not been tested in children younger than 16 months of age or adults 65 years of age or older.
Commercialization and Disease Context
PTC Therapeutics is progressing with launch preparations for Upstaza, including designating centers of excellence and training surgeons to administer the gene therapy. The company was granted a Rare Disease Priority Review Voucher by the FDA along with Upstaza's approval and intends 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.
"PTC has once again pioneered a new approach to treating highly morbid neurologic diseases," said Matthew B. Klein, MD, the chief executive officer of PTC Therapeutics. "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."
