FDA Approves Gene Therapy to Treat AADC Deficiency

Aromatic I-amino acid decarboxylase (AADC) deficiency will soon be treatable via gene therapy, as the FDA announced on November 13, 2024,¹ that it had approved PTC Therapeutics Inc.’s eladocagene exuparvovec-tneq (Kebilidi), which is the first gene therapy available in the US capable of being administered to the brain directly. The treatment will be available to both children and adults.

Patients who live with AADC deficiency, a rare genetic disorder that can lead to a shorter or highly morbid life, are unable to synthesize dopamine. It can also lead to severe disability and suffering for the first months of a child’s life, causing seizure-like oculogyric crises, behavioral problems, frequent vomiting, and difficulty sleeping. Eladocagene exuparvovec, which is designed to correct underlying genetic defects by delivering the DDC gene,² can be administered into a patient’s putamen in the brain. The gene replacement therapy is inserted through a stereotactic neurosurgical procedure and leads to de novo synthesis of dopamine and a progressive acquisition of motor development milestones.

The new gene therapy can help patients aged between 18 months and 65 years with AADC deficiency | Image credit: Siarhei - stock.adobe.com

The approval comes after the FDA accepted the Biologics License Application for the therapy in May 2024. Data from the phase 1/2 PTC-AADC-GT-002 clinical trial, which found that there was a change from baseline in motor milestone achievement after 48 weeks, provided the basis of the FDA decision.³ The approval marks the third approval overall for the medication, as the United Kingdom and European Union have previously approved it for use.

Previous studies⁴ tested the efficacy of the treatment through performing the surgical administration on patients and completing follow-ups for several years. A study found that the treatment was associated with improvements across all patients, with children seeing the greatest improvements. Improvements in both motor and cognitive function were noted within 1 year of the surgery and all improvements lasted through 5 years after the surgery. Brain injuries related to treatment did not occur and underlying disease was the most common reason for adverse events.⁴

Patients can only receive eladocagene exuparvovec if they have achieved skull maturity. Respiratory and cardiac arrest were both reported within 24 hours of the procedure and during postsurgical care after receipt of the treatment. Cerebrospinal fluid leakage, neuroinflammation, intracranial bleeding, infection, and acute infarction are all possible adverse events related to the initial surgery. Dyskinesia was also reported after the surgery; all cases came within 3 months of the initial surgery. Dyskinesia was the most common adverse reaction overall (77%), followed by pyrexia (38%), anemia (31%), hypotension (31%), hypokalemia (23%), salivary hypersecretion (23%), hypophosphatemia (23%), insomnia (23%), and procedural complications (15%).

The treatment will be available to patients aged 18 months to 65 years, as patients younger or older than the specified range were not studied.

"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,” Matthew B. Klein, MD, CEO of PTC Therapeutics, said in a press release.¹

References

1. PTC Therapeutics announces FDA approval of AADC deficiency gene therapy. News release. PTC Therapeutics; November 13, 2024. Accessed November 14, 2024. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-announces-fda-approval-aadc-deficiency-gene
2. PTC Therapeutics announces FDA acceptance and priority review of the BLA for Upstaza. News release. PTC Therapeutics; May 14, 2024. Accessed November 14, 2024. https://www.prnewswire.com/news-releases/ptc-therapeutics-announces-fda-acceptance-and-priority-review-of-the-bla-for-upstaza-302144369.html
3. Stansfield N. FDA approves PTC Therapeutics’ gene therapy Kebilidi for AADC deficiency. CGTlive. November 13, 2024. Accessed November 14, 2024. https://www.cgtlive.com/view/fda-approves-ptc-therapeutics-gene-therapy-upstaza-aadc-deficiency
4. Tai CH, Lee NC, Chien YH, et al. Long-term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency. Mol Ther. 2022;30(2):509-518. doi:10.1016/j.ymthe.2021.11.005