FDA Approves Kebilidi: First Brain-Delivered Gene Therapy for Rare AADC Disease

The U.S. Food and Drug Administration (FDA) has approved Kebilidi (eladocagene exuparvovec-tneq), a gene therapy for aromatic L-amino acid decarboxylase (AADC) deficiency in adults and children. This one-time, virus vector-based treatment targets the ultra-rare and fatal genetic disorder, which causes severe physical, mental, and behavioral disabilities from infancy, according to PTC. This treatment, approved for both adult and pediatric patients, marks the first FDA-approved gene therapy for the condition and the first ever gene therapy administered directly into the brain.

Kebilidi is A Breakthrough Gene Therapy for AADC Deficiency, Restoring Dopamine and Serotonin Production

PTC’s therapy, tested in pediatric patients, has gained FDA approval for both children and adults with AADC deficiency. Known as eladocagene exuparvovec, it is already approved in Europe under the brand name Upstaza. PTC, based in Warren, New Jersey, will commercialize the therapy in the U.S. as Kebilidi.

FDA-backed gene and cell therapies have advanced rapidly since 2017, with Kebilidi becoming the first U.S. gene therapy delivered directly to the brain. AADC deficiency is a rare genetic disorder that prevents dopamine production, impacting motor skills, cognitive development, and muscle tone from infancy. This disorder disrupts neurotransmitter production, hindering nervous system communication. Patients typically require physical, occupational, and speech therapy, as well as surgical interventions for severe developmental challenges.

AADC is essential for producing dopamine and serotonin, critical neurotransmitters. Dopamine controls movement, motivation, and reward. Serotonin affects sleep, mood, appetite, and memory. AADC deficiency disrupts dopamine, serotonin, norepinephrine, and epinephrine production, causing motor dysfunction, hypotonia, and developmental delays. Other symptoms include ptosis, small pupils, excessive sweating, nasal congestion, drooling, temperature instability, hypotension, syncope, arrhythmias, and sleep problems.

Kebilidi: Replacing the Mutated DDC Gene with a Functional Version via Gene Therapy

Kebilidi is a gene replacement therapy that replaces the mutated DDC gene with a functional version, delivered via an adeno-associated virus. Administered in a single surgical session, the therapy involves four infusions into the putamen, a brain region involved in motor control and learning. The gene vector is injected using magnetic resonance-guided convection-enhanced delivery (CED), ensuring stable and effective gene transfer. The therapy restores the deficient enzyme, increasing dopamine production in the brain.

The FDA approved Kebilidi based on an open-label study of 13 AADC patients aged 16 months to 10 years. All the patients had no gross motor function. These patients were compared to untreated AADC patients. Results showed Kebilidi improved gross motor function in eight of the 12 treated patients at 48 weeks. Three patients achieved full head control, and two were able to sit with or without assistance. Earlier treatment led to better outcomes. Two patients treated before age 2 could walk backward by week 48. Four patients aged 2.8 to 10.8 years did not achieve new motor milestones.

PTC’s therapy received European approval in 2022 for patients 18 months and older. It has also been approved in Israel, Brazil, and Taiwan. The FDA delayed approval due to additional data requests but accepted PTC’s biologics drug application in May. The global prevalence of AADC deficiency is estimated at 1 in 30,000 to 90,000 newborns. It is more common in East and South Asia, especially in Taiwan, where the IVS6+4A>T mutation is common. A study of 20,000 high-risk cerebrospinal fluid samples found a 0.112% detection rate, suggesting underreporting in certain regions.

FDA Grants Accelerated Approval for Kebilidi: Effects Show Durability for Up to 10 Years

The FDA’s decision for Kebilidi was an accelerated approval, based on a smaller body of evidence. Typically, such approvals require additional data from confirmatory studies. PTC plans to provide this evidence through long-term follow-up with patients already treated. William Blair analyst Sami Corwin noted the therapy’s effects have shown durability for up to 10 years.

“We view the approval of Kebilidi in the U.S. favorably for PTC and think the FDA approval of the first gene therapy that is administered directly to the brain is a positive for the broader gene therapy space, particularly those pursuing similar routes of administration,” Corwin said.

Given the limited number of AADC patients—fewer than 350 reported—William Blair projects Kebilidi’s peak revenue to reach $266.3 million by 2026. However, the approval also benefits PTC in other ways. Kebilidi’s approval came with a priority review voucher, which PTC could use for a future rare disease drug. Biotechs usually sell such vouchers to larger pharma companies. Recently, Acadia Pharmaceuticals sold its voucher for $150 million after receiving FDA approval for a Rett syndrome drug.

Therapy Sales Expected to Reach $40 Million to $50 Million This Year

After being launched globally for two years, Citi analysts predict that the therapy’s sales will reach between $40 million and $50 million this year. In the U.K., the therapy is priced at 3 million pounds (approximately $3.71 million) per 0.5-mL infusion, although the actual price paid may be lower due to a confidential discount through England’s National Health Service (NHS).

Looking ahead, PTC has an FDA action date for sepiapterin, its treatment for phenylketonuria (PKU), set for July 2025. The company also plans to submit vatiquinone for Friedreich ataxia in December. Meanwhile, PTC’s Duchenne muscular dystrophy treatment, Translarna, will be reviewed again by the FDA after the agency accepted its application. However, in Europe, the drug faces potential market withdrawal due to regulatory challenges.

Despite these hurdles, analysts at William Blair have praised PTC’s management for its effective execution. The company is forecasting full-year revenues of between $750 million and $800 million from its approved products.

Author

Bernice Lottering