PTC Therapeutics Secures First FDA Nod for Brain-Administered Gene Therapy

An ultra-rare enzyme deficiency that prevents infants from developing proper muscle function and causes various developmental delays now has a groundbreaking treatment available. The U.S. Food and Drug Administration (FDA) has approved the first gene therapy administered directly into the brain. This treatment, developed by PTC Therapeutics, is a significant milestone for both children and adults suffering from aromatic L-amino acid decarboxylase (AADC) deficiency. Known as eladocagene exuparvovec during its development, the therapy will be marketed in the United States under the brand name Kebilidi. In Europe, it is already available and sold as Upstaza.

AADC deficiency arises from a mutation in the DDC gene, which is crucial for producing neurotransmitters like dopamine. Dopamine plays a vital role in movement, attention, learning, and memory. Current treatments for the deficiency include drugs that mimic dopamine, such as dopamine agonists, which activate dopamine receptors in the brain.

Kebilidi works by replacing the faulty DDC gene with a functioning one. This gene replacement is facilitated by an adeno-associated virus, introduced in a single surgical session that involves four infusions into the putamen, an area of the brain associated with learning and motor control. The goal of the therapy is to promote the expression of the missing enzyme, thereby increasing dopamine production in the brain.

The FDA's approval of Kebilidi is based on an open-label study involving 13 pediatric patients with AADC deficiency, aged between 16 months and 10 years. These patients had severe cases of the disease, with no gross motor function. Their progress was compared to historical data from untreated patients. The results showed that Kebilidi significantly improved gross motor functions in eight out of the 12 treated patients after 48 weeks. Notably, three patients gained full head control, and two were able to sit with or without assistance. The study indicated that earlier treatment led to better outcomes, as the two patients treated before the age of two were able to walk backwards by the 48-week mark. In contrast, the four patients dosed between 2.8 and 10.8 years of age did not achieve new gross motor milestones.

PTC’s gene therapy for AADC deficiency had previously received approval in Europe in 2022 for patients 18 months and older. Since then, it has also been approved in Israel, Brazil, and Taiwan. Progress for FDA approval faced delays due to the agency's requests for additional data. The FDA accepted PTC’s biologics drug application in May.

The FDA's decision for Kebilidi is an accelerated approval, which means it was based on a smaller body of evidence. Companies granted accelerated approval are typically required to provide additional data from confirmatory clinical studies. PTC plans to offer this evidence through long-term follow-up of patients already treated in their study. Analysts like William Blair's Sami Corwin have expressed optimism about the approval, noting that the effects of the PTC gene therapy have already shown durability for up to 10 years post-treatment.

The National Organization for Rare Disorders reports fewer than 350 known cases of AADC deficiency globally. Despite this rarity, William Blair projects that Kebilidi could generate peak revenues of $266.3 million by 2026. Beyond financial gains, Kebilidi’s approval came with a priority review voucher, which PTC can use for a faster regulatory review of another rare disease drug candidate. These vouchers are highly valuable; for example, Acadia Pharmaceuticals recently sold one for $150 million after receiving it for their treatment for Rett syndrome.