Kebilidi (eladocagene exuparvovec-tneq)

The first FDA-approved treatment for AADC deficiency and, according to PTC, the only approved gene therapy for it. It is given once and aims to restore dopamine production in the putamen rather than replace dopamine with medicines.

In AADC deficiency, changes in both copies of the DDC gene leave the body short of the AADC enzyme, which the brain needs to make dopamine and serotonin. Children with the severe form cannot reach motor milestones such as head control, have very low muscle tone and have episodes of a stuck upward gaze called oculogyric crises^[3]. Kebilidi uses a modified, non-replicating virus called AAV2 to carry a working copy of the DDC gene into the putamen, a brain area that helps control movement. Brain cells there then make the AADC enzyme and start producing dopamine. In the main study, homovanillic acid, a breakdown product of dopamine, rose in the spinal fluid of every child, and PET brain scans showed a median 271% increase in AADC activity in the putamen at week 48^[1].

Kebilidi has no boxed warning. It must not be given until brain imaging shows the skull has matured enough for the surgery. The label warns about complications of the brain surgery: in the main study of 13 children, 2 (15%) had breathing and heart arrest within 24 hours of surgery, during post-surgical care^[1], and both recovered^[3]. Other possible surgical risks include a spinal fluid leak, bleeding in the brain, brain inflammation, a stroke (acute infarction) and infection. The most common side effect was dyskinesia, involuntary movements such as fidgeting, writhing or head bobbing, which affected 77% of children; every case began within 3 months, 2 needed a hospital stay, and medicines that block dopamine can help. Other common side effects were fever (38%), low blood pressure (31%), anemia (31%), excess saliva (23%), low potassium (23%), low phosphate (23%), trouble sleeping (23%) and low magnesium (15%). One child had longer and more frequent oculogyric crises while in the hospital after treatment. The study had no placebo group^[1].

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Approved for children and adults with AADC deficiency, confirmed as caused by changes in both copies of the DDC gene. Brain imaging must show the skull is mature enough for the surgery. It has not been studied in children younger than 16 months or in adults 65 and older, and the main study enrolled only children with the severe form, although the FDA review judged the benefit and risk favorable for all patients regardless of severity. There is no experience in people with high levels of existing neutralizing antibodies to AAV2 (titers above 1:1200).

Source: PTC Cares for AADC deficiency

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Approval rested on Study 1, PTC-AADC-GT-002 (NCT04903288), an open-label study with no placebo group in 13 children aged 16 months to 10 years with genetically confirmed, severe AADC deficiency whose skulls had matured enough for surgery. Of the 12 children assessed at week 48 (1 left the study early), 8 (67%) reached a new gross motor milestone: 3 gained full head control, 2 could sit with or without help, 2 could walk backwards, and 1 child with a variant of the severe form learned to sit without help. Both children who walked backwards had been treated before age 2, while the 4 who gained no new milestone were treated between ages 2.8 and 10.8. By comparison, none of 43 untreated children with severe AADC deficiency in a natural history group had reached a motor milestone at a median age of 7.2 years^[1][6]. The FDA review also drew on 2 earlier studies at National Taiwan University Hospital (NCT01395641 and NCT02926066)^[2]. A 2022 report on 26 treated children who had no head control before treatment found motor and thinking gains within 12 months that lasted through more than 5 years of follow-up, with younger children improving more^[8].

The therapy was first tested at National Taiwan University Hospital under the name AAV2-hAADC^[7]. It received FDA orphan drug designation on June 8, 2016 and rare pediatric disease designation on November 7, 2016. Europe and the UK approved it in 2022, and Israel in 2023, under the brand name Upstaza for children 18 months and older with the severe form^[3]. PTC Therapeutics submitted its US application on March 15, 2024, and the FDA granted accelerated approval on November 13, 2024 under priority review, with a rare pediatric disease priority review voucher and without an advisory committee meeting^[2][3]. PTC called Kebilidi the first gene therapy approved in the United States that is given directly into the brain^[5]. To keep the approval, PTC must submit data from patients treated in the US showing clinical benefit, with a final report due by September 30, 2029^[2].