The FDA’s decision was based on findings from an ongoing global clinical trial demonstrating safety and efficacy of Kebilidi as a treatment for AADC deficiency. The open-label, single-arm clinical study includes 13 pediatric participants with confirmed diagnosis of AADC deficiency with no gross motor function and decreased AADC activity in plasma. No gross motor function comprises the most severe presentation of AADC deficiency. All participants received treatment with Kebilidi with outcomes compared with a natural history cohort.12 of the 13 participants completed motor milestone assessments at week 48 after receiving treatment.
8 of 12 treated participants showed gross motor function improvement, which has not been reported in untreated patients, demonstrating the efficacy of Kebilidi treatment.
The most common adverse reactions are dyskinesia, fever, low blood pressure, anemia, increased saliva production, insomnia, procedural complications (eg, respiratory and cardiac arrest), and low levels of potassium, phosphate, and/or magnesium.
Confirmatory evidence will be provided after long-term follow-up of study participants.
"I am proud of our team's unwavering commitment to achieve this important regulatory milestone,” said Matthew B. Klein, MD, CEO of PTC Therapeutics. “We look forward to bringing this transformational gene therapy to children and adults with AADC deficiency in the United States."
AADC deficiency is a rare genetic disorder associated with mutations in the DDC gene that encodes the aromatic L-amino acid decarboxylase enzyme. People present symptoms within the first few months of life, including hypotonia, developmental delay, dystonia and dyskinesia, gastrointestinal dysmotility, autonomic symptoms, and oculogyric crises. Children with this disorder are at high risk of death within the first 10 years of life.
The FDA authorized the use of the SmartFlow Neuro Cannula (Clearpoint Neuro, Solana Beach, CA) for use in administering Kebilidi.
https://practicalneurology.com/news/fda-grants-accelerated-approval-to-gene-therapy-for-the-treatment-of-aadc-deficiency
Kanjia MK, Jooste EH, Illig M, Neifeld Capps J, Eisner C, Fan SZ, Lenarczyk J, Wojdacz R. Optimizing the anesthetic care of patients with aromatic l-amino acid decarboxylase deficiency. Paediatr Anaesth. 2024 Oct 22. doi: 10.1111/pan.15025. Epub ahead of print. PMID: 39435566.
Abstract
Aromatic l-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disorder that results in a lack of the monoamine neurotransmitters dopamine, serotonin, norepinephrine, and epinephrine. Patients present with a wide spectrum of symptoms, including motor and autonomic dysfunction, hypotonia, and developmental delay, often before the age of one. Until recently, treatment options were limited to symptom control, but the recent approval of the first gene therapy for AADC deficiency in Europe and the UK has provided an alternative to treating symptoms for this disease. Eladocagene exuparvovec is a one-time gene therapy, administered bilaterally to the putamen by magnetic resonance imaging-guided stereotactic neurosurgery. While administration of the gene therapy itself is minimally invasive, the anesthetic management of patients with AADC deficiency is challenging due to the absence of sympathetic regulation secondary to the lack of adrenergic neurotransmitters. Optimal anesthetic management requires an understanding of the complex and heterogeneous nature of the disease. Hemodynamic instability, temperature dysregulation, and hypoglycemia are of primary concern, but there are also challenges regarding intravenous access and airway management. A thorough preoperative assessment is essential and should be guided by the patient's history. Advanced planning is necessary regarding the timing of the procedure schedule and operative plan; meticulous preparation, simulation for the operating room, as well as communication with all perioperative staff members, are crucial. Intraoperatively, utmost care must be taken to protect the skin, maintain body temperature, and to prepare for inotropic and/or glycemic support as needed. Postoperative intensive care management is necessary for consideration of postoperative extubation and provision of supportive care. With careful planning, preparation, and vigilance, patients with AADC deficiency can safely undergo anesthesia.
Lee HM, Mercimek-Andrews S, Horvath G, Marchese D, Poulin RE 3rd, Krolick A, Tierney KL, Turna J, Wei J, Hwu WL. A position statement on the post gene-therapy rehabilitation of aromatic I-amino acid decarboxylase deficiency patients. Orphanet J Rare Dis. 2024 Jan 18;19(1):17. doi: 10.1186/s13023-024-03019-x. PMID: 38238766; PMCID: PMC10797739.
Abstract
Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder of monoamine neurotransmitter synthesis that presents with a range of symptoms, including motor dysfunction and limited attainment of developmental motor milestones. The approval of eladocagene exuparvovec, a gene therapy for AADC deficiency with demonstrated efficacy for motor improvements, now expands the range of motor outcomes possible for patients with this disorder. However, recommendations and guidelines for therapy following treatment with gene therapy are lacking. To ensure patients can reach their full potential following treatment with gene therapy, it is essential they receive rehabilitation therapies designed specifically with their impairments and goals in mind. Therefore, we highlight specific rehabilitative needs of patients following gene therapy and propose a set of recommendations for the post-treatment period based on collective experiences of therapists, physicians, and caregivers treating and caring for patients with AADC deficiency who have been treated with gene therapy. These recommendations include a focus on periods of intensive therapy, facilitating active movements, training for functional abilities, cognitive and communication training, parent/caregiver empowerment, collaboration between therapists and caregivers to develop in-home programs, and the incorporation of supplemental forms of therapy that patients and their families may find more enjoyable and engaging. Many of these rehabilitative strategies may be employed prior to gene therapy. However, these recommendations will be valuable for therapists, caregivers, and wider treatment teams as they prepare for the post-treatment journey with these patients. Furthermore, the considerations and recommendations presented here may prove beneficial outside the AADC deficiency community as gene therapies and other treatments are developed and approved for other rare diseases.
Simons CL, Hwu WL, Zhang R, Simons MJHG, Bergkvist M, Bennison C. Long-Term Outcomes of Eladocagene Exuparvovec Compared with Standard of Care in Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency: A Modelling Study. Adv Ther. 2023 Dec;40(12):5399-5414. doi: 10.1007/s12325-023-02689-6. Epub 2023 Oct 6. PMID: 37803205; PMCID: PMC10611606.
Abstract
Introduction: Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare disease with symptoms including movement disorders, developmental delays, and autonomic symptoms starting from birth; further, patients with AADC deficiency are at a high risk of death in the first decade of life. Limited information on the impact of treatment with gene therapy on patients' disease trajectories and survival, quality-of-life, and resource usage benefits are available.
Method: A cohort-based model with a lifetime horizon has been developed, based on motor milestones, to estimate the long-term benefits for patients after treatment with eladocagene exuparvovec compared to best supportive care (BSC). The model takes a National Health Service (NHS) perspective using a UK setting. The model comprises two parts: the developmental phase, in which patients with initially no motor function can progress to other motor milestone states, and a long-term projection phase. Efficacy for eladocagene exuparvovec is derived from clinical trial data with a duration up to 120 months. As the incidence of AADC deficiency is low, data for key model inputs is lacking; therefore estimates of survival by motor milestone were based on proxy diseases. A disease-specific utility study provided quality of life inputs and a burden of illness study informed inputs for disease management.
Results: The model indicates survival (25.25 undiscounted life years gained) and quality-of-life benefits (20.21 undiscounted quality-adjusted life years [QALYs] gained) for patients treated with eladocagene exuparvovec compared to BSC. Resource usage costs are greater for patients treated with eladocagene exuparvovec, mainly due to the increased life expectancy during which patients accrue additional healthcare resource usage. Scenario analyses indicate robust results.
Conclusion: This study assessed long-term outcomes for patients with AADC deficiency. Patients treated with eladocagene exuparvovec were found to have improved survival and quality of life benefits compared to patients treated with BSC.
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