The FDA granted accelerated approval to elivaldogene autotemcel (eli-cel; Skysona), a gene therapy to treat early, active cerebral adrenoleukodystrophy (CALD) in boys ages 4 to 17 years, drugmaker bluebird bio announced Friday.
Childhood CALD is a rare, neurologically debilitating form of adrenoleukodystrophy that generally occurs in young boys. It is caused by a mutation in the ABCD1 gene that leads to the overproduction of very long-chain fatty acids primarily in the white matter of the brain and spinal cord that destroys myelin.
Eli-cel is a one-time therapy that adds functional copies of the ABCD1 gene to a patient's stem cells. The added gene allows patients to produce adrenoleukodystrophy protein to help break down these very long-chain fatty acids.
Hematopoietic stem cell transplant (HSCT) can slow or stop CALD progression and improve survival. Compared with children who have related donors, however, those with mismatched unrelated donors run greater risks of graft failure, graft-versus-host disease, and mortality.
Eli-cel was approved based on data from the phase II/III ALD-102 and phase III ALD-104 trials. Both open-label, single-arm studies enrolled patients with early, active CALD with elevated very long-chain fatty acid values, a Loes score between 0.5 and 9, and gadolinium-enhanced demyelinating lesions on MRI. Participants also were required to have limited changes in neurologic function. Eli-cel's efficacy was compared with a natural history population.
Patients were monitored for six major functional disabilities (MFD) associated with CALD progression that could emerge, including loss of communication, cortical blindness, requirement for tube feeding, total incontinence, wheelchair dependence, or complete loss of voluntary movement.
Eli-cel's accelerated approval was based on 24-month MFD-free survival. A post-hoc enrichment analysis in symptomatic patients assessed MFD-free survival from onset of symptoms in 11 treated and seven untreated patients, and found that treated patients had an estimated 72% likelihood of MFD-free survival at 24 months from the time of their first neurologic function score of 1 or more, compared with a 43% likelihood of MFD-free survival for untreated patients.
As a condition of accelerated approval, bluebird will provide confirmatory long-term clinical data to the FDA, including results of the ongoing study LTF-304, which is following patients treated in clinical trials for 15 years, and data from commercially treated patients.
The most common non-laboratory adverse reactions in patients treated with eli-cel included mucositis, nausea, vomiting, febrile neutropenia, alopecia, decreased appetite, abdominal pain, constipation, pyrexia, diarrhea, headache, and rash (all 20% or more). The most common grade 3/4 laboratory abnormalities included leukopenia, lymphopenia, thrombocytopenia, neutropenia, anemia, and hypokalemia (all 40% or more). The treatment carries a boxed warning for hematologic malignancy.
Eli-cel had the full backing of the FDA's advisory committee in June, which voted 15-0 that the treatment was best indicated for childhood CALD patients without an available matched sibling HSCT donor.
The wholesale acquisition cost of eli-cel in the U.S. will be $3 million, topping the $2.8 million price tag bluebird set for its recently approved betibeglogene autotemcel (beti-cel; Zynteglo) to treat adults and children with beta-thalassemia who require regular red blood cell transfusions.
The company anticipates eli-cel will be available by the end of 2022 at qualified treatment centers. The company also confirmed that the previous clinical hold on the eli-cel development program issued in August 2021 has been lifted. The hold followed reports of myelodysplastic syndrome after eli-cel treatment.