What is CALD? Childhood cerebral adrenoleukodystrophy (CALD) is very rare, serious neurological disorder caused by mutations in the ABCD1 gene. Mutations in this gene cause defects in how cells metabolize very long-chain fatty acids (VLCFAs), causing them to build up in the central nervous system and the blood. The accumulation of VLCFA in the adrenal cortex and white matter of the brain and spinal cord leads to the progressive destruction of myelin, the protective sheath of the nerve cells in the brain that are responsible for thinking and muscle control. Without myelin, these nerves can no longer relay information to and from the brain.
CALD is a subtype of adrenoleukodystrophy (ALD). ALD is estimated to affect 1 in 5,000 to 1 in 17,000 newborns (both male and female), and approximately 1 in 21,000 newborn males. Within this group, CALD develops in approximately 40% of affected boys and in a smaller number of adult men. Although it can develop in females, it rarely occurs in the severity seen in males. CALD mostly affects boys because the disease-causing mutation is located on the X chromosome. Because girls have a second copy of the X chromosome, this can compensate for the mutation.
Symptoms, diagnosis, and treatment window. The earliest symptoms of CALD develop in boys ages 4-10 when they may show learning and behavioral problems, including difficulty learning to read and write. As the disease progresses, aggressive behavior, vision problems, difficulty swallowing, poor coordination, and impaired adrenal gland function may occur. The disease results in rapid loss of neurological function after the initial onset of symptoms, and nearly half of patients who do not receive treatment die within five years of symptom onset, many in their 20s. Therefore, early diagnosis is essential, as the outcome of treatment varies with the clinical stage of the disease.
Treatment must be administered before the disease progresses too far. For this reason, newborn screening is a critical for early diagnosis of ALD and provides access to a window of timely treatment. In the US, newborn screening for ALD has been recommended since 2016. Currently, 20 states and the District of Columbia screen for this disease, accounting for >60% of U.S. newborns.
Why is it in the news now? Lenti-D (elivaldogene autotemcel or eli-cel) is an investigational gene therapy being developed by bluebird bio for the treatment of childhood cerebral adrenoleukodystrophy (CALD). The FDA advisory committee reviewed it in June 2022 and unanimously approved drug/therapy 15-0. The FDA’s scheduled decision date on the therapy is September 16, 2022.
Eli-cel (Lenti-D) was approved in Europe as Skysona in June 2021. Bluebird bio was unable to reach a consensus with authorities in Europe around fair gene therapy pricing and has since withdrawn from the European market to concentrate on the US market.
Treatment: To date, there have been very few treatments available for CALD. Allogeneic Stem Cell transplant is the current standard of care for those in the early stages of the disease. Although it cannot repair the damage already done, it can in some cases prevent further damage. However, not all patients can receive stem cell transplants and the risks of complications are high without a matched sibling donor. Lorenzo’s Oil is a treatment that has not been fully tested but may help some patients. Lenti-D offers a potential alternative.
How Does It Work? Lenti-D therapy uses stem cells from the patient’s own bone marrow. These are then genetically modified, with the help of a viral vector, to include a functional copy of the ABCD1 gene. Patients then undergo myeloablative chemotherapy to lower the number of blood-forming cells in the bone marrow and increase the chance of a successful transplant. The modified stem cells are then transplanted back into the patient through an intravenous infusion. Researchers hope that these stem cells will develop into different cell types, including nerve cells, and produce ALD protein. It takes six to eighteen months for the transplanted cells to fully engraft and be functional. During this time, the disease continues to progress.
Cost: Lenti-D is anticipated to fall in the seven-figure, million dollar plus range for the one-time treatment.
Article written by Ginny Fisher, RN, BSN, Managed Care Specialist for Summit Reinsurance Services, Inc. For more information about how this may affect your plan, please contact your Summit ReSources care specialist. The following sources were used as reference material for this article:
https://adrenoleukodystrophynews.com/childhood-cerebral-adrenoleukodystrophy-cald/
https://www.biopharmadive.com/news/bluebird-withdraw-gene-therapy-europe-skysona/608666/
https://pharmaphorum.com/news/fda-panel-backs-bluebirds-cald-gene-therapy-despite-safety-worries/