FDA PalynziqThe FDA has granted Breakthrough Therapy designation to Lenti-D for the treatment of patients with cerebral adrenoleukodystrophy (CALD), a rare, serious and life-threatening hereditary neurological disorder. This FDA designation is designed to quicken the development and review of drugs that may work better than existing therapies, based on preliminary clinical evidence.

Lenti-D is intended to treat boys suffering from CALD, a hereditary disease that involves a breakdown of the protective sheath of the nerve cells in the brain that are responsible for thinking and muscle control.

Lenti-D therapy replaces a mutated gene with a functional gene in a patient’s own immature bone marrow cells, called autologous hematopoietic stem cells. When the modified cells are given back to the patient, they develop into different cell types, including brain cells, and begin producing a protein that is lacking. The restored protein is believed to prevent the buildup of fatty acids in the brain that are thought to contribute to neurodegeneration.

“The founding of bluebird was inspired by the potential to develop a one-time gene therapy for boys suffering from this potentially fatal form of adrenoleukodystrophy,” said David Davidson, M.D., chief medical officer, bluebird bio. “With Lenti-D, we hope the modified, autologous hematopoietic stem cells will keep these boys alive and free from major functional disabilities while avoiding many of the safety risks of the current standard of care, allogeneic hematopoietic stem cell transplant. The FDA’s Breakthrough Therapy designation for Lenti-D brings us one step closer to realizing this mission to bring new hope to the patients and families affected by this devastating disease. We look forward to continuing to work closely with the FDA and EMA to expedite development of Lenti-D as a treatment for CALD.”

Breakthrough Therapy designation is supported by preliminary data from the ongoing Phase 2/3 Starbeam Study (ALD-102) evaluating Lenti-D investigational gene therapy in boys with CALD, 17 years of age or less who do not have a matched sibling donor. Findings from 17 patients were published in theNew England Journal of Medicine in October 2017 and showed that 15 of the 17 patients (88 percent) infused with Lenti-D remained alive and free of major functional disabilities at 2 years post-treatment, the primary efficacy endpoint of the trial. Results also showed that the safety profile of Lenti-D remains consistent with myeloablative chemotherapy. Additionally, no engraftment failure, graft versus host disease or treatment-related mortality occurred, nor was there any evidence of insertional oncogenesis.

bluebird’s Lenti-D investigational gene therapy previously was granted Orphan Drug designation by the FDA and European Medicines Agency (EMA), as well as Rare Pediatric Disease designation by the FDA for the treatment of adrenoleukodystrophy (ALD). Under the FDA’s Rare Pediatric Disease Priority Review Voucher program, a sponsor who receives a marketing application approval for a rare pediatric indication may be eligible for a Priority Review Voucher, which can be redeemed to obtain Priority Review for a subsequent marketing application for a different product.

The Starbeam Study
Starbeam is a two-year study assessing the safety and efficacy of an investigational gene therapy in boys 17 years of age and under with CALD. This therapy is comprised of a patient’s own immature bone marrow cells that are modified to include a functional copy of the ABCD1 gene to express functional ALD protein (ALDP) which is lacking in patients with CALD.

When the modified cells are provided back to the patient, they develop into different cell types, including brain cells. Presumably, expression of ALDP in the brain can lead to a reduction in very long chain fatty acids (VLCFA). The accumulation of VLCFA in the brain is what is thought to contribute to potentially fatal neurodegeneration in CALD. Patients who complete the Starbeam study subsequently enroll in LTF-304, a long-term follow-up study of patients with CALD who were treated with Lenti-D.

About CALD
Also known as Lorenzo’s Oil disease, adrenoleukodystrophy (ALD) is estimated to affect one in every 21,000 male births worldwide. Forty percent of boys born with ALD will progress to the cerebral form of the disease, cerebral adrenoleukodystrophy (CALD), a potentially fatal form of ALD. CALD involves a breakdown of the protective sheath of the nerve cells in the brain that are responsible for thinking and muscle control.

Currently, the only therapeutic option for patients with CALD is allogeneic hematopoietic stem cell transplant (HSCT); beneficial effect has been reported if performed early in the course of CALD progression. Potential complications of allogeneic HSCT, which can be fatal, include graft failure, graft versus host disease (GVHD) and opportunistic infections, particularly in patients who undergo allogeneic HSCT using cells from a donor who is not a matched, unaffected sibling.

Early diagnosis of CALD is important, as the outcome of HSCT varies with clinical stage of the disease at the time of transplant. Favorable outcomes have been observed in patients who undergo transplant in the early stages of cerebral disease. Newborn screening for ALD is a critical enabler of early diagnosis and successful treatment of ALD. In the United States, newborn screening for ALD was added to the Recommended Universal Screening Panel (RUSP) in February 2016. Newborn screening for ALD is active in a limited number of states in the U.S.