Compared with stem cell therapy — the current standard of care for CALD patients — which requires cells from a donor, Lenti-D uses genetically modified patient-derived stem cells. Researchers hope that this will lead to fewer complications such as graft-versus-host disease.
How does Lenti-D work?
ALD is caused by mutations in the ABCD1 gene, which resides on the X-chromosome. This gene provides instructions necessary for cells to make the ALD protein, which mediates the transport of saturated very-long-chain fatty acids (VLCFAs) into the peroxisome. These are small compartments within the cell that play a crucial role in energy metabolism and the breakdown of many molecules, including VLCFAs.
The inability to transport VLCFAs into the peroxisomes leads to their abnormal accumulation in the blood and tissues of the central nervous system. This causes damage to myelin, the protective sheath that insulates nerve cells.
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 18 months for the transplanted cells to fully engraft and be functional. During this time, the disease continues to progress.
Lenti-D in clinical trials
An ongoing Phase 2/3 clinical trial (NCT01896102) called STARBEAM is assessing the safety and effectiveness of Lenti-D. A total of 32 boys with CALD under age 17 have received the therapy.
At the time of an interim analysis, the median follow-up was 29.4 months, and 15 of the 17 boys were still alive and free of major functional disability (MFDs). One patient died from disease progression. Another withdrew from the study to undergo allogeneic stem cell transplant (transplanting stem cells from a donor). He later died from transplant-related complications.
Researchers could detect the genetically modified cells and ALD protein in all patients. No toxic effects related to the infusion of Lenti-D were observed. Most adverse side effects appeared two weeks after the infusion. They were consistent with side effects that usually occur with myeloablative chemotherapy.
Patients who completed the STARBEAM study subsequently enrolled in the long-term follow-up study, LTF-304 (NCT02698579), where they will be monitored for an additional 13 years.
Researchers presented additional results of the STARBEAM and LTF-304 trials at the 46th Annual Meeting of the European Society for Blood and Marrow Transplantation. These showed that 31 out of 32 patients had stable neurologic function scores. This is a metric to test the amount of neurological dysfunction present in 15 symptoms across six categories. Twenty of the 23 patients with at least 24 months of follow-up since their Lenti-D treatment were free of MFDs at the time of data analysis. The other nine who were in the study for fewer than 24 months also showed no evidence of developing MFDs. Fourteen patients had reached four years since treatment without MFDs. Of those, 10 had been in the study for more than five years without MFDs.
Another open-label Phase 3 clinical trial, ALD-104 (NCT03852498), is currently recruiting another 35 boys up to age 17 at locations in the U.S. and Europe. As in the STARBEAM trial, patients will undergo stem cell collection, modification, and reimplantation after myeloablative chemotherapy. Investigators will study patients for 24 months after receiving the treatment to look for any changes in MFDs. They estimate to complete the trial in February 2024.
Based on data from the STARBEAM study, the U.S. Food and Drug Administration (FDA) granted breakthrough therapy designation to Lenti-D in May 2018. The treatment was also granted orphan drug status in the U.S. and EU, and rare pediatric disease designation in the U.S. and priorities medicines program designation in the EU. In addition, the European Medicines Agency accepted Bluebird Bio’s marketing authorization application for Lenti-D, the company announced in October 2020.
Last updated: Jan. 6, 2020
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