bluebird bio presents long-term data for elivaldogene autotemcel (eli-cel, Lenti-D) gene therapy for cerebral adrenoleukodystrophy (CALD).

bluebird bio, Inc. announced new data from the clinical development program for its investigational elivaldogene autotemcel (eli-cel, Lenti-D) gene therapy in patients with cerebral adrenoleukodystrophy (CALD), including updated results from the pivotal Phase II/III Starbeam study (ALD-102) and the long-term follow-up study LTF-304, as well as safety outcomes from the Phase III ALD-104 study. Data were presented in an oral presentation during the Presidential Symposium at the 47th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT 2021), taking place virtually from March 14 - 17, 2021. The progression of CALD may occur rapidly, leading to severe neurological decline, and often death, of boys with this disease if untreated. The results presented show that at 24 months of follow-up, 90% of patients (27/30) in the pivotal study of eli-cel (ALD-102) were alive and free of major functional disabilities (MFDs) . As long-term follow-up continues for these patients, there are now 14 boys who have reached at least their Year 5 follow-up visit and continue to be living without MFDs, demonstrating the potential for a prolonged treatment effect,” said Richard Colvin, M.D., Ph.D., VP, head of severe genetic diseases clinical research and development, bluebird bio. “There is a great need for alternative treatment options that reduce the risk of the serious immune complications associated with allogeneic stem cell transplantation, the current standard of care for CALD. This presentation continues to illustrate the potential of eli-cel as a one-time, durable treatment option for this devastating disease.” Adrenoleukodystrophy (ALD) is a rare, X-linked metabolic disorder that is estimated to affect one in 21,000 male newborns worldwide. ALD is caused by mutations in the ABCD1 gene that affect the production of adrenoleukodystrophy protein (ALDP) and subsequently cause toxic accumulation of very long-chain fatty acids (VLCFAs) primarily in the adrenal cortex and white matter of the brain and spinal cord. Starbeam Study (ALD-102)/Long-Term Follow-Up Study (LTF-304): The ALD-102 study has completed enrollment. All reported data below from ALD-102 are as of October 2020 and all reported data below from LTF-304 are as of November 2020. These data reflect a total population of 32 patients with a median follow-up time of 38.6 months (13.4 – 82.7 months). Of the 32 patients who have received eli-cel in ALD-102, 27 have completed the study and enrolled in a long-term follow-up study (LTF-304). Two additional patients continue to be followed in ALD-102 and have not reached 24 months post-treatment. As previously reported, two patients withdrew from the study at investigator discretion, and one experienced rapid disease progression early on-study resulting in MFDs and subsequent death. To date, 124 patient-years of follow-up have been collected for ALD-102 and LTF-304. The primary efficacy endpoint in the study is the proportion of patients who are alive and free of MFDs at Month 24. Of those patients who have reached Month 24, 90% (n=27/30) have met the primary endpoint and continue to be alive and MFD-free at two years of follow-up . There is no evidence of MFDs through nearly seven years (up to 82.7 months) of follow-up in the 27 patients who completed ALD-102. Fourteen patients in LTF-304 have reached at least their Year 5 follow-up visit, including seven patients who have reached at least their Year 6 follow-up visit. The two patients from ALD-102 that have not reached Month 24 have also shown no evidence of MFDs. Data on several secondary and exploratory efficacy outcomes are reported , including changes in neurologic function score (NFS), a 25-point score used to evaluate the severity of gross neurologic dysfunction across 15 symptoms in six categories; resolution of gadolinium enhancement (GdE), an indicator of active inflammation in the brain; and change in Loes score, an MRI measurement of white matter changes in CALD. Stable NFS at last assessment is defined as maintaining an NFS <4 without an increase of>3 points from baseline. Of the 32 patients treated, 31 had stable NFS at last available visit following treatment with eli-cel, and 23 patients maintained an NFS of 0. An NFS of 0 indicates that there is no observed impairment in the neurologic functions that are assessed on the 25-point scale. As of available last visit, 26 of 32 patients had stable Loes scores ( less than 9 or change from baseline less than 6) and 28 of 32 were GdE-negative. The primary safety endpoint is the proportion of patients who experience acute ( greater than grade 2) or chronic graft-versus-host disease (GvHD) by Month 24. GvHD is a condition that may occur after an allogeneic hematopoietic stem cell transplant (allo-HSCT), where the donated cells view the recipient’s body as foreign and attack the body. No events of acute or chronic GvHD have been reported post-eli-cel treatment. There have been no reports of graft failure or graft rejection. In addition, there have been no cases of replication competent lentivirus or insertional oncogenesis to date. The treatment regimen, comprising mobilization/apheresis, conditioning, and eli-cel infusion, had a safety and tolerability profile primarily reflective of the known effects of mobilization/apheresis and conditioning. In ALD-102, as previously reported, three adverse events (AEs) were considered possibly related to drug product and include one serious AE (SAE), BK viral cystitis (n=1, SAE), and two non-serious AEs, vomiting (n=2). All three AEs resolved with standard measures. ALD-104 Study :ALD-104 is a Phase III study assessing the efficacy and safety of eli-cel in patients with CALD after myeloablative conditioning using busulfan and fludarabine, a different chemotherapy conditioning regimen than what is used in ALD-102 (busulfan and cyclophosphamide). The primary efficacy endpoint is the proportion of patients who are alive and free of MFDs at Month 24 , and the primary safety endpoint is the proportion of patients with neutrophil engraftment after eli-cel infusion. All reported data below are as of October 202 0.In ALD-104, the 19 patients currently treated with eli-cel have a median follow-up of 8.6 months (min-max: 0.1 – 16.8 months) to date. Due to the limited duration of follow-up, only safety data are being presented. Efficacy data will be presented in a future scientific forum when sufficient follow-up is reached.Seventeen of 19 evaluable patients achieved neutrophil engraftment (NE; pending in two patients as of data cut date) and 15 of 19 evaluable patients had platelet engraftment (PE; pending in two patients who are awaiting neutrophil engraftment and in two additional patients as of data cut date). All patients with pending neutrophil or platelet engraftment had 35 or fewer days of follow-up. No events of acute or chronic GvHD have been reported and there have been no reports of graft failure, graft rejection, cases of insertional oncogenesis, or replication competent lentivirus. The treatment regimen, comprising mobilization/apheresis, conditioning, and eli-cel infusion had a safety and tolerability profile primarily reflective of the known effects of mobilization/apheresis and conditioning. As previously reported, two serious AEs of pancytopenia were considered possibly related to eli-cel. These two ongoing SAEs were diagnosed approximately two months post-eli-cel infusion and following NE in two patients. Both patients achieved PE (Day 104 and 108) and as of last visit (~13 months post-eli-cel infusion) were clinically stable.An additional previously reported SAE of transverse myelitis was ongoing as of the data cut. The SAE was diagnosed in the presence of viral infection (adenovirus and rhinovirus/enterovirus positivity) approximately six months after eli-cel infusion and assessed as unrelated to eli-cel. As of the data cut, the patient was partially responsive to steroids and plasmapheresis and was experiencing incontinence and ambulation issue.