bluebird bio presents new results from elivaldogene autotemcel (eli-cel, Lenti-D) gene therapy for cerebral adrenoleukodystrophy. (CALD).

bluebird bio, Inc. announced updated results from the clinical development program for its investigational elivaldogene autotemcel (eli-cel, Lenti-D ) gene therapy in patients with cerebral adrenoleukodystrophy (CALD) , including long-term results from the Phase II/III Starbeam study (ALD-102/LTF-304) and data from the Phase III ALD-104 study. These data were presented at the 46th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT 2020), taking place virtually from August 29 - September 1, 2020. “CALD is a fatal neurodegenerative disease primarily affecting young boys. Currently, the only treatment available is allogeneic hematopoietic stem cell transplantation (allo-HSCT), which comes with associated, significant risks, including transplant-related mortality, graft failure or rejection, and graft-versus-host disease (GVHD),” said David Davidson, M.D., chief medical officer, bluebird bio. “Eighty-seven percent of patients in our Phase II/III Starbeam study of eli-cel are alive and free of major functional disabilities (MFDs) at 24 months or more of follow-up. Importantly, there were no reports of graft failure, graft rejection, or GVHD. It is gratifying to see the consistent outcomes with eli-cel and the durability of the treatment effect demonstrated in the children participating in our long-term follow-up study – including 10 boys who have now reached at least their Year 5 follow-up visit.” “Patients with CALD experience a rapid decrease in neurologic function after the initial onset of clinical symptoms, so early diagnosis and treatment is critical in order to stop the disease progression and preserve their neurological function. In the Phase II/III Starbeam study, 31 of 32 patients had a stable neurologic function score, suggesting that disease progression had stabilized and minimal neurological function was lost, following eli-cel infusion,” said Dr. Jörn-Sven Kühl, Department of Pediatric Oncology, Hematology and Hemostaseology, Center for Women's and Children's Medicine, University Hospital Leipzig. “These results presented at EBMT 2020 are very encouraging and suggest treatment with eli-cel may prevent neurological decline in boys with CALD.” Starbeam Study (ALD-102)/Long-Term Follow-Up Study (LTF-304): The ALD-102 study has completed enrollment. All reported data below are as of January 2020 and reflect a total population of 32 patients with a median follow-up time of 30.0 months (9.1 – 70.7 months). Of the 32 patients who have received eli-cel as of January 2020, 20 have completed ALD-102 and enrolled in a long-term follow-up study (LTF-304). Nine 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 death. To date, 104.3 patient-years of follow-up have been reported 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 or would have reached Month 24, 87% have met the primary endpoint and continue to be alive and MFD-free at more than two years of follow-up (N=20/23). Fourteen patients have at least four years of follow-up, including 10 patients who have reached at least their Year 5 follow-up visit. The nine patients from ALD-102 that have not reached Month 24 have 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. Of the 32 patients treated, 31 had stable NFS following treatment with eli-cel, defined as NFS <4, without a change of greater than 3 from baseline, and 24 patients maintained an nfs of 0. an nfs of 0 indicates that there are no concerns with the neurologic functions that are assessed on the 25-point scale. loes scores generally stabilized within 12-24 months and gde was no longer seen in most patients following eli-cel treatment. the primary safety endpoint is the proportion of patients who experience acute (?grade 2) or chronic gvhd by month 24. gvhd is a condition that may occur after an 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. integration site analysis (isa) was conducted to determine the pattern of integration post-eli-cel infusion and assess whether dominant or expanding clones were present. in one patient, now enrolled in ltf-304 for long-term follow up, a case of benign clonal expansion was observed with three separate integrations in the dna of the cell at acer3, rfx3, and mecom. as of the patient’s month 62 visit in march 2020, the patient remained clinically stable. bone marrow analyses showed no dysplasia (abnormal cell growth) or molecular abnormalities. 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 (ae) were considered possibly related to drug product and include one serious ae (sae), bk viral cystitis (n="1," sae, grade 3), and two non-serious aes, vomiting (n="2," grade 1). all three aes resolved using standard measures. ald-104 study : bluebird bio is currently enrolling patients for ald-104, a phase iii study designed to assess 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 february 2020. in ald-104, the 13 patients currently on study have a median of 6.1 months of follow-up to date (min-max: 2.2 – 10.3 months). all 13 patients achieved neutrophil engraftment and 12 13 evaluable patients had platelet engraftment (platelet engraftment pending in one patient as of data cut date). due to the limited duration of follow-up, only safety data are being presented. 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. in ald-104, two aes of pancytopenia were considered possibly related to eli-cel. these two ongoing aes were deemed as suspected unexpected serious adverse reactions (susars) by the principal investigator and were diagnosed approximately two months post-eli-cel infusion in two patients (one grade 2 and one grade 3). an additional ae was ongoing as of february 2020, a grade 3 sae of transverse myelitis that was diagnosed in the presence of viral infection (adenovirus and rhinovirus enterovirus positivity) approximately six months after eli-cel infusion and deemed unrelated to eli-cel.>