Ninety percent of patients with cerebral adrenoleukodystrophy who were treated with elivaldogene autotemcel were alive and free of major functional disabilities at 2-years.
Ninety percent of patients with cerebral adrenoleukodystrophy (CALD) who were treated with elivaldogene autotemcel (eli-cel) were alive and free of major functional disabilities (MFD) at 2-years, according to findings from the phase 2/3 ALD-102 study (Starbeam) presented at the Virtual 47th Annual Meeting of the EBMT.
After 2 years in the ALD-102 trial, patients transferred to a long-term follow-up trial labeled LTF-304. No MFDs have been observed in the follow-up trial across 27 enrolled participants, including in patients reaching 5 years' follow-up and 7 at 6 years’ follow-up. Moreover, there have been no signs of MFDs at the longest follow up of 82.7 months. For the primary safety end point, there was no grade ≥2 acute or chronic graft-vs-host disease (GVHD) at 24 months or through the longest follow up.
“The results presented today show that at 24 months of follow-up, 90% of patients (27/30) in our pivotal study of eli-cel (ALD-102) were alive and free of MFDs," Richard Colvin, MD, PhD, VP, head of severe genetic diseases clinical research and development, bluebird bio, the company developing the gene therapy, said in a statement. "As we continue the long-term follow-up of these patients, we are encouraged that 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.”
The study enrolled male patients aged 17 years or younger, who first received granulocyte colony-stimulating factor with or without plerixafor to mobilize cells for apheresis. To create eli-cel, these autologous CD34+ hematopoietic stem cells were transduced with the Lenti-D lentiviral vector to encode the ABCD1 gene, which is mutated in X-linked adrenoleukodystrophy. Prior to infusion of the modified cells, a myeloablative conditioning regimen was administered that contained busulfan with cyclophosphamide in ALD-102 or busulfan plus fludarabine in ALD-104.
The phase 2/3 ALD-102 study enrolled 32 patients with CALD. Upon completion of the 2-year study, patients went on to a long-term follow-up group known as LTF-304. At the time of the analysis, 27 patients had enrolled in LTF-304 and 2 remained in ALD-102. Two patients withdrew and 1 progressed. The median follow-up time across groups was 38.6 months (range, 13.4-82.7).
Following treatment with eli-cel, patients had a stabilization in their Loes MRI severity score, which is a measurement of white matter changes. Overall, 81% of patients (26 of 32) experienced a stable Loes score (≤9 or change from baseline ≤6) at the data cutoff. In addition to Loes, 97% of patients (31 of 32) had stable neurologic function score (NFS), with 72% maintaining a score of 0, which indicates no impairment.Additionally, 88% of patients (28 of 32) were negative by gadolinium enhancement MRI.
“These data from the phase 2/3 Starbeam study show some potentially promising evidence, with up to almost seven years of follow-up and nearly all patients have a stable neurologic function score, indicating that minimal neurologic function was lost following eli-cel infusion," Jörn-Sven Kühl, MD, Department of Pediatric Oncology, Hematology and Hemostaseology, Center for Women’s and Children’s Medicine, University Hospital Leipzig, said in a statement. “These long-term results therefore suggest treatment with eli-cel may stabilize disease progression and consequently preserve as much neurological function as possible in boys with CALD.”
Safety data were available for ALD-102 and the LTF-304 study along with early results for patients enrolled in the phase 3 ALD-104 study. In this study, 19 patients had received treatment with eli-cel and the median follow-up was 8.6 months. Efficacy data were not yet presented from this cohort. Early findings showed that 17 of the 19 assessable patients had neutrophil engraftment, with the remaining 2 still bending. Additionally, 15 of 19 experienced with platelet engraftment, with 4 patients still pending assessment. There was no GVHD, graft failure, or evidence of oncogenesis or replication competent lentivirus across the study.
Overall, the treatment regimen was deemed tolerable across all three studies, with the primary adverse events associated with the conditioning and cell mobilization therapies. There were 3 serious adverse events possibly related to eli-cel, including BK viral cystitis and pancytopenia. There were 2 non-serious events of vomiting also deemed potentially related to eli-cel.
“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," Colvin said. "Today’s presentation continues to illustrate the potential of eli-cel as a one-time, durable treatment option for this devastating disease.”
Based on earlier assessments of data, the FDA has granted eli-cel a breakthrough therapy designation along with orphan drug and rare pediatric disease designations, all for its potential as a treatment for CALD. In October 2020, the European Medicines Agency accepted a marketing authorization application for the gene therapy in CALD, and, according to bluebird, the company is on track to submit a biologics license application to the FDA in the middle of 2021.
J.-S. Kühl, C. Duncan, F. Eichler, et al. Elivaldogene autotemcel (eli-cel; Lenti-D) gene therapy for cerebral adrenoleukodystrophy: Updated results from the Phase 2/3 study and safety outcomes report from the Phase 3 study. Presented at: Virtual 47th Annual Meeting of the EBMT, March 14-17, 2021. Abstract GS2-8.