The FDA's Cellular, Tissue, and Gene Therapies Advisory Committee voted in favor of the benefits of bluebird bio's eli-cel in patients with cerebral andrenoleukodystrophy despite substantial safety concerns.
The FDA Cellular, Tissue, and Gene Therapies Advisory Committee voted unanimously in support of the benefits of bluebird bio’s elivaldogene autotemcel (eli-cel; Lenti-D) benefit for patients with early active cerebral adrenoleukodystrophy (CALD) ahead of its Prescription Drug User Fee Act (PDUFA) date of September 16, 2022.1
The committee of 15 voting members voted 15 Yes when answering question 2, "Do the benefits of eli-cel outweigh the risks for the treatment of any sub-population of children with early active cerebral andrenoleukodystrophy (CALD)?"
The committee also voted on a question concerning safety, in which they voted No (13), Yes (1), and Abstain (1) on whether lovo-cel safety data are relevant to the safety assessment of eli-cel.
A driving decision in many committee members' votes was the need for treatment in children with HLA-unmatched donors, overriding concerns for other sub-populations.
“MDS is certainly seen by the committee as a real concern and is likely to increase in frequency given the current data. But, the risks of Graft-versus-host disease toxicity versus the risks of the CALD disease are nonetheless currently seen as favorable," meeting chair Lisa Butterfield, PhD, Vice President, Research and Development, Parker Institute for Cancer Immunotherapy, summarized opinions. "There's an agreed need for detailed surveillance and sequencing biopsies to be able to intervene early in the MDS to have the best opportunity for treatment and understand the mechanism of action with this vector."
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Eli-cel is currently being evaluated in the phase 3 ALD-104 study (NCT03852498). It was granted priority review in December 2021 based on positive data from 23 participants in ALD-104 as well as 32 participants from the completed phase 2/3 Starbeam study (ALD-102; NCT01896102).2 An additional long-term follow-up study (LTF-304; NCT02698579) is ongoing.
The Starbeam study met its primary endpoint of Major Functional Disabilities (MFD)-free survival at 24 months, with 29 patients (90.6%) achieving this endpoint. Two participants withdrew at investigator discretion and 1 participant experienced rapid disease progression, MFD, and death. Median follow-up, including in the long-term follow-up study, is 3.5 years (42.3 months; range, 13.4-83.7).
Eli-cel was previously placed on clinical hold by the FDA in August 2021 following the Suspected Unexpected Serious Adverse Reaction (SUSAR) of MDS in the ALD-104 study.3 This case, along with 2 others that developed, are thought to be mediated by the use of their lentiviral vector (LVV). The clinical hold is ongoing, with treated participants being closely monitored.
Opinions were initially split during the discussions, with Wilson W. Bryan, MD, Director, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, FDA stating that eli-cel is "challenging due to issues with the evidence of effectiveness as well as our concerns regarding safety, particularly the risk of hematologic malignancy."1
On the other hand, Christine Duncan, MD, Senior Physician, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Medical Director of Clinical Research and Clinical Development, Gene Therapy Program, Boston Children’s Hospital, and Associate Professor, Pediatrics, Harvard Medical School, said that “boys who do not have a match-related donor need options for alternative therapies."1
FDA concerns have included uncertain efficacy and durability as they state 24 months to be an insufficient amount of follow-up especially in the context of the MDS cases. The FDA is also concerned with differences in population characteristics between studies and bias due to assessments done by unblinded clinical investigators.
"With all of these uncertainties, it is unclear if eli-cel is efficacious on month 24 [major functional disability] survival," Shelby Elenburg, MD, medical officer, FDA, said during the meeting.
Recent analyses on the LVV-mediated MDS cases presented at the 2022 American Society of Gene and Cell Therapy Annual Meeting, by David A. Williams, MD, associate chairman, department of pediatric oncology, Dana-Farber Cancer Institute, and chief, hematology/oncology, Boston Children's Hospital, concluded that more study is necessary of the LVV-mediated oncogenesis but that the gene therapy offers significant clinical benefit to patients with CALD.4
Insertion site analysis (ISA) revealed that both patients that developed MDS from ALD-104 had clonal predominance at 6 months post-infusion that included a single insertion in the MECOM gene. Further analysis revealed no typical driver mutation of myeloid neoplasms. The patient from ALD-102 had insertions in multiple genes, including PRDM16, but not MECOM and another patient with benign clonal predominance did have insertion in MECOM.
The vote is the first of 2 on bluebird’s gene therapies, with the company anticipating tomorrow’s discussion and vote on betibeglogene autotemcel (beti-cel; LentiGlobin) being developed for the treatment of transfusion-dependent β-thalassemia in adult and pediatric patients with a non–β0/β0 genotype.