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Eli-Cel Approved for CALD, Marking Second Gene Therapy Win for bluebird bio

The approval follows unanimous support of eli-cel's benefits in CALD from an FDA AdComm meeting and an approval for beti-cel in beta-thalassemia.

The FDA has granted accelerated approval to bluebird bio's elivaldogene autotemcel (eli-cel; Lenti-D) for the treatment of early, active cerebral adrenoleukodystrophy (CALD) in patients without an HLA-matched donor.1 The approval follows similar action by the FDA in August when it approved the biotech company's gene therapy betibeglogene autotemcel (beti-cel; Zynteglo) intended for the treatment of transfusion-dependent β-thalassemia.2

After a challenging start to 2022, bluebird bio has seemingly bounced back on the heels of 2 very favorable meetings of the FDA Cellular, Tissue, and Gene Therapies Advisory Committee, who cast a unanimous vote in support of both eli-cel and beti-cel, stating that the benefits of the lentiviral vector gene therapies outweighed the risks in each patient population.

"For the ALD community, this long-awaited approval represents significant hope and offers families a new option where, for many, there had been none," Andrew Obenshain, chief executive officer, bluebird bio, said in a statement.1 "We are grateful to every individual who was involved in the development of SKYSONA and are committed to working with providers and payers to make this important treatment option available to patients and their families."

Eli-cel, which is currently on clinical hold and is continuing to be evaluated in the phase 3 ALD-104 study (NCT03852498), 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).3 An additional long-term follow-up study (LTF-304; NCT02698579) is ongoing.

The Starbeam study met its primary end point of Major Functional Disabilities (MFD)-free survival at 24 months, with 29 patients (90.6%) achieving this end point. Two participants withdrew at investigator discretion and 1 participant experienced rapid disease progression, MFD, and death. Median follow-up, including the long-term follow-up study, is 3.5 years (42.3 months; range, 13.4-83.7).

In August 2021, the FDA placed the first in class, one-time gene therapy product on hold due the report of a suspected unexpected serious adverse reaction of myelodysplastic syndrome in a patient treated with the therapy.4 The hematologic malignancy, of which 2 other cases have since developed, is thought to be mediated by the use of the lentiviral vector.

David A. Williams, MD, associate chairman, department of pediatric oncology, Dana-Farber Cancer Institute, and chief, hematology/oncology, Boston Children's Hospital, who presented an analysis of the cases earlier this year at the 2022 American Society of Gene and Cell Therapy Annual Meeting, concluded that more study is necessary of the LVV-mediated oncogenesis but that the gene therapy offers significant clinical benefit to patients with CALD.5

Insertion site analysis (ISA) revealed that both patients that developed MDS from ALD-104 had clonal predominance at 6 months postinfusion 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.

Notably, both eli-cel and beti-cel were previously approved in Europe; however, bluebird bio withdrew from the European market late last year due to payor challenges. Upon FDA approval, beti-cel's one-time treatment was priced at $2.8 million, making it the most expensive gene therapy available. The company launched a major restructuring earlier this year, citing the "tough biotech market" in its move to cut its workforce by 30% and slow its cash burn in order to continue supporting its efforts in gene therapy development and commercialization.

REFERENCES
1. bluebird bio Receives FDA Accelerated Approval for SKYSONA® Gene Therapy for Early, Active Cerebral Adrenoleukodystrophy (CALD). News release. bluebird bio. September 16, 2022. https://finance.yahoo.com/news/bluebird-bio-receives-fda-accelerated-035100645.html
2. bluebird bio Announces FDA approval of ZYNTEGLO® , the first gene therapy for people with beta-thalassemia who require regular red blood cell transfusions. News release. bluebird bio. August 17, 2022.
3. bluebird bio announces FDA priority review of biologics license application for eli-cel gene therapy for cerebral adrenoleukodystrophy (CALD) in patients without a matched sibling donor. News release. bluebird bio. December 17, 2021. https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-announces-fda-priority-review-biologics-license-0
4. bluebird bio reports second quarter financial results and provides operational update. News release. bluebird bio. August 9, 2021. https://www.businesswire.com/news/home/20210809005334/en/bluebird-bio-Reports-Second-Quarter-Financial-Results-and-Provides-Operational-Update
5. Williams DA, Bledsoe JR, Duncan CN, et al. Myelodysplastic syndromes after eli-cel gene therapy for cerebral adrenoleukodystrophy (CALD). Presented at: ASGCT 25th Annual Meeting; May 16-19, 2022. Washington DC.