FDA Extends BLA Review for bluebird bio’s β-Thalassemia and CALD Gene Therapies


Eli-cel remains on clinical hold in cerebral adrenoleukodystrophy after a report of persistent anemia.

The FDA has extended the review dates for bluebird bio’s biologics license applications (BLAs) for its investigative gene therapies: betibeglogene autotemcel (beti-cel) for β-thalassemia and elivaldogene autotemcel (eli-cel) for cerebral adrenoleukodystrophy (CALD).1

The FDA extended each of the reviews by 3 months, moving beti-cel's PDUFA date from May 20, 2022, to August 19, 2022, and eli-cel's from June 17, 2022, to September 16, 2022. The extension is intended to give the FDA time to review new clinical information received from bluebird in response to previous information requests.

“Gene therapies are complex, potentially transformative treatment options for those living with severe genetic diseases, and we all share a responsibility to be diligent for patients as we progress this novel field,” Andrew Obenshain, chief executive officer, bluebird bio, said in a statement.1 “We look forward to continuing to work with the FDA on its ongoing reviews of beti-cel and eli-cel, and to bringing these therapies to patients with β-thalassemia and CALD in the US later this year.”

The FDA previously accepted bluebird’s BLA for beti-cel in November 2021 for patients with β-thalassemia across all genotypes who require regular blood transfusions.2 The submission was based on data from the phase 3 studies HGB-207 (Northstar-2; NCT02906202) and HGB-212 (Northstar-3; NCT03207009), the Phase 1/2 HGB-204 (Northstar; NCT01745120) and HGB-205 (NCT02151526) studies, and the long-term follow-up study LTF-303 (NCT02633943).

READ MORE: The State of Gene and Cell Therapy for Sickle Cell Disease

Data from the LTF-303 trial were presented at the 2021 ASH Annual Meeting and Exposition that demonstrated the gene therapy candidate’s durable effect in β-thalassemia.3 Three previously transfusion-dependent participants exhibited normal or near-normal levels of total hemoglobin and have remained transfusion-free with stable iron markers through up to 7years of follow-up.

bluebird's BLA for eli-cel for the potential treatment of CALD was accepted for priority review in December 2021.4 The BLA submission was based on efficacy and safety data from 32 participants in the completed Phase 2/3 Starbeam study (ALD-102; NCT01896102) and 23 participants in the Phase 3 ALD-104 study (NCT03852498), in which follow-up is ongoing. An additional long-term follow-up study (LTF-304; NCT02698579) is ongoing.

Beti-cel and eli-cel, if approved, would be the first lentiviral vector gene therapies for patients with severe genetic diseases to enter the market. While lentiviral vectors are certainly a promising avenue for gene therapy, bluebird bio has run into more than their share of trouble with the vectors, with their programs put on multiple clinical holds in 2021.

Clinical holds were lifted in June 2021 on programs that use the lentiviral vector BB305, including their phase 1/2 HGB-206 and phase 3 HGB210 trials of lovotibeglogene autotemcel (lovo-cel) for SCD as well as the HGB-207 and HGB-212 studies for β-thalassemia.5 

Just 6 months later in December 2021, the lovo-cel program was placed and remains on partial clinical hold following a report of persistent anemia in an adolescent patient.6 The patient is doing clinically well, with no evidence of malignancy or clonal predominance. bluebird has received written questions from the FDA and will update the public in February 2022 if they no longer expect a BLA submission in the first quarter of 2023.

“The safety of patients treated with our gene therapies is always our top priority,” Richard Colvin, MD, chief medical officer, bluebird bio said in a statement.6 “Consistent with the FDA’s direction, we have paused enrollment and treatment of patients younger than 18 in our SCD clinical program, and we will continue to work collaboratively with the FDA to understand and address their concerns.”

Meanwhile, the eli-cel program remains on hold since August 2021 following the Suspected Unexpected Serious Adverse Reaction (SUSAR) of MDS in the ALD-104 study thought to be mediated by the use of their lentiviral vector.7 Two other cases of MDS have been reported in participants treated with eli-cel and treated participants are being closely monitored.

“Eli-cel is an important potential therapeutic option for patients with CALD—a devastating neurodegenerative disease—and we are encouraged to be moving forward given the urgent unmet need for these children and their families,” Obenshain said in a previous statement.7

1. bluebird provides update on FDA review timelines for betibeglogeneautotemcel (beti-cel) for beta-thalassemia and elivaldogeneautotemcel (eli-cel) for cerebral adrenoleukodystrophy (CALD). News release. bluebird bio. January 18, 2022. https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-provides-update-fda-review-timelines-betibeglogene
2. bluebird bio Announces FDA Priority Review of Biologics License Application for beti-cel Gene Therapy for Patients with β-thalassemia Who Require Regular Red Blood Cell Transfusions. News release. bluebird bio. November 22, 2021. https://www.biospace.com/article/releases/bluebird-bio-announces-fda-priority-review-of-biologics-license-application-for-beti-cel-gene-therapy-for-patients-with-%CE%B2-thalassemia-who-require-regular-red-blood-cell-transfusions/
3. Thompson AA, Locatelli F, Yannaki E, et al. Restoring Iron Homeostasis in Pts Who Achieved Transfusion Independence after Treatment with Betibeglogene Autotemcel Gene Therapy: Results from up to 7 Years of Follow-up. Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 573.
4. 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
5. bluebird bio announces the lifting of FDA clinical hold for sickle cell disease and β-Thalassemia studies. News release. bluebird bio. June 7, 2021. https://www.businesswire.com/news/home/20210607005267/en/bluebird-bio-Announces-the-Lifting-of-FDA-Clinical-Hold-for-Sickle-Cell-Disease-and-%CE%B2-Thalassemia-Studies
6. bluebird bio Announces Partial Clinical Hold for Patients Under 18 in Sickle Cell Gene Therapy Clinical Program. News release. bluebird bio. December 20, 2021. https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-announces-partial-clinical-hold-patients-under-18
7. 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
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