FDA Places Clinical Hold on Bluebird Bio’s eli-cel for CALD


Bluebird Bio’s latest clinical hold follows another report of MDS in a treated patient.

The FDA has placed a clinical hold on Bluebird Bio’s elivaldogene autotemcel (eli-cel, Lenti-D™) for cerebral adrenoleukodystrophy (CALD) following a Suspected Unexpected Serious Adverse Reaction (SUSAR) of myelodysplastic syndrome (MDS) thought to be mediated by the use of their lentiviral vector.1

The patient who developed MDS was treated with eli-cel over a year ago as part of the Phase 3 ALD-104 study. Bluebird does not anticipate the hold to affect their sickle cell disease (SCD), β-thalassemia, or oncology programs, with plans to file a biologic license application (BLA) in 2021 pending the resolution of the clinical hold.

Notably, the gene therapy, marketed as Skysona, was recently approved in the European Union for pediatric patients with early CALD with an ABCD1 mutation and no matched sibling donors.

“Our hearts go out to this patient and his family, who are dealing with a challenging diagnosis,” said Nick Leschly, president and chief executive officer, Bluebird, in the company’s update. “Given what we know, we remain confident that eli-cel can offer hope for patients and families impacted by this devastating disease who have very few treatment options. We are committed to working with regulators and physicians in order to resolve this hold as soon as possible and bring this important therapy to patients in need.”

READ MORE: Long-Term Data Show No MFDs for Eli-Cel in CALD

The company’s announcement comes amid a period of restructuring and refocusing for bluebird, who said they intend to scale back operations in Europe and focus on the US market, as least partly due to struggles with marketing betibeglogene autotemcel (Zynteglo), which the company previously withdrew from Germany due to price disputes.2 The company will seek a licensing partner to allow access to their therapies in the EU. 

“Bluebird’s decision to focus on the US market is driven by the challenges of achieving appropriate value recognition and market access for Zynteglo in Europe, which makes bringing its transformative gene therapies like Zynteglo and Skysona to patients and physicians in Europe untenable for a small innovative company at this time,” Andrew Obenshain, president, severe genetic diseases, Bluebird Bio, added. “While European regulators have been innovative partners in supporting accelerated regulatory paths for these therapies, European payers have not yet evolved their approach to gene therapy in a way that can recognize the innovation and the expected life-long benefit of these products. We are committed to and hope to find a potential partner who can help us carry forward our therapies in Europe.” 

The FDA only recently lifted their previous clinical holds in June 2021 on Bluebird’s programs that use the lentiviral vector BB305, including their phase 1/2 HGB-206 and phase 3 HGB210 trials of LentiGlobin for SCD and the phase 3 Northstar-2 (HGB-207) and Northstar-3 (HGB-212) studies of Zynteglo for patients with transfusion-dependent β-thalassemia (TDT).3 

The vector was being investigated following the diagnosis of acute myeloid leukemia (AML) in a patient treated with bb1111 approximately 6 years ago in a phase 1/2 study and another SUSAR of MDS. Further investigation concluded that the MDS was a misdiagnosis and the AML was not due to the lentiviral vector.

Despite these setbacks, the company remains optimistic about the future directions of the soon-to-be bluebird bio and 2seventy bio. bluebird provided more updates of their pipeline, including beti-cel's anticipated, completed rolling BLA submission in Q3 2021 and more data presentation from the HGB-206 study of bb1111 for SCD by the end of 2021.

1. 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
2. Bluebird to withdraw Zynteglo from Germany after price negotiations failed to recognize drug’s value. News release. April 24, 2021. Accessed August 10, 2021. https://www.eversana.com/2021/04/21/bluebird-to-withdraw-zynteglo-from-germany-after-price-negotiations-failed-to-recognize-drugs-value/
3. 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
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