FDA Advisory Committee Unanimously Endorses eli-cel Gene Therapy for Cerebral Adrenoleukodystrophy

If approved, eli-cel will be the first and only gene therapy for the treatment of early active CALD, a rare neurodegenerative disease that primarily affects young children and leads to irreversible loss of neurologic function and death

PDUFA goal date is set for September 16, 2022

bluebird bio, Inc. (Nasdaq: BLUE) today announced the outcome of the U.S. Food and Drug Administration’s (FDA) Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) discussion of elivaldogene autotemcel (eli-cel) for the treatment of early active cerebral adrenoleukodystrophy (CALD) in patients less than 18 years of age who do not have an available and willing human leukocyte antigen (HLA)-matched sibling hematopoietic stem cell (HSC) donor.

On the question “Do the benefits of eli-cel outweigh the risks, for the treatment of any sub-population of children with early active cerebral adrenoleukodystrophy (CALD)?” the CTGTAC voted 15 (yes) to 0 (no).

“For decades, the CALD community has fought for the opportunity to stave off the rapid, irreversible decline associated with this devastating disease,” said Andrew Obenshain, chief executive officer, bluebird bio. “Today we are one step closer to delivering a potentially lifesaving therapy for CALD. We are grateful to the families, clinicians and committee members who participated in today’s advisory committee discussion and remain committed to working with the FDA as it completes its review of the eli-cel Biologics License Application.”

CALD is a rare, progressive, neurodegenerative disease that primarily affects young boys and causes behavioral, cognitive, and neurological deficits. Nearly half of patients who do not receive treatment die within five years of symptom onset. Allogeneic hematopoietic stem cell transplant (allo-HSCT) is currently the only effective treatment option but is associated with serious potential complications and mortality that increase in patients without a matched sibling donor. If approved, eli-cel will be the first approved gene therapy to address the underlying genetic cause of disease for patients living with CALD in the U.S. – offering the more than 70% of patients diagnosed with CALD who do not have a matched sibling donor an alternative to allo-HSCT.

The committee’s recommendation is based on the Biologics License Application (BLA) currently under priority review by the FDA with a PDUFA goal date set for September 16, 2022. The BLA for eli-cel is supported by efficacy and safety data from the completed Phase 2/3 Starbeam study (ALD-102) (N=32). Additionally, the BLA contains data for 35 subjects dosed in the Phase 3 ALD-104 study. In clinical studies, patients treated with eli-cel were more likely to achieve both overall and event-free survival than allo-HSCT patients without a matched sibling donor, with the clearest benefit for patients without a matched donor of any type.

The eli-cel clinical program was placed on a clinical hold following a Suspected Unexpected Serious Adverse Reaction (SUSAR) of myelodysplastic syndrome (MDS) in August 2021. Consistent with this known risk, two additional cases of MDS have subsequently been reported. All patients who received eli-cel in the clinical program continue to be closely monitored, per study protocols.

The CTGTAC also discussed the overall safety of lentiviral vector (LVV) gene therapies, concluding in a 13 to 1 vote that the safety data from lovo-cel for sickle cell disease is not relevant to the review of eli-cel. In addition to granting eli-cel BLA priority review, the FDA previously granted eli-cel Orphan Drug status, Rare Pediatric Disease designation, and Breakthrough Therapy designation. bluebird bio is eligible to receive a priority review voucher upon potential approval of eli-cel.

Tomorrow, June 10, 2022, the CTGTAC will convene to discuss the efficacy and safety of betibeglogene autotemcel (beti-cel), an investigational LVV gene therapy for patients with beta-thalassemia who require regular red blood cell transfusions.

About CALD

Adrenoleukodystrophy (ALD) is a rare, X-linked metabolic disorder that primarily affects males; worldwide, an estimated one in 21,000 male newborns are diagnosed with ALD. The disorder is caused by mutations in the ABCD1 gene that affect the production of adrenoleukodystrophy protein (ALDP) and subsequently leads to toxic accumulation of very long-chain fatty acids (VLCFAs), primarily in the adrenal gland and white matter of the brain and spinal cord. Approximately 40% of boys with ALD will develop CALD, the most severe form of ALD. CALD is a progressive and irreversible neurodegenerative disease that involves the breakdown of myelin, the protective sheath that nerve cells need to function effectively, especially for thinking and muscle control. The onset of symptoms of CALD typically occurs in childhood (median age 7). Early diagnosis and treatment of CALD is essential, as nearly half of patients who do not receive treatment die within five years of symptom onset.

About elivaldogene autotemcel (eli-cel) gene therapy

eli-cel (pronounced ELL ee cell) uses ex vivo transduction with the Lenti-D lentiviral vector (LVV) to add functional copies of the ABCD1 gene into a patient’s own hematopoietic stem cells (HSCs). The addition of the functional ABCD1 gene allows patients to produce the ALD protein (ALDP), which is thought to facilitate the breakdown of very long-chain fatty acids (VLCFAs). The expression of ALDP and effect of eli-cel is expected to be life-long. The goal of treatment with eli-cel is to stop the progression of CALD and, consequently, preserve as much neurological function as possible, including the preservation of motor function and communication ability. Importantly, with eli-cel, there is no need for donor HSCs from another person.

bluebird bio’s clinical development program for eli-cel includes the completed pivotal Phase 2/3 Starbeam study (ALD-102) and the ongoing Phase 3 ALD-104 study, which has completed enrollment and treatment of all patients. Additionally, bluebird bio is conducting a long-term safety and efficacy follow-up study (LTF-304) for patients who have received eli-cel for CALD and completed two years of follow-up in ALD-102 or ALD-104. Enrollment into studies of eli-cel is currently on hold with the FDA and follow-up of all patients continues, per protocol.

In ALD-102, 90.6% (29/32) of patients met the primary endpoint of Major Functional Disabilities (MFD)-free survival at 24 months. As previously reported, two patients withdrew from study ALD-102 at investigator discretion, and one additional subject experienced rapid disease progression early after treatment, resulting in MFDs and subsequent death. All patients who completed ALD-102 enrolled in a long-term follow-up study (LTF-304). The median duration of follow-up is approximately four years (49 months; 13.4, 88.1).

Adverse reactions attributed to eli-cel observed in clinical trials include myelodysplastic syndrome, viral cystitis, pancytopenia, and nausea and vomiting. There have been no reports of graft-versus-host-disease, graft failure or rejection, transplant-related mortality, or replication competent lentivirus in the 67 patients who received eli-cel in clinical studies (ALD-102, ALD-104, LTF-304).

About bluebird bio, Inc.

bluebird bio is pursuing curative gene therapies to give patients and their families more bluebird days.

With a dedicated focus on severe genetic diseases, bluebird has industry-leading clinical and research programs for sickle cell disease, beta-thalassemia and cerebral adrenoleukodystrophy and is advancing research to apply new technologies to these and other diseases. We custom design each of our therapies to address the underlying cause of disease and have developed in-depth and effective analytical methods to understand the safety of our lentiviral vector technologies and drive the field of gene therapy forward.

Founded in 2010, bluebird has the largest and deepest ex-vivo gene therapy data set in the world—setting the standard for industry. Today, bluebird continues to forge new paths, combining our real-world experience with a deep commitment to patient communities and a people-centric culture that attracts and grows a diverse flock of dedicated birds. ​

For more information, visit bluebirdbio.com or follow us on social media at @bluebirdbio, LinkedIn, Instagram and YouTube.

Lenti-D and bluebird bio are trademarks of bluebird bio, Inc.

bluebird bio Cautionary Statement Regarding Forward-Looking Statements

This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on historical performance and current expectations and projections about our future goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect bluebird bio’s business, particularly those identified in the risk factors discussion in bluebird bio’s Annual Report on Form 10-K, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. These risks and uncertainties include, but are not limited to: the risk that the efficacy and safety results from our prior and ongoing clinical trials will not continue; the risk that additional insertional oncogenic or other safety events associated with lentiviral vector, drug product, or myeloablation will be discovered or reported over time; and the risk that any one or more of our product candidates, will not be successfully developed, approved by the FDA or commercialized. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, bluebird bio undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise.

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