Bluebird Bio's Beti-Cel Gains Unanimous Support of Benefit in β-thalassemia


The FDA's Cellular, Tissue, and Gene Therapies Advisory Committee again voted in favor of the risk-benefit of bluebird bio's gene therapy candidate.

The FDA Cellular, Tissue, and Gene Therapies Advisory Committee has again cast a unanimous vote in favor of the benefit of bluebird bio’s betibeglogene autotemcel (beti-cel; LentiGlobin) for the treatment of transfusion-dependent β-thalassemia (TDT) in adult and pediatric patients with a non–β0/β0 genotype ahead of its Prescription Drug User Fee Act (PDUFA) date of August 19, 2022.1 

Calling the efficacy of the drug "remarkable" and "life-changing," the 13 voting committee members expressed clear support of the long term benefit of the gene therapy with a unanimous "yes" vote, with zero no votes and no abstentions.

This is the second vote of confidence for bluebird bio's gene therapy candidates this week, as the committee also cast a unanimous vote yesterday in support of the company's candidate for the treatment of early active cerebral adrenoleukodystrophy (CALD), elivaldogene autotemcel (eli-cel; Lenti-D).

The Institute for Clinical and Economic Review (ICER) recently gave beti-cel a rating of B+, concluding that therapy is superior to standard of care for patients with β-thalassemia, but the magnitude of this superiority is still uncertain due to known risks with myeloablative conditioning and unknown durability.2

Beti-cel is currently being evaluated in the phase 3 HGB-207 study (NCT02906202). Recent results published in the New England Journal of Medicine found that treatment with beti-cel produced transfusion independence in 20 of 22 evaluable patients (91%), including 6 of 7 patients (86%) younger than 12 years of age.3

The FDA lifted a previous clinical hold in June 2021 on Bluebird’s programs that use the lentiviral vector (LVV) 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 TDT.4

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 suspected unexpected serious adverse reaction (SUSAR) of myelodysplastic syndrome. Further investigation concluded that the MDS was a misdiagnosis and the AML was not due to the lentiviral vector.

"Different disease states, different vectors, and the lack of evidence of insertional mutagenesis to date, makes this less of a concern," meeting chair Lisa Butterfield, PhD, Vice President, Research and Development, Parker Institute for Cancer Immunotherapy, summarized the committee's opinions on the risk of hematologic malignancies with beti-cel compared to eli-cel.

"The clinical benefit seems to be quite significant. But the bar is also a little bit higher here because these patients can live with their disease for quite a period of time even though there are great difficulties and challenges," John F. DiPersio, MD, PhD, chief of oncology, Washington University School of Medicine in St. Louis.

FDA concerns have mainly included unknown risks with the LVV after SUSARs of MDS in the ALD-104 study of elivaldogene autotemcel (eli-cel; Lenti-D), which is currently on clinical hold.5 Although both eli-cel and beti-cel both use LVVs, the panel concluded that the LVVs are distinct and separate during the meeting.

1. Cellular, Tissue, and Gene Therapies Advisory Committee June 9-10, 2022. Meeting. FDA. June 10, 2022.
2. Beaudoin FL, Richardson M, Synnott PG, et al. Betibeglogeneautotemcel for beta thalassemia: Effectiveness and value; evidence report. ICER, June 2, 2022.
3. Locatelli F, Thompson AA, Kwiatkowski JL, et al. Betibeglogeneautotemcelgenetherapy for non–β0/β0 genotype β-thalassemia. N Eng J Med. 2022; 386:415-427. doi: 10.1056/NEJMoa2113206
4. bluebird bio announces the lifting of FDA clinical hold for sickle cell disease and β-Thalassemia studies. News release. bluebird bio. June 7, 2021.
5. bluebird bio reports second quarter financial results and provides operational update. News release. bluebird bio. August 9, 2021
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