The FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee voted unanimously in favor of the benefit of betibeglogene autotemcel (beti-cel; Zynteglo) for the treatment of transfusion-dependent β-thalassemia (TDT) in adult and pediatric patients with a non–β

Calling the efficacy of the drug “remarkable” and “life-changing,” the 13-member committee expressed support of the long-term benefit of the gene therapy ahead of beti-cel’s Prescription Drug User Fee Act (PDUFA) date of August 19, 2022.

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

Beti-cel is currently being evaluated in the phase 3 HGB-207 trial (NCT02906202). Recent results published in the

 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.

In June 2021, the FDA lifted a previous clinical hold on bluebird’s programs using the lentiviral vector (LVV) BB305, including their phase 1/2 HGB-206 trial (NCT02140554) and phase 3 HGB210 trial (NCT04293185) of beti-cel for sickle cell disease and the phase 3 HGB-207 and phase 3 HGB-212 trial (NCT03207009) of beti-cel for patients with transfusion-dependent β-thalassemia.

The vector was investigated following an unexpected adverse reaction of acute myeloid leukemia (AML) reported in a patient treated with beti-cel approximately 6 years ago. In March 2021, it was announced that it was very unlikely that the effect was related to the agent. In April 2021, the company announced a revised diagnosis for the previously reported case of myelodysplastic syndrome (MDS) in the phase 1/2 study; further investigation revealed that the case was not MDS, but transfusion-dependent anemia.

“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, stated in the committee’s opinions on the risk of hematologic malignancies with beti-cel compared with elivaldogene autotemcel (eli-cel; Skysona).

“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 even though there are great difficulties and challenges,” said John F. DiPersio, MD, PhD, chief of the Division of Oncology at the Washington University School of Medicine in St. Louis.

FDA concerns have mainly included unknown risks with the LVV after suspected unexpected serious adverse effects of MDS in the phase 3 ALD-104 study (NCT03852498) of eli-cel, which is currently on clinical hold.

 Although both eli-cel and beti-cel both use LVVs, the panel concluded that the LVVs are distinct and separate during the meeting.

Cellular, Tissue, and Gene Therapies Advisory Committee June 9-10, 2022 Meeting Announcement. FDA. June 9, 2022. Accessed June 13, 2022. 

Beaudoin FL, Richardson M, Synnott PG, et al. Betibeglogene autotemcel for beta thalassemia: effectiveness and value. ICER. June 2, 2022. Accessed June 13, 2022. 

Locatelli F, Thompson AA, Kwiatkowski JL, et al. Betibeglogene autotemcel gene therapy for non–β0/β0 genotype β-thalassemia. 

. 2022;386(5):415-427. doi:10.1056/NEJMoa2113206

bluebird bio announces the lifting of FDA clinical hold for sickle cell disease and β-thalassemia studies. News release. bluebird bio. June 7, 2021. Accessed June 13, 2022. 

bluebird bio reports second quarter financial results and provides operational update. News release. bluebird bio. August 9, 2021. Accessed June 13, 2022. 

Articles

The FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee voted unanimously in favor of the benefit of betibeglogene autotemcel for the treatment of transfusion-dependent β-thalassemia in adult and pediatric patients with a non–β0/β0 genotype.

Victoria Johnson

Articles

FDA Panel Gives Beti-Cel Unanimous Support of Benefit in β-thalassemia