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FDA Pipeline: Reviews and Designations in Hematology


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Recently, the U.S. Food and Drug Administration (FDA) granted Priority Review to a gene therapy for patients with β-thalassemia, and Fast Track designation to a SETD2 inhibitor for patients with relapsed or refractory diffuse large B-cell lymphoma.

Priority Review: Betibeglogene Autotemcel for Patients With β-thalassemia Who Require Regular Red Blood Cell Transfusions

The FDA accepted a biologics license application for betibeglogene autotemcel (beti-cel) for Priority Review. Beti-cel is a gene therapy for adult, adolescent, and pediatric patients with β-thalassemia across all genotypes who require regular red blood cell transfusions. If approved, beti-cel will be the first one-time treatment that addresses the underlying genetic cause of disease for patients living with β-thalassemia in the United States—offering an alternative to regular red blood cell transfusions and iron chelation therapy. The agency has set a Prescription Drug User Fee Act goal date of May 20, 2022.

β-thalassemia is a severe genetic disease for those requiring regular red blood cell transfusions, caused by mutations in the β-globin gene, which may cause significantly reduced adult hemoglobin. This can result in severe anemia and lifelong dependence on red blood cell transfusions. While transfusions temporarily relieve symptoms associated with severe anemia, including fatigue, weakness, and shortness of breath, they do not address the underlying genetic cause of β-thalassemia and can lead to unavoidable iron overload and serious complications, including progressive multiorgan damage and organ failure.

Beti-cel is a one-time gene therapy custom-designed to treat the underlying cause of β-thalassemia in patients who require regular red blood cell transfusions. Beti-cel adds functional copies of a modified form of the β-globin gene (βA-T87Q-globin gene) into a patient’s own hematopoietic stem cells in order to correct the deficiency of adult hemoglobin that is the hallmark of β-thalassemia. Once a patient has the βA-T87Q-globin gene, they have the potential to produce beti-cel–derived adult hemoglobin at levels that may eliminate the need for transfusions. In phase III beti-cel studies, 89% of evaluable patients across all ages and genotypes, including pediatric patients as young as age 4 years and those with the most severe (β00) genotypes, achieved transfusion independence, which is defined as no longer needing red blood cell transfusions for at least 12 months while maintaining a weighted average hemoglobin of at least 9 g/dL.

Beti-cel is manufactured using the BB305 lentiviral vector, a third-generation, self-inactivating lentiviral vector that has been studied for more than a decade across multiple therapeutic areas.

The biologics license application for beti-cel is based on data from several studies: the phase III studies HGB-207 (Northstar-2) and HGB-212 (Northstar-3); the phase I/II HGB-204 (Northstar) and HGB-205 studies; and the long-term follow-up study LTF-303. Additional data through August 2021 will be presented at the 63rd American Society of Hematology Annual Meeting & Exposition, taking place December 11 to 14, 2021.

The FDA previously granted beti-cel Orphan Drug status and Breakthrough Therapy designation.

Fast Track Designation for EZM0414 in Relapsed or Refractory DLBCL

The FDA has granted Fast Track designation to EZM0414, a novel, first-in-class, oral SETD2 inhibitor, as an investigational agent for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In addition, a phase I/Ib study has been initiated to evaluate safety and determine the optimal dose of EZM0414 (ClinicalTrials.gov identifier NCT05121103). Following this dose-ranging phase, the study will be expanded to evaluate EZM0414 in three patient cohorts: t(4;14) multiple myeloma, non-t(4;14) multiple myeloma, and DLBCL.

SETD2 is a histone methyltransferase, similar to EZH2, which plays multiple important roles in oncogenesis. Data demonstrating potent preclinical in vitro and in vivo activity for a selective inhibitor of the SETD2 histone methyltransferase was shared at the 2021 European Hematology Association meeting (Abstract S176).

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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