Alpha-thalassemia - Emerging treatments

Betibeglogene autotemcel

Gene therapy with betibeglogene autotemcel involves transducing hematopoietic stem cells (HSCs) with lentiglobin BB305 lentiviral vector containing a functional beta-globin gene and beta-globin regulatory elements. In a phase 3 clinical trial, treatment with betibeglogene autotemcel resulted in transfusion independence for 20 of 22 evaluable patients, including patients <12 years, with an acceptable safety profile.[110] The US Food and Drug Administration (FDA) has approved betibeglogene autotemcel for children ≥4 years of age and adults with transfusion-dependent beta-thalassemia. The European Medicines Agency (EMA) withdrew the marketing authorization for the product in 2022 at the request of the manufacturer for commercial reasons.

In utero hematopoietic stem cell (HSC) transplantation

The University of California, San Francisco (UCSF) is conducting a phase 1 study to evaluate the safety and feasibility of in utero HSC transplantation in fetuses with alpha-thalassemia major.[111] HSCs are collected from the mother and transplanted at the same time as intrauterine red blood cell transfusion (currently the only treatment option for fetal alpha-thalassemia major) to reduce procedural risk. In utero transplantation harnesses the developing fetal immune system to induce tolerance to the HSCs without the need for conditioning or immunosuppression.

Pyruvate kinase activators

Mitapivat and etavopivat are oral small molecule pyruvate kinase activators. In a phase 2 clinical trial of mitapivat in adults with non-transfusion-dependent thalassemia, all 5 (100%) individuals with alpha-thalassemia and 11 of 15 (73%) individuals with beta-thalassemia had a hemoglobin response.[112] The most common treatment-emergent adverse events were initial insomnia, dizziness, and headache.[112] The FDA has granted orphan drug designation to mitapivat for the treatment of thalassemia; phase 3 trials are ongoing. A second investigational pyruvate kinase activator, etavopivat, is being studied in a phase 2 trial for transfusion-dependent and non-transfusion-dependent thalassemia, including alpha-thalassemia.[113]

Luspatercept

A recombinant fusion protein containing a modified extracellular domain of the activin receptor type IIB (ActRIIB), luspatercept ameliorates ineffective erythropoiesis. Luspatercept reduced the need for transfusion in a phase 3, double-blind, randomized trial of patients with beta-thalassemia who need regular transfusion.[114] Luspatercept is approved in the US and Europe for the treatment of anemia in patients with transfusion-dependent beta-thalassemia. Clinical trials investigating luspatercept for non-transfusion-dependent beta-thalassemia reported a rise in hemoglobin level of at least 1 g/dL in 77% of treated individuals.[115] Its potential in alpha-thalassemia has yet to be explored.