Beta-thalassemia - Emerging treatments

Gene therapy: lentiviral vectors

The self-inactivating LentiGlobin® vector carries a gene encoding adult HbA with a single point mutation. In two phase I/II open-label studies, autologous CD34+ cells were obtained from 22 patients with transfusion dependent beta-thalassemia. Patients underwent myeloablative conditioning and, following ex vivo transduction of LentiGlobin® into the CD34+ T cells, the cells were infused into patients. At a median of 26 months follow up, gene therapy had reduced or eliminated the need for long-term transfusion.[64] LentiGlobin® has been granted a marketing authorization by the European Medicines Agency, and has been granted fast track designation by the Food and Drug Administration. A phase I and II study of autologous CD34+ T cells transduced with the GLOBE lentiviral vector (OTL-300) is also underway (NCT03275051).

Other gene therapy approaches

Include coregulation of globin transgene expression and RNA interference, globin gene transfer by homologous recombination, gene transfer of the hepcidin gene (HAMP) to reduce intestinal iron absorption, and the use of antisense mRNA.[65][66][67][68][69] Studies are ongoing.

Activin trap agents to promote effective erythropoiesis

Luspatercept is a recombinant fusion protein containing a modified extracellular domain of the activin receptor type IIB (ActRIIB). It binds to GDF11 and other ligands, inhibits Smad 2/3 signaling, and promotes late-stage erythroid differentiation, thus ameliorating ineffective erythropoiesis. Luspatercept reduced the need for red blood cell transfusion in a phase III, double-blind, randomized trial of patients with beta-thalassemia who need regular transfusion.[70] 21.4% of patients in the luspatercept group and 4.5% of patients in the placebo group achieved the primary endpoint of a ≥33% reduction in red blood cell transfusion over weeks 13-24, compared with baseline weeks 0-12. The reduction in red blood cell transfusion in the luspatercept group was sustained over weeks 24-48 of the study. 58% of patients in each group had undergone a splenectomy. The FDA approved luspatercept for the treatment of anemia in adults with transfusion dependent beta-thalassemia in November 2019, and the European Medicines Agency granted marketing authorization in April 2020.[71][72]

Hepcidin mimetics

Ineffective erythropoiesis and, to a lesser degree, anemia result in downregulation of expression of hepcidin and enhanced absorption of iron from the intestine in patients with beta-thalassemia.[17] PTG-300, an injectable hepcidin mimetic, has been granted Orphan Drug Designation by the FDA for development in the treatment of beta-thalassemia. A phase I study demonstrated a reduction in serum iron and transferrin saturation and a phase II trial is underway (NCT04054921).

Stimulation of hemoglobin F production

Hydroxyurea may increase hemoglobin levels in patients with non-transfusion-dependent thalassemias, including beta-thalassemia intermedia and Hb E beta-thalassemia, but there is no robust evidence that hydroxyurea has any effect on reducing the need for transfusions in these patients.[73] Neither azacitidine, erythropoietin, butyrate derivatives, nor hemin, as monotherapy or in combination, has been shown to be consistently efficacious in patients with beta-thalassemia intermedia with adequate erythropoiesis.[62][74]