Phase 2a randomized study to evaluate sapablursen in patients with non-transfusion dependent β-thalassemia intermedia

Non-transfusion-dependent b-thalassemia intermedia (NTDT) is a genetically heterogeneous disorder characterized by decreased β-globin production in erythroid cells resulting from mutations in the β-globin gene that is not treated with transfusion. NTDT is further characterized by a relative excess of a-globin which drives ineffective erythropoiesis resulting in increased iron absorption and ultimately iron overload. Sapablursen is an antisense oligonucleotide (ASO) that reduces the production of transmembrane protease serine 6 (TMPRSS6) and increases hepcidin production. This phase 2a study evaluated the safety, pharmacokinetics, and efficacy of sapablursen in patients with NTDT. Eligible patients had a clinical diagnosis of NTDT with genotypic confirmation of b-globin gene mutations. Twenty-nine patients with NTDT were treated with sapablursen at doses ranging from 30 to 160 mg once every 4 weeks (Q4W) for up to 2 years. Sapablursen was generally safe and well-tolerated. The study did not meet its primary or secondary endpoints of increased blood hemoglobin or reduced liver iron content (LIC). In earlier studies, including a phase 1 trial in healthy volunteers and a phase 2 trial in patients with polycythemia vera, sapablursen produced dose-dependent increases in serum hepcidin levels. However, in patients with non-transfusion-dependent thalassemia (NTDT), similar doses and exposures did not lead to consistent dose-dependent increases in serum hepcidin.. LIC and serum erythroferrone were elevated at baseline and throughout the current study. These two factors may prevent the elevation of serum hepcidin via the TMPRSS6 pathway. The companion article by Zhang et al. explores this mechanism in a mouse model of NTDT. Trial Registration Number: NCT04059406.