Safety and pharmacodynamics of the ferroportin inhibitor vamifeport in patients with non-transfusion-dependent β-thalassemia: results from a randomized phase 2a study

Background Non-transfusion-dependent beta-thalassemia (β-NTDT) is characterized by ineffective erythropoiesis, increased intestinal iron absorption, and iron overload. The ferroportin inhibitor, vamifeport, has been shown to improve erythropoiesis via decreases in serum iron and transferrin saturation levels in preclinical models and healthy volunteer studies. Objective The objective of this 12-week, double-blind, randomized, placebo-controlled, phase 2a study was to assess the safety and tolerability of vamifeport versus placebo in adults with β-NTDT (primary endpoint). Iron-related pharmacodynamic effects (preliminary efficacy) were also assessed as a secondary endpoint. Methods Randomized, adult patients weighing 40–59 kg and 60–100 kg received vamifeport 60 mg and 120 mg (once [QD] or twice [BID] daily), respectively, for 12 weeks. Non-transfusion-dependent thalassemia was defined as transfusion requirements < 5 units of red blood cells during the 24 weeks before randomization. Results Twenty-five patients were included (vamifeport QD n = 9, BID n = 12; placebo n = 4); 64% were male and 56% weighed < 60 kg. Baseline serum iron and transferrin saturation levels were similar across treatment groups. All treatment-emergent adverse events were mild/moderate, and rates were similar across groups (vamifeport QD 67%, BID 58%; placebo 75%). There were no deaths or serious treatment-emergent adverse events and no clinically relevant changes in safety parameters. Serum iron and transferrin saturation levels decreased by 2 h after the first vamifeport dose (mean [standard deviation] decreased QD − 12.2 [6.5], BID − 14.5 [12.1] µmol/L and QD − 33.6 [18.9], BID − 37.2 [27.6] %, respectively) and remained below baseline levels at each subsequent visit. There were no clinically meaningful changes in the placebo group. Conclusion In this 12-week study, vamifeport had a favorable safety/tolerability profile, with no changes in hemoglobin levels ≥ 1.0 g/dL, and promising pharmacodynamic effects versus placebo in adults with β-NTDT. Trial registration ClinicalTrials.gov, NCT04364269. Registered 01 April 2020; Prospectively registered, https://clinicaltrials.gov/study/NCT04364269?term=NCT04364269&rank=1 .