Roxadustat for the treatment of anemia in patients with lower‐risk myelodysplastic syndrome: Open‐label, dose‐selection, lead‐in stage of a phase 3 study

Abstract

Anemia is the predominant cytopenia in myelodysplastic syndromes (MDS) and treatment options are limited. Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor approved for the treatment of anemia of chronic kidney disease in the UK, EU, China, Japan, South Korea, and Chile. MATTERHORN is a phase 3, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of roxadustat in anemia of lower risk-MDS. Eligible patients had baseline serum erythropoietin ≤ 400 mIU/mL, and a low packed RBC transfusion burden. In this openlabel (OL), dose-selection, lead-in phase, enrolled patients were assigned to 1 of 3 roxadustat starting doses (n = 8 each): 1.5, 2.0, and 2.5 mg/kg. The primary efficacy endpoint of the OL phase was the proportion of patients with transfusion independence (TI) for ≥ 8 consecutive weeks in the first 28 treatment weeks. A secondary efficacy endpoint was the proportion of patients with a ≥ 50% reduction in RBC transfusions over an 8-week period compared with baseline. Adverse events were monitored. Patients were followed for 52 weeks. Of the 24 treated patients, TI was achieved in 9 patients (37.5%) at 28 and 52 weeks; 7 of these patients were receiving 2.5 mg/kg dose when TI was achieved. A ≥ 50% reduction in RBC transfusions was achieved in 54.2% and 58.3% of patients at 28 and 52 weeks, respectively. Oral roxadustat dosed thrice weekly was well tolerated. There were no fatalities or progression to acute myeloid leukemia. Based on these outcomes, 2.5 mg/kg was the chosen starting roxadustat dose for the ongoing double-blind study phase. | INTRODUCTIONMyelodysplastic syndromes (MDS) affect about 60 000 Americans, with an annual incidence of 4.5 per 100 000 people. [1][2][3] About 77% of patients diagnosed with MDS have a disease that is classified as lower risk (LR-MDS) at diagnosis, as defined by the revised International Prognostic Scoring System (IPSS-R) score of ≤ 3.5. [4][5][6] More than 90% of patients diagnosed with MDS have anemia at the time of their diagnosis, and over 60% of patients with MDS experience severe anemia at later stages of their disease. 7,8 Currently, there are limited anemia treatments with variable response rates approved for patients with LR-MDS in the US and EU for small subsets of LR-MDS patients. Epoetin alfa is approved in Europe for patients with LR-MDS with symptomatic anemia (hemoglobin < 10 g/dL). It was also granted orphan drug designation in the US for the study of adult patients with MDS. Red blood cell Clinical trial registration: NCT03263091.

Hypoxia and chronic kidney disease

“…Roxadustat, as a first-in-class orally administered small molecule HIF-PHI, has received approval in China, Japan, South Korea, Chile, the United Kingdom, and the European Union, although it was not approved by the USA Food and Drug Administration. 60 , 61 , 62 , 63 In addition, several other HIF-PHIs were also approved for marketing in Japan, including daprodustat, 64 vadadustat, 65 and enarodustat. 66 In a recently published meta-analysis including 2045 patients, HIF-PHIs exerted a medium to large positive effect on the haemoglobin rate for dialysis-dependent (DD) and nondialysis-dependent (NDD) CKD patients.…”

Real‐world experience with luspatercept and predictors of response in myelodysplastic syndromes with ring sideroblasts

“…Regardless, current deficit in terms of effective anti-anemia drugs in low-risk MDS, including MDS-RS, underscores an unmet need that might be addressed faster by targeting the underlying neoplastic clone 7,13,14 rather than the associated ineffective erythropoiesis. 15,16 The latter approach has proven more successful in anemias associated with beta-thalassemia. 17…”

Clinical Potential of Hypoxia Inducible Factors Prolyl Hydroxylase Inhibitors in Treating Nonanemic Diseases

“…In addition to CKD anemia, a phase 3 study was carried out to assess the efficacy and safety of roxadustat in patients with low-risk myelodysplastic syndrome recently obtained preliminary satisfactory results in reducing transfusions ( Henry et al, 2021 ). More immature but promising therapeutic strategies are under consideration and tested in preclinical studies, which will be discussed in detail hereinafter.…”