The first-in-class hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor roxadustat may be a potential new treatment option for lower-risk myelodysplastic syndromes (MDS) and may alleviate the need for treatment with erythropoietin-stimulating agents (ESAs), iron overload, and blood transfusions, according to the results of a small open-label study.
The lead-in study, published in the American Journal of Hematology, tested roxadustat at three starting doses. Of the 24 patients included, more than one-third (37.5%) achieved transfusion independence for eight or more consecutive weeks within 28 weeks and at 52 weeks.
“The take-home message here for hematologists is that this new class of drugs, HIF-1 alpha stabilizers, will provide another option for treating anemic MDS patients, low-to-intermediate risk, who require transfusion,” said study author David H. Henry, MD, of the University of Pennsylvania.
According to Dr. Henry, ESAs have been a mainstay of therapy for patients with MDS and anemia with an erythropoietin (EPO) level less than 200 mIU/mL.
“ESA simply provides more stimulation to the bone marrow red cell precursors when there is not enough native EPO around,” Dr. Henry said.
Roxadustat is approved for treatment of anemia in chronic kidney disease in China, Japan, Chile, South Korea, the United Kingdom, and the European Union.
“The HIF-1 alpha stabilizers like roxadustat do two things,” Dr. Henry explained. “They actually help the kidney increase secretion of EPO, but more importantly, they decrease the inflammatory mediator hepcidin, so that the bone marrow is better able to respond to EPO stimulation.”
Based on roxadustat’s efficacy in chronic kidney disease, the phase III MATTERHORN trial was designed to test it in anemia of lower-risk MDS. Dr. Henry and colleagues reported outcomes from the open-label, lead-in, dose-selection stage of the trial.
Twenty-four patients with baseline serum EPO of 400 mIU/mL or less and low packed red blood cell transfusion burden were included.
Patients were assigned to roxadustat at a starting dose of 1.5 mg/kg, 2.0 mg/kg, or 2.5 mg/kg with eight patients in each arm. The median age of patients was 73. The majority of patients were in a low-risk category, with some considered intermediate risk (16.7%).
Of the 37.5% of patients who were transfusion independent for eight or more consecutive weeks within the first 28 weeks and at 52-week follow-up, three were started at the 1.5 mg/kg dose, one at the 2.0 mg/kg dose, and five at the 2.5 mg/kg dose.
The researchers noted that at the time of transfusion independence, seven patients were receiving the 2.5 mg/kg dose and two patients were receiving 3.0 mg/kg because they required dose escalation to become transfusion
independent.
“Different from the ESAs, this molecule will augment native EPO production and, more importantly, decrease hepcidin inflammatory effect, allowing the MDS bone marrow to respond better to EPO and decrease transfusion
requirements,” Dr. Henry said.
More than half of patients achieved a 50% or greater reduction in baseline red blood cell transfusion at 28 weeks (54.2%) and 52 weeks (58.3%). The drug was well-tolerated, the researchers reported, with no fatalities or progression to acute myeloid leukemia. Thirty-three percent of patients treated with roxadustat reported serious adverse events.
“While these data demonstrate that roxadustat increased hemoglobin in 38% of this [low risk]-MDS population, the results of the double-blind, placebo-controlled phase of this study will provide more information on the efficacy and safety of roxadustat,” the researchers wrote.
The 2.5 mg/kg dose was selected as a starting dose for the double-blind portion of the study.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Henry DH, Glaspy J, Harrup R, et al. 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 [published online ahead of print, 2021 Nov 1]. Am J Hematol. doi: 10.1002/ajh.26397.
