Sponsor Terminates MATTERHORN Trial of Roxadustat for Low-Risk MDS

A new phase 3 study of roxadustat (Evrenzo; Astellas Pharma) in patients with lower-risk myelodysplastic syndrome (MDS) failed to achieve a statistically significant improvement in transfusion independence compared with placebo.

However, the authors of the MATTERHORN trial (NCT04592913) say the results still suggest the therapy may offer meaningful help for certain subgroups of patients. The study was published in the American Journal of Hematology.¹

Roxadustat is an oral hypoxia-inducible factor-prolyl hydroxylase inhibitor that has been approved in some countries to treat symptomatic anemia in adults with chronic kidney disease. The drug works by improving hemoglobin concentrations and inducing erythropoiesis.

The study authors note that the easy administration of roxadustat makes it an attractive potential option for patients with lower-risk MDS, only about half of whom respond to first-line erythropoiesis-stimulating agents (ESAs) and most of whom will relapse even if they respond. Luspatercept (Reblozyl; Bristol Myers Squibb) and lenalidomide (Revlimid; Celgene/Bristol Myers Squibb) have both been found to improve transfusion independence in some patients with MDS, but both are only approved for certain subsets of patients.

“Therefore, effective anemia treatments are still needed for patients unresponsive or refractory to first-line options,” the authors said.

In an earlier, phase 2/3 MATTERHORN trial, investigators found roxadustat to be well tolerated and effective in some patients with ESA-naïve or ESA-refractory, red blood cell–dependent lower- or intermediate-risk MDS. In that open-label study, about one-third of patients achieved transfusion independence.²

The new phase 3 study followed up on those results, this time with a randomized, double-blind trial design pitting roxadustat against placebo. To qualify for the study, patients had to be diagnosed with very low–, low-, or intermediate-risk MDS and have a transfusion burden of 1 to 4 packed red blood cell units every 8 weeks. The study included both patients with and without prior ESA treatment. Participants were randomized on a 3:2 basis, with 82 patients receiving 2.5 mg/kg of roxadustat 3 times per week and 58 patients receiving placebo on the same schedule. Participants were considered “transfusion-independence responders” if they met the study’s primary end point, which was transfusion independence for at least 8 weeks within 28 weeks.

The MATTERHORN trial was halted after roxadustat failed to produce statistically significant improvements in patients | Image Credit: Parilov-stock.adobe.com

About half (47.5%) of patients in the roxadustat arm and one-third (33.3%) of patients in the placebo arm met the transfusion-independence benchmark, the investigators said. However, those data did not achieve statistical significance (P = .217), prompting the trial’s sponsor to terminate the trial. In addition, the authors said 3 patients in the roxadustat arm progressed to acute myeloid leukemia, and 7 patients (4 in the roxadustat arm and 3 in the placebo arm) died during the trial for reasons deemed unrelated to treatment.

The investigators noted that patients with a higher baseline transfusion burden of at least 2 packed red blood cell units every 4 weeks had higher rates of treatment independence responses compared with the placebo group (36.1% vs. 11.5%; nominal P = .047). Other factors, such as ESA-refractory status or having MDS-ring sideroblasts did not affect patient outcomes, the authors said.

The investigators said one potential reason for the lack of a statistically significant benefit in the roxadustat group was the 8-week screening period used to assess baseline transfusion burden. Following the study’s initiation, the International Myeloma Working Group released new guidelines recommending a 16-week screening period. The investigators said it is possible that some patients assessed within 8 weeks of enrollment had a lower transfusion burden than was estimated. They noted that none of the 10 transfusion-independence responders in the placebo group maintained the transfusion burden criteria with 52 weeks of placebo treatment.

“This suggests that these patients may not have met the transfusion-dependence eligibility criteria if the screening period were extended to 16 weeks and/or may not have progressed to transfusion dependence,” they wrote.

They said despite failing to achieve the desired results, the data show that roxadustat was well tolerated and that it can help some patients, particularly those with a high transfusion burden. However, they said the findings also show that there is still a considerable unmet need for safe and effective therapies that reduce the transfusion burden for this patient group and that further analysis is warranted to better understand if roxadustat should have a role in filling that gap.

References

1. Mittelman M, Henry DH, Glaspy JA, et al. Roxadustat versus placebo for patients with lower-risk myelodysplastic syndrome: MATTERHORN phase 3, double-blind, randomized controlled trial. Am J Hematol. Published online June 17, 2024. doi:10.1002/ajh.27410

2. 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. Am J Hematol. 2022;97(2):174-184. doi:10.1002/ajh.26397