Roxadustat Phase 3 Trial for Anemia in Lower-Risk MDS Receives FDA Go-Ahead

The development of roxadustat (Evrenzo) has taken a significant step forward for the treatment of anemia in patients with lower-risk myelodysplastic syndromes (LR-MDS) who have a high red blood cell (RBC) transfusion burden.¹ Following a positive Type C meeting with the US FDA, FibroGen, the sponsor, plans to submit a phase 3 trial protocol in the fourth quarter of 2025. This milestone signals a clear regulatory path for the oral hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor in a patient population with a substantial unmet medical need.

“We are very pleased with the feedback we received from the FDA regarding roxadustat in patients with LR-MDS and anemia with high transfusion burden. This indication, despite recent approvals, still represents a patient population with significant unmet need,” said Thane Wettig, CEO of FibroGen, in a press release. “We believe roxadustat’s differentiated mechanism of action, favorable tolerability profile, and oral route of administration can potentially be an important addition to the treatment options for patients with high transfusion burden.”

Background and Clinical Rationale

Anemia is a hallmark of LR-MDS, a group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis. The resulting cytopenias, particularly anemia, lead to a high dependency on blood transfusions, which significantly impacts quality of life, increases healthcare costs, and carries risks such as iron overload. Current treatment options for transfusion-dependent LR-MDS patients are limited, often consisting of injectable agents like erythropoiesis-stimulating agents (ESAs) or luspatercept (Reblozyl), which may be ineffective or have undesirable side effects. The potential of an oral, non-ESA treatment like roxadustat, which is currently FDA-approved to treat anemia associated with chronic kidney disease, to reduce transfusion burden represents a critical therapeutic advance.

Roxadustat's mechanism of action is distinct from ESAs. As a HIF-PH inhibitor, it stabilizes the HIF transcription factor, which in turn upregulates the expression of erythropoietin and other genes involved in erythropoiesis and iron metabolism. This mimics the body's natural response to hypoxia, promoting the production of RBCs in a manner more aligned with physiological processes.

The FDA's willingness to support a new phase 3 trial is based on a compelling post hoc subgroup analysis of the MATTERHORN phase 3 trial that showed promising efficacy in this specific patient group. In that analysis, 36% of LR-MDS patients with high transfusion burden treated with roxadustat achieved transfusion independence for at least 56 days, compared with only 7% of those on placebo.²

Trial Design and Regulatory Alignment

The planned phase 3 trial will be a randomized, double-blind, placebo-controlled study enrolling approximately 200 patients.¹ The FDA and FibroGen have reached an agreement on several key design elements, which reduces risk in the development pathway. The patient population will be defined as adult patients with LR-MDS (IPSS-R very low, low, or intermediate risk) who are either refractory to or ineligible for ESAs and have a high transfusion burden. This focused approach is intended to demonstrate a clear treatment effect in those most in need.

The primary end point for the trial will be an 8-week or 16-week RBC transfusion independence, a clinically meaningful outcome that directly addresses the core challenge of transfusion dependency in LR-MDS. The trial design also incorporates a safety monitoring plan, particularly for potential thrombotic risk, which has been a consideration with some other erythropoiesis-promoting agents. This careful attention to both efficacy and safety reflects a commitment to providing a treatment that is not only effective but also well-tolerated in a vulnerable patient population.

The upcoming submission of the phase 3 protocol in Q4 2025 and the subsequent initiation of the trial will be closely watched by the hematology and oncology community. The potential approval of roxadustat for this indication could offer another much-needed oral alternative for patients struggling with transfusion dependency, potentially improving their quality of life and clinical outcomes.

REFERENCES:

1. FibroGen Announces Positive Type C Meeting with the FDA for Roxadustat in Patients with Anemia Associated with Lower-Risk Myelodysplastic Syndromes. News release. FibroGen Inc. August 7, 2025. Accessed August 7, 2025. https://tinyurl.com/y99sw8nf

2. 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. 2024 Sep;99(9):1778-1789. doi: 10.1002/ajh.27410. Epub 2024 Jun 17.