Roxadustat (Evrenzo) Demonstrates Non-Inferiority to Darbepoetin Alfa in Phase 3 DOLOMITES Study for Anemia in Non-Dialysis-Dependent CKD Patients

June 08, 2020 /BioValleyBIOON/ -- Astellas recently announced positive results from the Phase III DOLOMITES study. The study was conducted in adult patients with non-dialysis-dependent (NDD) Stage 3-5 chronic kidney disease (CKD) and is evaluating Evrenzo (Chinese brand name: Airuizhuo; generic name: roxadustat) versus darbepoetin alfa for treatmentAnemiaefficacy and safety. Data showed that Evrenzo was non-inferior to darbepoetin alfa in correcting hemoglobin levels during the first 24 weeks of treatment (89.5% vs. 78.0%; difference = 11.5% [95% CI: 5.66%, 17.36%]), meeting the primary endpoint with a lower bound of the 95% CI > 0.

The secondary endpoints were non-inferiority and superiority in stratified tests. The data showed that Evrenzo was superior to darbepoetin alfa in terms of low-density lipoprotein cholesterol (LDL-C) reduction (least squares mean [LSM] difference = -0.403 mmol/L; 95% CI: -0.510, -0.296; p < 0.01) and time to first intravenous iron administration (hazard ratio [HR] = 0.45; 95% CI: 0.26, 0.78; p = 0.004); for mean arterial pressure (LSM difference = -0.372 mmHg; 95% CI: -1.587, 0.842) andHypertensionIn terms of time to event (HR=0.83; 95% CI: 0.56, 1.22), Evrenzo was non-inferior to darbepoetin alfa. Regarding safety, the overall incidence of treatment-emergent adverse events (TEAEs) was comparable between Evrenzo and darbepoetin alfa (91.6% vs 92.5%). An unconfirmed analysis of adjudicated major adverse cardiovascular events (MACE)/MACE+ (MACE plus hospitalization for unstable angina and hospitalization for congestive heart failure) outcomes yielded HR estimates of 0.81 (95% CI: 0.52, 1.25) and 0.90 (95% CI: 0.61, 1.32), respectively.

Dr. Jonathan Barratt, Professor of Nephrology at the University of Leicester in the United Kingdom, stated: “The goal of treating anemia in chronic kidney disease (CKD) is to raise and stabilize hemoglobin levels; however, up to half of patients with CKD-related anemia have hemoglobin levels outside the recommended target range, often experiencing debilitating symptoms that make daily activities extremely challenging. The results of the DOLOMITES study demonstrated that Evrenzo can correct and maintain hemoglobin levels for up to two years in non-dialysis-dependent patients with anemia associated with CKD.”

Dr. Bernhardt G. Zeiher, Chief Medical Officer of Astellas, stated: “The DOLOMITES study data add to the substantial body of evidence demonstrating the efficacy of Evrenzo in adult patients with anemia associated with chronic kidney disease (CKD) who are not dependent on dialysis, this time compared against an active comparator, darbepoetin alfa. This study was designed to evaluate the novel mechanism of action of Evrenzo in correcting and maintaining hemoglobin levels, reinforcing Astellas’ commitment to translating innovative science into patient value and addressing unmet medical needs and complications arising from anemia in CKD patients.”

Renal anemia is one of the major complications during the decompensated phase of renal function in chronic kidney disease (CKD). As CKD progresses, the prevalence and severity of CKD-related anemia gradually increase. Renal anemia is more difficult to correct than conventional anemia, leading to severe fatigue and reduced quality of life in patients. Currently, the standard treatment for renal anemia involves erythropoietin (EPO hormone) replacement therapy using erythropoiesis-stimulating agents (ESAs), such as epoetin alfa, combined with intravenous iron supplementation administered via subcutaneous injection. This approach aims to increase hemoglobin (Hb) levels in CKD patients and improve clinical symptoms.

The active pharmaceutical ingredient of Evrenzo is roxadustat, an oral hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) inhibitor. Roxadustat increases hemoglobin levels through a mechanism of action distinct from that of erythropoiesis-stimulating agents (ESAs). As an HIF-PH inhibitor, roxadustat activates the body’s natural protective response to decreased oxygen levels in the blood. This response involves the regulation of multiple complementary processes, promoting coordinated erythropoiesis and enhancing the oxygen-carrying capacity of the blood.

Roxadustat was discovered by FibroGen, andAstraZenecaCollaborative development in the United States, China, and other markets; collaborative development with Astellas in Japan and the European Union.

In December 2018, roxadustat (brand name: Evrenzo) was first approved in China for the treatment of anemia in patients with chronic kidney disease (CKD) on dialysis. In August 2019, the drug received approval in China for a new indication: the treatment of anemia in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD). As a global first-in-class novel drug, roxadustat was first comprehensively applied in China to treat anemia in both dialysis-dependent and non-dialysis-dependent CKD patients, bringing a groundbreaking therapeutic advancement to the broad population of Chinese patients with chronic kidney disease.

In Japan, roxadustat has been approved for the treatment of dialysis-dependent patients, and a supplemental application for the treatment of non-dialysis-dependent patients has been submitted. In the United States and Europe, marketing applications for roxadustat for the treatment of both dialysis-dependent and non-dialysis-dependent patients are under regulatory review.

Roxadustat is the first small-molecule hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) approved globally for the treatment of renal anemia. The physiological role of hypoxia-inducible factor (HIF) not only increases erythropoietin expression but also upregulates the expression of erythropoietin receptors and proteins that promote iron absorption and circulation. Roxadustat inhibits prolyl hydroxylase (PH) by mimicking one of its substrates, α-ketoglutarate, thereby modulating the role of PH in maintaining the balance between HIF synthesis and degradation, ultimately correcting anemia.

As the world’s first HIF-PHI, roxadustat promotes the production of endogenous erythropoietin, improves iron absorption and utilization, reduces hepcidin levels, and effectively stimulates erythropoiesis without being adversely affected by inflammation on hemoglobin and red blood cell production. Roxadustat has been confirmed to induce erythropoiesis. In multiple subgroups of patients with chronic kidney disease, roxadustat maintains erythropoietin levels at or near the normal physiological range, thereby increasing red blood cell counts. It remains effective regardless of inflammatory status and can also avoid the need for intravenous iron supplementation. (Bioon.com)

Original Source: Roxadustat Demonstrates Non-Inferiority to Darbepoetin in Phase 3 DOLOMITES Study of Anemia in Non-Dialysis-Dependent Adult Patients with Chronic Kidney Disease