Roxadustat Demonstrates Positive Cardiovascular Safety Profile, NDA Expected to be Filed in the U.S. This Year

Recently, AstraZeneca and FibroGen announced the pooled efficacy and cardiovascular (CV) safety analysis of roxadustat. Roxadustat is a first-in-class hypoxia-inducible factor prolyl hydroxylase inhibitor. The pooled CV safety analysis demonstrated that, in patients with non-dialysis-dependent (NDD) renal anemia, roxadustat did not increase the risk of major adverse cardiovascular events (MACE) or all-cause mortality compared with placebo. In patients with dialysis-dependent (DD) renal anemia, roxadustat did not increase the risk of MACE or all-cause mortality compared with the current standard of care, erythropoietin.

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-associated anemia gradually increase. Renal anemia is more refractory to correction than conventional anemia, leading to severe fatigue and reduced quality of life in patients. Both dialysis-dependent and non-dialysis-dependent CKD patients exhibit high morbidity and mortality rates.

Roxadustat is a first-in-class hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI). The physiological role of hypoxia-inducible factor (HIF) not only increases the expression of erythropoietin (EPO), but also upregulates the expression of EPO receptors and proteins that promote iron absorption and circulation. Roxadustat inhibits prolyl hydroxylase (PH) by mimicking one of its substrates, alpha-ketoglutarate, thereby modulating the role of PH in maintaining the balance between HIF synthesis and degradation, ultimately correcting anemia. It has been approved in China for the treatment of renal anemia in both non-dialysis-dependent and dialysis-dependent patients, and approved in Japan for the treatment of renal anemia in dialysis-dependent patients.

Efficacy data for roxadustat have been published in The New England Journal of Medicine. In the pooled cardiovascular safety analysis released today, the primary safety endpoints included all-cause mortality, time to first occurrence of major adverse cardiovascular events (MACE, defined as all-cause death, stroke, and myocardial infarction), and time to first occurrence of MACE+ (MACE plus hospitalization for unstable angina and hospitalization for congestive heart failure).

▲Key Results of Roxadustat Safety Trials (Image Source: Reference [1])

The test results indicate:

·In patients with non-dialysis-dependent renal anemia (NDD), the risks of MACE, MACE+, and all-cause mortality in the roxadustat group were similar to those in the placebo group.

·In patients with dialysis-dependent renal anemia (DD), the risks of MACE, MACE+, and all-cause mortality in the roxadustat group were similar to those in the erythropoiesis-stimulating agent group.

· Among patients who initiated dialysis within four months prior to randomization (incident dialysis patients), the roxadustat group demonstrated a 30% reduction in the risk of major adverse cardiovascular events (MACE) and a 34% reduction in the risk of MACE+ compared with erythropoiesis-stimulating agents, along with a decrease in all-cause mortality.

Dr. Mene Pangalos, Executive Vice President of BioPharmaceuticals R&D at AstraZeneca, said, “These results strengthen our confidence in roxadustat. It will help address the significant unmet medical needs of patients with renal anemia, particularly those who have recently initiated dialysis.”

References: [1] Roxadustat Phase III programme pooled analyses showed positive efficacy and no increased cardiovascular risk in patients with anaemia from chronic kidney disease. Retrieved November 8, 2019, from https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2019/roxadustat-phase-iii-programme-pooled-analyses-showed-positive-efficacy-and-no-increased-cv-risk-in-patients-with-anaemia-from-chronic-kidney-disease.html [2] The world’s first new drug for renal anemia, roxadustat, was approved first in China, marking the entry of Chinese original drugs into a new era of first-in-class innovation. Retrieved November 8, 2019, from https://www.astrazeneca.com.cn/zh/media/press-releases/2018/_1.html

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