Roxadustat Demonstrates Cardiovascular Safety in Global Phase III Program, Supporting Regulatory Submissions in the US and EU

Recently, AstraZeneca and its partner FibroGen announced the top-line results of a pooled cardiovascular (CV) safety analysis from the global Phase III program for roxadustat, a novel anemia treatment. The program enrolled patients from more than 50 countries worldwide and evaluated the efficacy and safety of roxadustat for the treatment of anemia in patients with chronic kidney disease (CKD), including those who are non-dialysis-dependent (NDD), incident dialysis (ID), and dialysis-dependent (DD).

Pooled cardiovascular assessment is part of the overall benefit/risk evaluation of roxadustat. For the New Drug Application (NDA) to be submitted to the U.S. Food and Drug Administration (FDA), one of the key safety endpoints requires a pooled analysis of pivotal Phase III studies to evaluate the major adverse cardiac events (MACE) associated with roxadustat compared with placebo in patients with non-dialysis-dependent (NDD) chronic kidney disease, and compared with the standard-of-care erythropoiesis-stimulating agent (ESA), epoetin alfa, in patients with dialysis-dependent (DD) chronic kidney disease. For the Marketing Authorization Application (MAA) to be submitted to the European Medicines Agency (EMA), the key safety assessment is MACE+, a composite endpoint consisting of MACE, heart failure requiring hospitalization, and unstable angina requiring hospitalization.

Thomas B. Neff, CEO of FibroGen, Inc., expressed strong satisfaction with the favorable results from the MACE and MACE+ analyses in patients with DD-, ID-, and NDD-CKD, which support the safety profile of roxadustat in CKD patients. The company is currently preparing regulatory submission dossiers for roxadustat to the U.S. and European Union authorities.

• MACE/MACE+ Outcomes in Different Patient Populations

• DD-CKD Patients

In a pooled analysis of approximately 4,000 dialysis patients, the upper bound of the 95% confidence interval (CI) for the time to first MACE+ event was below the prespecified non-inferiority margin. Based on the MACE safety analysis in this patient population, there was no clinically meaningful difference in MACE risk between roxadustat and epoetin alfa.

• Patients with ID-CKD

The Phase III roxadustat program enrolled more than 1,500 patients with incident dialysis-dependent chronic kidney disease (ID-CKD), a subgroup of the dialysis-dependent CKD (DD-CKD) population, providing a more favorable comparative setting than the stable dialysis population, which exhibits stability in both dialysis and erythropoiesis-stimulating agent (ESA) use. Data showed that, in the ID-CKD population, roxadustat was superior to alfaepoetin in terms of time to first major adverse cardiovascular event plus (MACE+). In the MACE analysis, roxadustat demonstrated a trend toward risk reduction compared with alfaepoetin.

• NDD-CKD Patients

In a pooled analysis of approximately 4,300 non-dialysis patients, roxadustat demonstrated non-inferiority compared with placebo in time to first occurrence of MACE+, as the upper bound of the 95% confidence interval was below the prespecified non-inferiority margin. Based on the MACE safety analysis in this population, there was no clinically meaningful difference in MACE risk between roxadustat and placebo.

Currently, multiple MACE and MACE+ analyses are being conducted on NDD-CKD from the Roxadustat Phase III program within the intention-to-treat (ITT) analysis framework. In the ITT analysis, Roxadustat has been demonstrated to be comparable to placebo. In these analyses, based on the commonly used non-inferiority margin of 1.3, Roxadustat was found to be comparable to placebo.

Mene Pangalos, Executive Vice President of BioPharmaceuticals R&D at AstraZeneca, stated that the results announced this time add to the positive evidence supporting the use of roxadustat for the treatment of anemia in patients with chronic kidney disease (CKD), following the achievement of primary efficacy endpoints in the OLYMPUS and ROCKIES studies last December.

AstraZeneca and FibroGen plan to submit an NDA to the FDA in the second half of 2019.

• World’s First Novel Drug for Renal Anemia Approved in China, with Annual Peak Sales Potentially Reaching $4–5 Billion

▲ Molecular structure of roxadustat (Image source: Wikimedia)

It is estimated that chronic kidney disease (CKD) affects over 200 million people worldwide, with its prevalence increasing significantly over time and being more common in the aging population. Anemia is a common complication of CKD; as the disease progresses, both the prevalence and severity of CKD-related anemia gradually increase. The current standard of care involves erythropoietin (EPO) replacement therapy using erythropoiesis-stimulating agents (ESAs), such as epoetin alfa, combined with intravenous iron administered via subcutaneous injection, to raise hemoglobin (Hb) levels and improve clinical symptoms in CKD patients. Compared with existing injectable therapies, roxadustat offers the promise of a more convenient (oral) and safer treatment option.

Currently, FibroGen is collaborating with AstraZeneca to develop and commercialize roxadustat in the United States, China, and other markets for the treatment of anemia in patients with chronic kidney disease (CKD). FibroGen is also partnering with Astellas Pharma to treat anemia in patients with CKD and myelodysplastic syndromes in regions including Europe, the Commonwealth of Independent States, the Middle East, and South Africa.

In December 2018, roxadustat became the first drug to receive approval from Chinese regulatory authorities for the treatment of anemia in patients with dialysis-dependent chronic kidney disease (DD-CKD). The industry holds strong optimism regarding the commercial prospects of roxadustat. In March this year, Clarivate Analytics released a report projecting that roxadustat’s sales would reach $2 billion in 2023. Analysts at Leerink further pointed out that if sufficient safety data support its use in the non-dialysis CKD patient population, roxadustat would have even greater growth potential, with annual sales possibly reaching $4–5 billion. (Compiled by Sina Medicine/newborn)

Reference Source:

[1]Pooled analyses of the roxadustat global Phase III programme confirmed cardiovascular safety

[2]FibroGen Announces Positive Topline Results from Pooled Safety Analyses of Roxadustat Global Phase 3 Program

[3]AZ preps new roxadustat filings, though data foxes investors