AstraZeneca shows cardiovascular safety for roxadustat in global Phase III trials

New Delhi: AstraZeneca recently announced top-line results from the pooled cardiovascular (CV) safety analyses of the global Phase III programme for roxadustat, a first-in-class hypoxia-inducible-factor prolyl hydroxylase inhibitor (HIF-PHI).

The global pivotal Phase III trials evaluated roxadustat for treatment of anaemia in patients with chronic kidney disease (CKD) across the non-dialysis-dependent (NDD), incident (newly-initiated) dialysis (ID), and stable dialysis patient groups.

These pooled CV safety assessments of roxadustat are part of the overall benefit/risk assessment that will inform discussions with regulatory authorities. One of the key CV safety endpoints is major adverse CV events (defined as MACE), evaluating a composite of all-cause mortality, stroke and myocardial infarction in pooled analyses comparing roxadustat vs. placebo in NDD and vs. epoetin alfa in dialysis-dependent (DD) patients. Another key CV safety endpoint evaluated MACE plus heart failure requiring hospitalisation and unstable angina requiring hospitalisation (defined as MACE+).

In the pooled analysis of over 4,300 patients, and based on the totality of the adjudicated evidence, the MACE/MACE+ analyses between roxadustat and placebo showed no clinically meaningful difference.

In the pool of 1,500 ID patients, a pre-specified sub-population of DD patients, MACE/MACE+ results indicate that ID patients on roxadustat do better than those who are on epoetin alfa. ID patients are a better population to compare roxadustat vs. epoetin alfa than the stable dialysis population, where patients are stable not only on dialysis but also on erythropoietin.

In the pooled analysis of around 4,000 patients, and based on the totality of the adjudicated evidence, the MACE/MACE+ analyses between roxadustat and epoetin alfa showed no clinically-meaningful difference.

Mene Pangalos, Executive Vice President, R&D BioPharmaceuticals, said, “We are pleased to report these data from the largest clinical programme in the world evaluating this new class of medicines. These results add to the growing body of positive evidence to support roxadustat for the treatment of anaemia in chronic kidney disease patients, following our announcement that the primary efficacy endpoints were met for the OLYMPUS and ROCKIES trials in December 2018. There is a significant unmet medical need among patients living with chronic kidney disease, and we look forward to working with FibroGen to prepare for regulatory submissions of roxadustat.”

Further analyses of overall safety are ongoing and will inform the benefit/risk profile.

AstraZeneca and FibroGen Inc. (FibroGen) will begin discussions with the US Food and Drug Administration (FDA) to prepare for regulatory submission, which is anticipated in the second half of 2019. Roxadustat is currently approved in China for the treatment of patients with anaemia in DD CKD.

Roxadustat is a HIF-PHI that promotes erythropoiesis by increasing endogenous production of erythropoietin and improving iron regulation and overcoming the negative impact of inflammation on haemoglobin synthesis and red-blood-cell production by downregulating hepcidin. Use of roxadustat has been shown to induce coordinated erythropoiesis, increasing red blood-cell count while maintaining plasma erythropoietin levels within or near normal physiologic range, in multiple subpopulations of CKD patients, including in the presence of inflammation and without a need for supplemental intravenous iron.

FibroGen, the originator, and AstraZeneca are collaborating on the development and commercialisation of roxadustat for the treatment of anaemia in patients with CKD in the US, China, and other global markets. FibroGen and Astellas Pharma Inc. (Astellas) are collaborating on the development and commercialisation of roxadustat for the treatment of anaemia in patients with CKD in territories including Japan, Europe, the Commonwealth of the Independent States, the Middle East, and South Africa.

The global Phase III programme consists of more than 9,000 patients and was conducted by AstraZeneca, FibroGen and Astellas.

The OLYMPUS, ALPS and ANDES trials evaluated roxadustat vs. placebo in NDD patients; HIMALAYAS evaluated roxadustat vs. epoetin alfa in ID patients; and ROCKIES, SIERRAS and PYRENEES evaluated roxadustat vs. epoetin alfa in DD patients.

The AstraZeneca-sponsored trial OLYMPUS demonstrated a statistically-significant and clinically meaningful improvement in haemoglobin vs. placebo in NDD patients. The AstraZeneca-sponsored trial ROCKIES demonstrated a statistically significant improvement in haemoglobin vs. epoetin alfa in DD patients.

In the CV pooled safety analyses, safety was characterised based on a number of key CV analyses from the Phase III programme, including MACE outcomes and MACE+ outcomes (MACE plus hospitalisation for unstable angina and hospitalisation for heart failure outcomes). Overall, the analyses will evaluate the totality of evidence for roxadustat and assess the overall benefit-risk profile, to overcome the potential bias of a single-arm trial analysis.

Anaemia can be a serious medical condition in which patients have insufficient red blood cells and low levels of haemoglobin, a protein in red blood cells that carries oxygen to cells throughout the body.^1,2 Anaemia in CKD is associated with increased risk of hospitalisation, CV complications and death,³ also frequently causing significant fatigue, cognitive dysfunction and decreased quality of life.⁴ Severe anaemia is common in patients with CKD, cancer, myelodysplastic syndrome, inflammatory diseases and other serious illnesses.

Anaemia is particularly prevalent in patients with CKD, which affects more than 200 million patients worldwide and is generally a progressive disease characterised by gradual loss of kidney function that may eventually lead to kidney failure.

In the US, according to the United States Renal Data System, a majority of dialysis-eligible CKD patients are currently on dialysis. Of the approximately 507,000 patients receiving dialysis in the US as of 2016, approximately 80% were being treated with erythropoiesis-stimulating agents (ESA) for anaemia.⁵ Patients seldom receive ESA treatment until they initiate dialysis therapy.