TIDMAZN
RNS Number : 8848S
AstraZeneca PLC
11 November 2019
11 November 2019 07:00 GMT
Roxadustat Phase III programme pooled analyses showed
positive efficacy and no increased cardiovascular risk in
patients with anaemia from chronic kidney disease
In non dialysis-dependent patients receiving roxadustat, the
risk of
MACE, MACE+ and all-cause mortality was comparable to
placebo
Dialysis-dependent patients receiving roxadustat had a lower
risk of MACE+
and no increased risk of MACE or all-cause mortality versus
epoetin alfa
In incident dialysis patients, roxadustat had a lower risk of
MACE and MACE+ and showed a trend towards lower risk of all-cause
mortality relative to epoetin alfa
AstraZeneca and FibroGen Inc. (FibroGen) have presented pooled
efficacy and cardiovascular (CV) safety analyses from the pivotal
Phase III programme assessing roxadustat for the treatment of
patients with anaemia from chronic kidney disease (CKD).
The pooled CV safety analyses showed that roxadustat, an oral
first-in-class hypoxia-inducible factor prolyl hydroxylase
inhibitor (HIF-PHI), did not increase the risk of MACE, MACE+ and
all-cause mortality in non dialysis-dependent (NDD) patients
compared to placebo and dialysis-dependent (DD) patients compared
to epoetin alfa, a current medicine used to treat anaemia.
In a clinically important predefined subgroup of incident
dialysis (ID) patients, defined as patients who have been on
dialysis for four months or less, roxadustat reduced the risk of
MACE and MACE+ and showed a trend towards lower risk of all-cause
mortality relative to epoetin alfa.
Key safety endpoints consisted of time to major adverse CV
events (MACE), defined as all-cause mortality, stroke and
myocardial infarction, and time to MACE+, defined as MACE, unstable
angina requiring hospitalisation and congestive heart failure
requiring hospitalisation.
The results were presented in an oral late-breaking abstract
session at the American Society of Nephrology (ASN) Kidney Week
2019 in Washington, D.C., US.
Mene Pangalos, Executive Vice President, BioPharmaceuticals,
R&D, said: "These highly anticipated results reinforce our
confidence in the potential of roxadustat to address significant
unmet medical needs among patients with anaemia from chronic kidney
disease, particularly for those who have recently started dialysis.
The pooled analyses showed incident dialysis patients receiving
roxadustat had a lower risk of cardiovascular events which is
important as these patients may experience higher rates of
morbidity and mortality than those on stable dialysis."
Robert Provenzano, MD, Associate Professor of Medicine, Wayne
State University, Detroit, Michigan, US and a primary investigator
on the global Phase III programme, said: "Roxadustat is the first
in a new class of medicines for the treatment of anaemia from
chronic kidney disease. This pooled cardiovascular safety data,
together with strong efficacy data, support its potential as an
important new treatment option for patients with anaemia from
chronic kidney disease who have seen little to no innovation in
decades."
Key headline data from the roxadustat Phase III programme pooled
safety analyses
Population MACE MACE+ All-cause Conclusion
Comparator mortality
NDD HR 1.08 HR 1.04 HR 1.06 The risk of MACE, MACE+
and all-cause mortality
in roxadustat patients
was comparable to placebo
(n=4,270) (95% CI, (95% CI, (95% CI,
0.94, 1.24) 0.91, 1.18) 0.91, 1.23)
Placebo
-------------- -------------- -------------- ------------------------------
ID(i,ii) HR 0.70 HR 0.66 HR 0.76 In ID patients, those
taking roxadustat had
a 30% lower risk of
MACE and 34% lower risk
of MACE+ compared to
those taking epoetin
alfa, with a trend towards
lower all-cause mortality
for roxadustat relative
to epoetin alfa
(n=1,526) (95% CI, (95% CI, (95% CI,
0.51, 0.96) 0.50, 0.89) 0.52, 1.11)
Epoetin
alfa
-------------- -------------- -------------- ------------------------------
DD HR 0.96 HR 0.86 HR 0.96 No increased risk of
MACE and all-cause mortality
and a lower risk of
MACE+ compared to epoetin
alfa
(n=3,880) (95% CI, (95% CI, (95% CI,
0.82, 1.13) 0.74, 0.98) 0.79, 1.17)
Epoetin
alfa
-------------- -------------- -------------- ------------------------------
i. ID patients are those who initiated dialysis within four months prior to randomisation
ii. ID patients are a subgroup of the DD patient population
The primary efficacy endpoint was achieved in the pooled
analyses for NDD and DD patients, and in all individual Phase III
trials. Data from the pooled efficacy and CV safety analyses,
together with other statistical analyses, will form part of the
regulatory submission in the US, which is anticipated in Q4
2019.
The pooled efficacy analyses in the NDD population showed
roxadustat was superior to placebo, regardless of iron-repletion,
with a mean increase from baseline in haemoglobin (Hb) levels
averaged over weeks 28 to 52 of 1.85 g/dL in patients treated with
roxadustat compared to 0.13 g/dL with placebo (p<0.001).
The pooled efficacy analyses in the DD population showed
roxadustat demonstrated a statistically significant mean increase
from baseline in Hb levels averaged over weeks 28 to 52 with 1.22
g/dL in patients treated with roxadustat compared to 0.99 g/dL with
epoetin alfa (p<0.001).
Roxadustat is currently approved in China for the treatment of
anaemia in patients with CKD, regardless of whether they require
dialysis, and in Japan for the treatment of dialysis patients with
anaemia from CKD.
About roxadustat
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 IV iron.
About the Phase III programme
FibroGen, Inc., (FibroGen) 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 chronic
kidney disease (CKD) in territories including Japan, Europe, the
Commonwealth of Independent States, the Middle East, and South
Africa.
The global Phase III programme includes more than 9,000 patients
and was conducted by AstraZeneca, FibroGen and Astellas together.
The OLYMPUS, ALPS and ANDES trials evaluated roxadustat vs. placebo
in NDD patients. ROCKIES, SIERRAS and HIMALAYAS evaluated
roxadustat vs. epoetin alfa in DD patients. HIMALAYAS evaluated
roxadustat vs. epoetin alfa in ID patients; there were ID patients
in ROCKIES and SIERRAS. PYRENEES was not included in the pooled CV
safety analyses.
About anaemia
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 from 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. CKD
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.
According to the United States Renal Data System, about 80% of
the approximately 509,000 patients receiving dialysis in the US in
2016 were being treated with erythropoiesis-stimulating agents
(ESA).(5) Patients seldom receive ESA treatment until they initiate
dialysis therapy.
About AstraZeneca in CVRM
Cardiovascular, Renal & Metabolism (CVRM) together forms one
of AstraZeneca's three therapy areas and is a key growth driver for
the Company. By following the science to understand more clearly
the underlying links between the heart, kidneys and pancreas,
AstraZeneca is investing in a portfolio of medicines to protect
organs and improve outcomes by slowing disease progression,
reducing risks and tackling co-morbidities. The Company's ambition
is to modify or halt the natural course of CVRM diseases and
potentially regenerate organs and restore function, by continuing
to deliver transformative science that improves treatment practices
and cardiovascular health for millions of patients worldwide.
About AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company
that focuses on the discovery, development and commercialisation of
prescription medicines, primarily for the treatment of diseases in
three therapy areas - Oncology, CVRM, and Respiratory. AstraZeneca
operates in over 100 countries, and its innovative medicines are
used by millions of patients worldwide. For more information,
please visit astrazeneca.com and follow the Company on Twitter
@AstraZeneca.
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References
1. National Kidney Foundation. "Managing Anaemia When You Have
Kidney Disease or Kidney Failure." 2014.
2. National Institute of Diabetes and Digestive and Kidney
Diseases. "Anaemia in Chronic Kidney Disease." 2014.
3. Babitt JL, Lin HY. Mechanisms of Anemia in CKD. J Am Soc Nephrol (2012); 23:1631-1634.
4. KDOQI Clinical Practice Guidelines and Clinical Practice
Recommendations for Anaemia in Chronic Kidney Disease. Am J Kidney
Dis. 2006 May; 47(5): S1-S132.
5. United States Renal Data System. "Annual Data Report." 2017.
Adrian Kemp
Company Secretary
AstraZeneca PLC
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