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2019-11-08

AstraZeneca: Roxadustat Phase III programme pooled analyses showed positive efficacy and no increased cardiovascular risk i...

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) today 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 (n=4,270) HR 1.08 (95% HR 1.04 (95% HR 1.06 (95% The risk of
Placebo CI, 0.94, CI, 0.91, CI, 0.91, MACE, MACE+
1.24) 1.18) 1.23) and all-cause
mortality in
roxadustat
patients was
comparable to
placebo
ID[i,ii] HR 0.70 (95% HR 0.66 (95% HR 0.76 (95% In ID
(n=1,526) CI, 0.51, CI, 0.50, CI, 0.52, patients,
Epoetin alfa 0.96) 0.89) 1.11) 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
DD (n=3,880) HR 0.96 (95% HR 0.86 (95% HR 0.96 (95% No increased
Epoetin alfa CI, 0.82, CI, 0.74, CI, 0.79, risk of MACE
1.13) 0.98) 1.17) and all-cause
mortality and
a lower risk
of MACE+
compared to
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 medici...

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