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2014-08-13

AstraZeneca: AstraZeneca announces top-line results from the phase III programme of lesinurad in combination with xanthine oxidase inhibitors in gout patients

AstraZeneca today announced positive top-line results from CLEAR1,
CLEAR2 and CRYSTAL, the pivotal Phase III clinical trials
investigating the potential of lesinurad, a selective uric acid
re-absorption inhibitor (SURI), as a combination therapy for the
treatment of patients with symptomatic gout. Lesinurad is an
investigational agent that inhibits the URAT1 transporter, increasing
uric acid excretion and thereby lowering serum uric acid (sUA).

CLEAR1 and CLEAR2 studied lesinurad (200mg and 400mg once daily) in
combination with the xanthine oxidase (XO) inhibitor allopurinol, in
symptomatic gout patients not achieving target sUA levels on their
current allopurinol dose. CRYSTAL studied lesinurad (200mg and 400mg
once daily) in combination with the XO inhibitor febuxostat (80mg
once daily) in gout patients with tophi (visible nodules of uric acid
crystals that are deposited in joints and skin).

In the CLEAR1 and CLEAR2 trials, both lesinurad 200mg and 400mg in
combination with allopurinol met the primary endpoint, with a
statistically significant higher proportion of patients reaching the
target sUA goal of <6.0mg/dL at month 6 compared to allopurinol alone
(p<0.0001).

In the CRYSTAL trial, lesinurad 400mg in combination with febuxostat
met the primary endpoint, with a statistically significant higher
proportion of patients reaching the target sUA goal of <5.0mg/dL at
month 6 compared to febuxostat alone (p<0.0001). Although lesinurad
200mg did not achieve statistical significance at month 6 (p=0.13),
this dose in combination with febuxostat, was superior to placebo
plus febuxostat at all other time points (measured at months 1 to 5,
8, 10 and 12; nominal p<0.05).

The three most commonly reported adverse events across the CLEAR1 and
CLEAR2 trials for patients receiving lesinurad in combination with
allopurinol were upper respiratory tract infection, nasopharyngitis
and back pain. In CRYSTAL, the three most commonly reported adverse
events for patients receiving lesinurad in combination with
febuxostat were nasopharyngitis, arthralgia and upper respiratory
tract infection.

The incidence of renal-related adverse events (including serious
events) and incidence of kidney stones with lesinurad 200mg plus XO
inhibitor was comparable to placebo plus XO inhibitor. The incidence
of renal-related adverse events and kidney stones was higher with
lesinurad 400mg plus XO inhibitor. A full assessment of the safety
and tolerability findings of all three studies is ongoing.

"Gout is a serious, chronic and debilitating inflammatory disease.
There is a significant unmet need, with 40 to 70 percent of gout
patients not reaching target levels of serum uric acid with the
current standard of care," said Briggs Morrison, Executive Vice
President, Global Medicines Development and Chief Medical Officer.
"We are encouraged by our initial review of the top-line results from
the CLEAR1, CLEAR2 and CRYSTAL studies which

provide important new information on the efficacy and safety of
lesinurad in combination with febuxostat and allopurinol. These data
indicate that combination therapy with lesinurad may be a potential
treatment option for gout patients."

CLEAR1, CLEAR2 and CRYSTAL were conducted by Ardea Biosciences, a
wholly-owned subsidiary of AstraZeneca. Results from these Phase III
clinical trials will be submitted to a scientific meeting later in
2014. The company is proceeding with preparation of regulatory
submissions for lesinurad (200mg) combination therapy.

- ENDS -

NOTES TO EDITORS

About the Design of the Studies

CLEAR1 and CLEAR2 (Combining Lesinurad with Allopurinol in Inadequate
Responders) were 12-month (US and global, respectively) multicenter,
randomised, placebo-controlled studies (n=603 and n=610,
respectively) comparing the efficacy and safety of lesinurad (200mg
and 400mg once daily) when added to the patient's current stable
medically-appropriate dose of allopurinol (at least 300mg daily, and
at least 200mg daily for those with moderate renal impairment)
compared to placebo plus allopurinol. Patients entering CLEAR1 and
CLEAR2 had multiple sUA levels above target and had also reported at
least two gout flares in the 12 months prior to randomisation.

CRYSTAL (Combination Treatment Study in Subjects with Tophaceous Gout
with Lesinurad and Febuxostat) was a 12-month global multicenter,
randomised, placebo-controlled study (n=324) comparing the efficacy
and safety of lesinurad (200mg and 400mg once daily) in combination
with febuxostat (80mg) compared to febuxostat (80mg) plus placebo in
gout patients with tophi and sUA levels above target. In the CRYSTAL
study all patients were started on febuxostat three weeks prior to
the initiation of the randomised study medication (with either
placebo or lesinurad).

Patients who completed the randomised pivotal Phase III clinical
studies had the option to enroll in two on-going open-label,
uncontrolled extension studies to continue to evaluate the safety and
efficacy of combination therapy with lesinurad 200mg and 400mg with
XO inhibitors.

About Gout

Gout is a serious, chronic and debilitating inflammatory arthritis.
There were 15.3 million diagnosed cases of chronic gout in major
markets in 2013 and this is forecast to grow to 17.7 million by 2021.
Gout is caused by a metabolic disorder, hyperuricemia (elevated sUA)
which leads to the deposition of crystals in musculoskeletal
structures including joints, in the kidneys, and in other tissues.

The goal of all urate lowering treatments is to reduce sUA levels to
the recommended targets. International treatment guidelines from the
American College of Rheumatology, European League Against Rheumatism
and the British Society for Rheumatology recommend achieving an sUA
target at a minimum of < 6 mg/dL in all gout patients and often to <
5 mg/dL in gout patients with greater disease severity and urate
burden, such as those with tophi.

About Ardea Biosciences

Ardea Biosciences, Inc. was acquired by AstraZeneca in June 2012. It
is located in San Diego, California and is a wholly owned subsidiary
of AstraZeneca PLC. Ardea is developing a portfolio of molecules for
the treatment of gout, including lesinurad and RDEA3170.

About AstraZeneca

AstraZeneca is a global, innovation-driven biopharmaceutical business
that focuses on the discovery, development and commercialisation of
prescription medicines, primarily for the treatment of
cardiovascular, metabolic, respiratory, inflammation, autoimmune,
oncology, infection and neuroscience diseases. AstraZeneca operates
in over 100 countries and its innovative medicines are used by
millions of patients worldwide. For more information please visit:
www.astrazeneca.com

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