AstraZeneca
(NYSE: AZN) today presented at the European League Against Rheumatism
Annual Congress (EULAR 2015) in Rome, results of its Phase III
double-blind, multicenter, placebo-controlled trial CRYSTAL,
investigating the potential of lesinurad, a selective uric acid
re-absorption inhibitor (SURI), when used in combination with the
xanthine oxidase inhibitor (XOI) febuxostat. The results demonstrated
that lesinurad in combination with febuxostat lowered serum uric acid
(sUA) levels and reduced tophus area to a greater extent than febuxostat
alone. Lesinurad is an investigational agent that inhibits the
uric acid transporter URAT1 in the kidney, increasing uric acid
excretion and thereby lowering sUA. Lesinurad works in combination with
febuxostat to provide a dual mechanism of action which increases
excretion and decreases production of uric acid.
The CRYSTAL study evaluated lesinurad (200mg or 400mg) in combination
with febuxostat 80mg in patients who had at least one measurable tophus
(deposits of uric acid crystals in joints and skin). Patients were
administered febuxostat 80 mg orally once daily for 3 weeks before
randomisation to the combination treatments.
Results showed lesinurad 200mg in combination with febuxostat
demonstrated greater (nominal p<0.05) sUA lowering to the target for
tophaceous gout of <5.0mg/dL compared to febuxostat alone at all months
except at the time of the primary endpoint, month 6 (56.6% vs. 46.8%,
non-significant). In the important subgroup of subjects with baseline
sUA ≥5.0mg/dL i.e. those above recommended sUA treatment target for
tophaceous gout, lesinurad 200mg in combination with febuxostat did
result in more subjects reaching target sUA of <5.0mg/dL compared to
febuxostat alone at month 6 (44.1% vs. 23.5% respectively; nominal
p=0.0243). Lesinurad 400mg in combination with febuxostat met the
primary endpoint, with a significantly (p<0.0001) higher proportion of
patients reaching the target sUA goal of <5.0mg/dL at month 6 compared
to febuxostat alone (76.1% vs. 46.8%).
Among the key secondary endpoints, lesinurad in combination with
febuxostat did not result in a significant difference in the proportion
of subjects achieving a complete resolution of at least one tophus by
month 12. However, lesinurad combination treatment with both 200mg and
400mg did result in greater total tophus area reduction at month 12
compared to febuxostat alone (nominal p<0.05).
“It’s important to note that CRYSTAL studied patients with gout and
visible tophi, also known as tophaceous gout, which is particularly
challenging to treat,” stated Dr. Nicola Dalbeth, Professor of Medicine
at the University of Auckland in New Zealand and principal investigator
of the study.
The goal of all urate lowering treatments is to reduce sUA levels to the
recommended treatment targets. International treatment guidelines from
ACR and EULAR recommend achieving an sUA target at a minimum of
<6.0mg/dL in all gout patients and to <5.0mg/dL in gout patients with
greater disease severity and urate burden, such as those with visible
tophi. Approximately half of patients do not achieve recommended sUA
goals with the current standard of care of XOIs allopurinol or
febuxostat alone.
Further, another AstraZeneca abstract being presented at EULAR evaluated
the relationship between lower sUA and greater reduction in both tophus
area and the rate of gout flares requiring treatment (GFRT). The
abstract, a post-hoc analysis of pooled data from the three lesinurad
Phase III studies, – CLEAR1, CLEAR2, and CRYSTAL – found that patients
who achieved the lowest sUA levels, irrespective of treatment
assignment, experienced a greater reduction in flares and tophus area.
In the CRYSTAL study, the most common adverse events with the lesinurad
200mg in combination with febuxostat and the lesinurad 400mg in
combination with febuxostat groups compared to febuxostat alone were
nasopharyngitis, hypertension and headache. Those taking lesinurad
experienced a higher incidence of predominately reversible serum
creatinine (sCr) elevations.
“While no oral agent has demonstrated a beneficial effect on flares in
12-month randomized controlled clinical trials, this analysis showed
that over time – as lower sUA levels were maintained – flares decrease
and tophus area reduced,” said Johan Hoegstedt, Global Medicines Leader
for lesinurad.
The Marketing Authorization Application (MAA) and New Drug Application
(NDA) for lesinurad 200mg tablets in combination with an XOI (febuxostat
or allopurinol) are currently under review by the Committee for
Medicinal Products for Human Use (CHMP)/European Medicines Agency (EMA)
and the US Food and Drug Administration (FDA), respectively.
The CRYSTAL study was conducted by Ardea Biosciences, a member of the
AstraZeneca Group. Ardea is responsible for the development of the
AstraZeneca gout portfolio.
– ENDS –
NOTES TO EDITORS
About the Design of the Study
CRYSTAL (Combination Treatment Study in Subjects with Tophaceous Gout
with Lesinurad and Febuxostat) was a 12-month (North America, Europe,
Australia, and New Zealand), multicenter, randomized, placebo-controlled
study (n=324) that evaluated the efficacy and safety of a once daily
dose of lesinurad in combination with febuxostat compared to febuxostat
alone in gout patients with tophi (deposits of uric acid crystals in
joints and skin). Patients entering CRYSTAL had sUA levels above target
and had at least one measurable tophus on the hands/wrists and/or
feet/ankles ≥5 mm and ≤20 mm in the longest diameter.
About Lesinurad
Lesinurad is a selective uric acid reabsorption inhibitor (SURI) that
inhibits the URAT1 transporter and is being studied as an
investigational agent for the treatment of gout. URAT1 is responsible
for the majority of the reabsorption of filtered uric acid from the
renal tubular lumen. By inhibiting URAT1, lesinurad increases uric acid
excretion and thereby lowers sUA. Lesinurad also inhibits OAT4, a uric
acid transporter involved in diuretic-induced hyperuricemia.
About Hyperuricemia and Gout
Gout is a serious, chronic and debilitating form of inflammatory
arthritis. There are more than 8.3 million diagnosed cases of gout in
the United States. The underlying cause of gout is hyperuricemia
(elevated sUA), which leads to the deposition of crystals in
musculoskeletal structures including joints, in the kidneys, and in
other tissues resulting in recurrent attacks of inflammatory arthritis
and if left untreated or suboptimally treated it could lead to chronic,
progressive arthropathy, and tophus formation.
About Ardea Biosciences
Ardea Biosciences, Inc. was acquired by AstraZeneca in June 2012. It is
located in San Diego, California and is a member of the AstraZeneca
Group. Ardea is leading the development of AstraZeneca’s gout portfolio,
including lesinurad and RDEA3170.
About AstraZeneca
AstraZeneca is a global, innovation-driven biopharmaceutical business
that focuses on the discovery, development and commercialization 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-us.com.
3139500 Last Updated 6/15
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