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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