AstraZeneca announces Phase III results for lesinurad in combination with febuxostat in tophaceous gout patients at European League Against Rheumatism Annual Congress (EULAR 2015)

Saturday, 13 June 2015

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.

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.

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