Monday, 9 November 2015
Efficacy and Safety Subanalysis Released at American College of Rheumatology 2015 Annual Meeting
AstraZeneca today announced positive subanalysis data of the Phase III lesinurad studies (CLEAR1, CLEAR2 and CRYSTAL) for the treatment of hyperuricemia associated with gout, in combination with a xanthine oxidase inhibitor (XOI).The results demonstrated a consistent efficacy and safety profile in patients with normal renal function, as well as patients with mild to moderate renal impairment.1,2 This subanalysis was presented at the American College of Rheumatology (ACR) 2015 Annual Meeting in San Francisco, California.
“As renal impairment and gout frequently co-exist we felt it was important to investigate the benefit and risk profile of lesinurad in patients with varying degrees of renal function,” said Chris Storgard, MD, Vice President, Clinical Research and Development, Ardea Biosciences, a member of the AstraZeneca Group. “These key findings showed that lesinurad, in combination with the current standard of care of XOIs, effectively lowered serum uric acid (sUA) and enabled more gout patients with mild or moderate renal impairment to achieve the recommended sUA treatment goals.”
In CLEAR1, CLEAR2 (full study results here) and CRYSTAL (full study results here) efficacy and safety endpoints from these pivotal Phase III trials were analyzed in patients with normal renal function (eCrCl ≥90 mL/min), patients with mild or moderate renal impairment (<90 ml/min) and specifically those with moderate renal impairment (<60 ml/min).1,2,3 Patients with severe renal impairment (<30 ml/min) were not studied.4 Lesinurad 200 mg in combination with an XOI resulted in consistent efficacy with a similar proportion of patients achieving sUA targets across these renal function categories. In addition, safety findings were consistent between treatment groups across all renal function categories.1,2
Renal related adverse events increased with decreasing renal function irrespective of lesinurad treatment, with no notable treatment group differences within renal function categories.1,2,4,5The incidence of serum creatinine (sCR) elevations was dose dependent but did not increase with decreasing renal function.4 Renal function (eCrCl) was stable over time in all treatment groups and across all renal function categories.1,2,4,5
Last month, the U.S. Food and Drug Administration’s Arthritis Advisory Committee voted 10 to 4 to recommend the approval of lesinurad 200 mg for the treatment of hyperuricemia associated with gout, in combination with a xanthine oxidase inhibitor (XOI).
The Prescription Drug User Fee Act (PDUFA) target goal date for lesinurad is December 29, 2015.
Lesinurad is also under regulatory review in the European Union and other territories.
Gout is a serious and debilitating form of inflammatory arthritis caused by hyperuricemia (elevated sUA).6,7 Gout affects millions of Americans, many of whom do not reach recommended sUA treatment goals on XOIs which decrease production of uric acid.8-12 For those inadequately controlled patients, the addition of a urate-lowering therapy to increase excretion of uric acid, may help them achieve treatment goals.13
NOTES TO EDITORS
If approved, lesinurad will be the first selective uric acid reabsorption inhibitor, or SURI, in the US. It inhibits the urate transporter, URAT1, which is responsible for the majority of the renal reabsorption of uric acid. By inhibiting URAT1, lesinurad increases uric acid excretion and thereby lowers serum uric acid (sUA). Lesinurad also inhibits organic anion transporter (OAT4) a uric acid transporter involved in diuretic-induced hyperuricemia. In addition, in patients, lesinurad does not inhibit OAT1 and OAT3, which are drug transporters in the kidney associated with drug-drug interactions.14
If approved, lesinurad in combination with an XOI would provide a dual mechanism of action to increase excretion and decrease production of uric acid enabling more patients with inadequately controlled gout to achieve target treatment goals.
About Hyperuricemia and Gout
Gout is a serious, chronic, progressive, and debilitating form of inflammatory arthritis.6,7Currently, there are more than 8.3 million patients suffering from gout in the US.9 The underlying cause of gout is hyperuricemia (elevated serum uric acid (sUA)), which leads to the deposition of crystals primarily in the joints and in other tissues.7 This can result in recurrent attacks of inflammatory arthritis and, if left uncontrolled, could lead to chronic, progressive arthritis, and tophus (visible deposits of urate crystals) formation.6,7,15
The goal of sUA-lowering treatment is to reduce sUA levels to the target level of <6.0 mg/dL as recommended by the American College of Rheumatology (ACR).13 To improve signs and symptoms such as tophaceous gout, the ACR guidelines state that achieving and maintaining sUA levels <5.0 mg/dL may be required.13
Among patients treated in clinical trials, less than 50% of patients on allopurinol 300 mg reached sUA target levels <6.0 mg/dL.9-12 This suggests approximately two million gout patients in the US on urate-lowering therapy remain inadequately controlled.8-12 For patients who cannot reach target on an XOI alone, the current ACR guidelines recommend adding an agent that increases uric acid excretion.13
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. RDEA3170 is a potent selective uric acid reabsorption inhibitor (SURI), also intended for use as a combination urate-lowering therapy with xanthine oxidase inhibitors (XOIs). RDEA3170 is our lead investigational urate lowering therapy (ULT) in Asia and is currently entering a Phase IIb trial in the US.
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.
|Abigail Bozarth||+1 302 885 2677|
|Melissa Garcia||+1 301 398 6470|
1. Saag KG, Bardin T, So A, Khanna P, Storgard C, Baumgartner S, Fung M, Bhakta N, Adler S, Kopicko J, Becker MA. Analysis of Gout Subjects Receiving Lesinurad and Allopurinol Combination Therapy By Baseline Renal Function [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/analysis-of-gout-subjects-receiving-lesinurad-and-allopurinol-combination-therapy-by-baseline-renal-function/. Accessed October 27, 2015.
2. Dalbeth N, Jones G, Terkeltaub R, Khanna D, Kopicko J, Adler S, Bhakta N, Fung M, Storgard C, Baumgartner S, Perez-Ruiz F. Lesinurad and Febuxostat Combination Therapy: Analysis of Treatment Based on Patient Baseline Renal Function [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10).http://acrabstracts.org/abstract/lesinurad-and-febuxostat-combination-therapy-analysis-of-treatment-based-on-patient-baseline-renal-function/. Accessed October 27, 2015.
3. The Renal Association. Normal GFR. 2013. Available at: http://www.renal.org/information-resources/the-uk-eckd-guide/ckd-stages#sthash.3dx1tzqp.3d6awTCl.dpbs. Accessed 5 November 2015.
4. Kenneth G. Saag, Thomas Bardin, Alexander So, Puja P. Khanna, Chris Storgard, Scott Baumgartner, Maple Fung, Nihar Bhakta, Scott Adler, Jeff Kopicko, Michael A. Becker. American College of Rheumatology 2015 Oral Presentation: Analysis of Gout Subjects Receiving Lesinurad and Allopurinol Combination Therapy by Baseline Renal Function. November 5, 2015.
5. Dalbeth N, et al. (2015 November). Lesinurad and Febuxostat Combination Therapy: Analysis of Treatment Based on Patient Baseline Renal Function. Poster session presented at the 79th Annual Meeting of the American College of Rheumatology (ACR) in San Francisco, CA, USA.
6. Perez-Ruiz F, Herrero-Beites A. Evaluation and Treatment of Gout as a Chronic Disease. Adv Ther. 2012;29(11):935–946.
7. Schumacher HR. The pathogenesis of gout. Cleve Clin J Med. 2008;75(5):S2-S4.
8. Data on file, 3189402, AstraZeneca Pharmaceuticals LP.
9. Zhu Y, et al. Prevalence of Gout and Hyperuricemia in the US General Population. Arthritis Rheum. 2011;63:3136–3141.
10. Becker MA, Schumacher HR Jr, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353(23):2450-2461.
11. Becker MA, Schumacher HR, Espinoza LR, et al. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther. 2010;12(2):R63.
12. Schumacher HR Jr, Becker MA, Wortmann RL, et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum. 2008;59(11):1540-1548.
13. Khanna D, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res. 2012;64:1431-1446.
14. Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for Industry: Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations. U.S. Department of Health and Human Services. February 2012.
15. Richette P, Bardin T. Gout. Lancet. 2010;375(9711):318-328.
3190819 Last Updated 11/15