Manufacturer: AstraZeneca FDA Approval Date: December 22, 2015 Zurampic® - Lesinurad Manufacturer: AstraZeneca FDA Approval Date: December 22, 2015

Zurampic® - Lesinurad Objectives At the end of this presentation participants will be able to: Appropriately recommend Zurampic® - Lesinurad Effectively educate patients on the purpose, proper use and potential adverse effects of Zurampic® - Lesinurad

Zurampic® - Lesinurad Clinical Application Indications: In combination with a xanthine oxidase inhibitor for the treatment of hyperuricemia associated with gout Place in therapy: Patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone Zurampic® [package insert].

Zurampic® - Lesinurad Clinical Application Contraindications: Severe renal impairment, end stage renal disease, and kidney transplant recipients Tumor lysis syndrome or Lesch-Nyhan syndrome Zurampic® [package insert].

Zurampic® - Lesinurad Clinical Application Black Box Warnings Acute renal failure has occurred with lesinurad and was more common when lesinurad was given alone Lesinurad should only be used in combination with a xanthine oxidase inhibitor Zurampic® [package insert].

Zurampic® - Lesinurad Clinical Application Pregnancy: No available human data No teratogenicity or effects on fetal development were observed in animal studies Lactation: Unknown excretion in human breast milk Zurampic® [package insert].

Zurampic® - Lesinurad Drug Facts Pharmacology: Uric Acid Transporter 1 (URAT1) Inhibitor URAT1 is responsible for the majority of the reabsorption of filtered uric acid from the renal tubular lumen Zurampic® [package insert].

Zurampic® - Lesinurad Drug Facts Pharmacokinetics: A Rapid with bioavailability ~100% D Mean ss volume of distribution ~20 L M Metabolized primarily via CYP2C9 E Estimated half-life of 5 hours Zurampic® [package insert].

Zurampic® - Lesinurad Drug Interactions Drug Interactions – Object Drugs: Sildenafil (30%) Amlodipine (35%) Colchicine (25%) Furosemide (30%) Indomethacin (30%) Zurampic® [package insert].

Zurampic® - Lesinurad Drug Interactions Drug Interactions – Precipitant Drugs: Rifampin (30%) Naproxen (20%) Fluconazole (60%) Zurampic® [package insert].

Zurampic® - Lesinurad Adverse Effects Common Adverse Effects: Headache (5.3%) [4.1%] Influenza (5.1%) [2.7%] Increased blood creatinine (4.3%) [2.3%] Gastroesophageal reflux disease (2.7%) [0.8%] Zurampic® [package insert].

Zurampic® - Lesinurad Monitoring Parameters Efficacy Monitoring: Serum uric acid levels every 2 to 5 weeks during uric acid lowering therapy titration then every 6 months Toxicity Monitoring: SCr and CrCl Zurampic® [package insert].

Zurampic® - Lesinurad Prescription Information Dosing: 200mg by mouth daily Administer in the morning with food and water at the same time in the morning as the dose of xanthine oxidase inhibitor Cost: Unknown Zurampic® [package insert].

Zurampic® - Lesinurad Literature Review RDEA594-203 Study Purpose: To assess the efficacy and tolerability of lesinurad in combination with allopurinol vs. allopurinol alone in patients with an inadequate response to allopurinol Perez-Ruiz F, et al. Ann Rheum Dis 2016;0:1–7.

Zurampic® - Lesinurad Literature Review Design: randomized, double-blind, placebo- controlled trial Conducted in: Canada, Georgia, Poland, Spain, Ukraine, the UK, and the USA November 2009 to January 2011 Perez-Ruiz F, et al. Ann Rheum Dis 2016;0:1–7.

Zurampic® - Lesinurad Literature Review Inclusion Criteria Exclusion Criteria Men and postmenopausal or surgically sterile women 18–80 years old Gout diagnosis Inadequate urate-lowering response (sUA ≥6 mg/dL on ≥2 occasions ≥2 weeks apart) to allopurinol monotherapy 200–600 mg daily for ≥6 weeks and sUA ≥6 mg/dL at screening History of kidney stones Active liver disease History of cardiac abnormalities Long-term use of medications that would worsen gout Uncontrolled hypertension SCr >1.5 mg/dL or CrCl <60 mL/min BMI >48 kg/m2 Perez-Ruiz F, et al. Ann Rheum Dis 2016;0:1–7.

Zurampic® - Lesinurad Literature Review Lesinurad 200mg with allopurinol vs. allopurinol alone Primary Endpoint: Percent reduction from baseline sUA levels at 4 weeks Perez-Ruiz F, et al. Ann Rheum Dis 2016;0:1–7.

Zurampic® - Lesinurad Literature Review Secondary Endpoint: Proportion of patients with sUA <6, <5 and <4 mg/dL at each visit Percent change from baseline in 24 h urine UA after 4 weeks Perez-Ruiz F, et al. Ann Rheum Dis 2016;0:1–7.

Zurampic® - Lesinurad Literature Review Baseline Characteristics: Placebo (N = 302) Lesinurad (N = 599) Age Male White 51.1 98.6% 93.1% 52.9 95.7% 91.3% Gout history Flares in 12 months sUA, mg/dL Years since gout diagnosis 4.2 6.7 7.3 4.1 6.4 10.2 Perez-Ruiz F, et al. Ann Rheum Dis 2016;0:1–7.

Zurampic® - Lesinurad Literature Review Results: Placebo Lesinurad P-value Reduction from baseline sUA levels at 4 weeks +2.6% -16% <0.0001 % of patient who achieved sUA <6 mg/dL 25% 63% Mean % change from baseline in renal UA clearance at 4 weeks 8% 43.7% <0.05 Perez-Ruiz F, et al. Ann Rheum Dis 2016;0:1–7.

Zurampic® - Lesinurad Literature Review Safety Endpoints: Adverse Event Placebo Lesinurad Any Discontinuation Death 45.8% 1.4% 0% 45.7% Common AEs Headache Nasopharyngitis Gout Flare Arthralgia 9.6% 20.8% 5.6% 6.5% 10.5% 21.7% Perez-Ruiz F, et al. Ann Rheum Dis 2016;0:1–7.

Zurampic® - Lesinurad Literature Review Trial Conclusion: Lesinurad decreased sUA levels by 16% from baseline after 4 weeks of treatment when used in combination with allopurinol 63% of patients on lesinurad achieved sUA <6 mg/dL Perez-Ruiz F, et al. Ann Rheum Dis 2016;0:1–7.

Zurampic® - Lesinurad Summary Zurampic, lesinurad, is first-in-class of Uric Acid Transporter 1 (URAT1) Inhibitor It is indicated for the treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor (XOI) alone Dosed: 200 mg by mouth once daily in the morning with food and water Contraindicated in severe renal impairment and should be avoided in patients with CrCl < 45mL/min Can cause serum creatinine elevations (generally reversible) – periodically monitor

Zurampic® - Lesinurad References www.zurampic.com Zurampic package insert. AstraZeneca. Dec. 2015. Roberts, S. “Zurampic Approved for Gout” https://www.nlm.nih.gov/medlineplus/news/fullstor y_156382.html. Accessed March 1, 2016. Perez-Ruiz F, et al. Lesinurad in combination with allopurinol: results of a phase 2, randomised, double-blind study in patients with gout with an inadequate response to allopurinol. Ann Rheum Dis 2016;0:1–7.