Tolvaptan for the Treatment of Hyponatremia

1. Tolvaptan for the Treatment of Hyponatremia Cardiovascular and Renal Drugs Advisory Committee Meeting June 25, 2008 Aliza Thompson, MD Medical Officer

2. Tolvaptan’s Phase 3 Hyponatremia Trials Study 156-03-238 Study 156-02-235 Washout Washout Tolvaptan Placebo Serum Sodium (mEq/L) Time (Days)

3. Outline • Who was studied in tolvaptan’s development program? • Is serum sodium a valid surrogate for benefit in this population? • Did the development program establish tolvaptan’s safety in this population?

4. Who was targeted? Inclusion criteria • Hyponatremia (sodium < 135 mEq/L) in euvolemic or hypervolemic states Exclusion criteria • Acute and transient hyponatremia associated with head trauma or postoperative state • Sodium < 120 mEq/L with associated neurologic impairment (symptoms such as apathy, confusion, seizures, etc) • Likely to require IV saline for correction of symptomatic or asymptomatic severe hyponatremia during the course of the study.

5. Who was enrolled? Sodium (mEq/L)

6. Published literature: key considerations Are the findings generalizable to the population treated with tolvaptan? • level of serum sodium • acute vs. chronic hyponatremia • underlying etiology

7. The clinical significance of “mild” hyponatremia Hyponatremia and… • falls in the elderly • morbidity and mortality in heart failure patients • morbidity and health related quality of life in cirrhotics Is this association or is this causation?

8. Phase 3 Hyponatremia Studies: Secondary Endpoints 1. Average daily area under the curve of change in sodium up to Day 4, sodium < 130 mEq/L subgroup 2. Average daily area under the curve of change in sodium up to Day 30, sodium <130 mEq/L subgroup 3. Percentage of subjects with normalized sodium at Day 4 4. Percentage of subjects with normalized sodium at Day 30 5. Time to first normalization in sodium 6. Change from baseline in sodium at Day 4 7. Change from baseline in sodium at Day 30 8. Percentage of subjects requiring fluid restriction 9. Urine output at Day 1 10. Change from baseline in body weight at Day 1 for hypervolemic subjects. 11. Fluid balance at Day 1 for hypervolemic patients 12.Change from baseline in the SF-12 Physical Component Summary and Mental Component Summary Scales 13. Categorical change in sodium at Day 4 and Day 30, subgroup with sodium < 130 mEq/L 14. Categorical change in sodium at Day 4 and Day 30, subgroup with sodium ≥ 130 mEq/L 15. Percentage of subjects designated as treatment failures due to need for saline infusion

9. Phase 3 hyponatremia studies: Mental Component of the SF-12(Day 30) Trial 156-02-235 Trial 156-03-238

10. Phase 3 hyponatremia studies: Hyponatremia Disease Specific Survey • Developed internally by sponsor • Conducted in trial 156-03-238 at 3 time points during the course of the study • Following submission to NDA, exploratory analyses combined 4 questions to calculate a “mental component” • Difference in mental component score at Day 30 (estimated treatment effect -1.9 and -2.7 for subjects with a serum sodium < 135 and < 130 mEq/L respectively)

11. Phase 3 hyponatremia studies: Neurologic Examination • Included physician assessment of level of consciousness, ataxia, stance, gait, coordination*, muscle strength and tone, reflexes, dysarthria, tremor… • Depending on trial, measurements appear to be made 6 to 7 times during the course of the study • Differences between tolvaptan and placebo-treatment arms: • reflexes R and L achilles Week 1 in trial 156-02-235 • stance with eyes closed at Week 2 in trial 156-03-238 • ataxia at Day 37 in trial 156-03-238 (when subjects had been off drug for 7 days) *Limited data collected on stance, gait and coordination in trial 156-02-235

12. Worsening heart failure indication Tolvaptan-treated subjects in phase 3 heart failure trials (N=2063) Hyponatremia indication Tolvaptan-treated subjects in phase 3 hyponatremia trials (N=223) N=242 Subjects with hyponatremia due to SIADH/Other, Heart Failure or Cirrhosis Subset of heart failure subjects who also happened to have hyponatremia Tolvaptan’s development programs

13. Hyponatremic subjects in Phase 3 Heart Failure Trials • No difference in Kansas City Cardiomyopathy Questionnaire • Changes in body weight at day 1 and inpatient day 7 or discharge (< 1 kg difference between treatment arms) • Changes in patient-assessed dyspnea at Day 1

14. The data tell us about tolvaptan as a treatment for worsening heart failure. What do they tell us about the clinical benefits of treating a patient with tolvaptan to raise serum sodium?

15. The Safety Database (N=3294) Subjects with heart failure or hyponatremia Subjects with hyponatremia Phase 3 heart failure trials Other trials Phase 3 hyponatremia trials Subjects with hyponatremia

16. Subjects with hyponatremia (N=607) By Serum Sodium Level (mEq/L) By Underlying Etiology

17. Hyponatremia indication Tolvaptan-treated subjects in phase 3 hyponatremia trials (N=223) Hyponatremia due to SIADH/Other, Heart Failure or Cirrhosis Tolvaptan’s development programs Worsening heart failure indication Tolvaptan-treated subjects in phase 3 heart failure trials (N=2063) N=242 Subset of heart failure subjects who also happened to have hyponatremia

18. Mortality in the phase 3 heart failure studies Deaths on treatment or within 7 days of stopping (CI: 22.5, 26.3); Total N= 2055 (CI: 22.3, 25.9); Total N= 2063 (CI: 36.3, 49.1); Total N=232 (CI: 41.2, 53.8); Total N= 242

19. Phase 3 heart failure trials 242 40% The Safety Database (N=3294) Subjects with heart failure or hyponatremia Subjects with hyponatremia 2687 82% 142 607 Phase 2 trials 23% 18% 223 37% Phase 3 hyponatremia trials Subjects with hyponatremia

20. Mortality in heart failure subjects with hyponatremia

21. Adverse events in subjects with cirrhosis 1.8% (CI: 0, 5.3) 9.5% (CI: 2.3, 16.7) 9.5% (CI: 2.3, 16.7) 1.8% (CI: 0, 5.3) 17.5 % (CI: 8.1, 26.9) *Includes hematomas

22. Can the findings in tolvaptan’s development program be extrapolated to a population with more severe hyponatremia?

23. 30 20 10 0 110 115 120 125 130 135 140 Efficacy in tolvaptan’s phase 3 hyponatremia trials Study 156-02-235 Study 156-03-238 Change in Sodium (mEq/L) Baseline Sodium (mEq/L)

24. Safety Subjects with hyponatremia: N=607 Serum Sodium Level (mEq/L) 137 130-134 23% 125-129 <125 52 9% 418 68%

25. Closing Comments • Who was studied in tolvaptan’s development program? • patients with mild and seemingly asymptomatic hyponatremia • Is serum sodium a valid surrogate for benefit in this population? • The clinical significance of raising serum sodium in this population remains unclear

26. Closing Comments • Did the development program establish tolvaptan’s safety in this population? • The database is limited, in particular with respect to subjects with SIADH, cirrhosis, and greater degrees of hyponatremia • In the setting of subtle or uncertain benefits, the tolerance for risk should be low

27. Closing Comments • Can we generalize these findings to a population with more severe hyponatremia?