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

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

3. 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. 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. 5 Who was enrolled? Sodium (mEq/L) Mean Sodium (mEq/L):129.1 mEq/L128.9 mEq/L

6. 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. 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. 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. 9 Phase 3 hyponatremia studies: Mental Component of the SF-12 (Day 30) Analysis Mean Baseline (SD) Mean Change (number of subjects) Treatment Effect P-value TolvaptanPlaceboTolvaptanPlacebo Last Observation Carried Forward 42.3 (11.7) 45.4 (11.8) 6.4 (N=83) 1.1 (N=71) 3.9.02 Observed Cases 42.2 (11.7) 46.7 (12.1) 8.0 (N=71) 0.9 (N=58) 5.3.004 Analysis Mean Baseline (SD) Mean Change (number of subjects) Treatment Effect P-value TolvaptanPlaceboTolvaptanPlacebo Last Observation Carried Forward 44.7 (12.0) 45.1 (11.9) 4.5 (N=101) 2.0 (N=103) 2.20.15 Observed Cases 45.2 (12.3) 45.4 (12.1) 4.9 (N=86) 2.4 (N=85) 2.40.12 Trial 156-02-235 Trial 156-03-238

10. 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. 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. 12 Tolvaptan’s development programs Hyponatremia indication Tolvaptan-treated subjects in phase 3 hyponatremia trials (N=223) Subjects with hyponatremia due to SIADH/Other, Heart Failure or Cirrhosis Worsening heart failure indication Tolvaptan-treated subjects in phase 3 heart failure trials (N=2063) Subset of heart failure subjects who also happened to have hyponatremia N=242

13. 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. 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. 15 The Safety Database (N=3294) Subjects with hyponatremia Phase 3 hyponatremia trials Phase 3 heart failure trials Other trials Subjects with heart failure or hyponatremia Subjects with hyponatremia

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

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

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

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

20. 20 Mortality in heart failure subjects with hyponatremia Other trials enrolling heart failure subjects with hyponatremia Subjects with hyponatremia enrolled in phase 2 heart failure trials Tolvaptan: 13.2% (12/91) Placebo: 10.0% (4/40) Subjects with heart failure enrolled in placebo-controlled hyponatremia trials Tolvaptan: 11.5% (10/87) Placebo: 7.6% (6/79)

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

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

23. 23 Efficacy in tolvaptan’s phase 3 hyponatremia trials Change in Sodium (mEq/L) Study 156-02-235Study 156-03-238 Baseline Sodium (mEq/L) 110115120125130135140 0 10 20 30

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

25. 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. 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. 27 Closing Comments Can we generalize these findings to a population with more severe hyponatremia?