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Tolvaptan for the Treatment of Hyponatremia

Aliza Thompson, MDAliza Thompson, MD

Medical OfficerMedical Officer

Cardiovascular and Renal Drugs Advisory Cardiovascular and Renal Drugs Advisory Committee MeetingCommittee Meeting

June 25, 2008June 25, 2008

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Tolvaptan’s Phase 3 Hyponatremia Trials

Time (Days)

Se

rum

So

diu

m (

mE

q/L

)

0 10 20 30 40Time (day)

128

130

132

134

136

Ser

um S

odiu

m L

evel

(m

)

OPC-15/60MGPLACEBO

0 10 20 30 40Time (day)

128

130

132

134

136

Ser

um

So

diu

m L

evel

(m

)

OPC-15/60MGPLACEBO

Tolvaptan

Placebo

Study 156-03-238 Study 156-02-235

Washout Washout

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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?

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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.

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Who was enrolled?

0

30

60

90

120

Number of Subjects

Tolvaptan Placebo

130-134 125-129 <125

Sodium (mEq/L)

Mean Sodium (mEq/L): 129.1 mEq/L 128.9 mEq/L

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Published literature: key considerations

Are the findings generalizable to the population treated with tolvaptan?

level of serum sodium acute vs. chronic hyponatremia underlying etiology

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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?

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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

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Phase 3 hyponatremia studies: Mental Component of the SF-12 (Day 30)

Analysis

Mean Baseline(SD)

Mean Change(number of subjects) Treatment

EffectP-value

Tolvaptan Placebo Tolvaptan Placebo

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

EffectP-value

Tolvaptan Placebo Tolvaptan Placebo

Last Observation Carried Forward

44.7(12.0)

45.1(11.9)

4.5(N=101)

2.0(N=103) 2.2 0.15

Observed Cases

45.2(12.3)

45.4(12.1)

4.9(N=86)

2.4(N=85) 2.4 0.12

Trial 156-02-235

Trial 156-03-238

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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)

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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

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Tolvaptan’s development programs

Hyponatremia indicationTolvaptan-treated subjects in phase 3

hyponatremia trials (N=223)

Subjects with hyponatremia due to SIADH/Other, Heart Failure or Cirrhosis

Worsening heart failure indicationTolvaptan-treated subjects in phase 3 heart

failure trials (N=2063)

Subset of heart failure subjects who also happened to have hyponatremia

N=242

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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

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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?

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The Safety Database (N=3294)

60718%

14223%

22337%

24240%

268782%

Subjects with hyponatremia

Phase 3 hyponatremia trials

Phase 3 heart failure trials

Other trials

Subjects with heart failure or hyponatremia

Subjects with hyponatremia

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Subjects with hyponatremia (N=607)

529%

13723%

41868%

130-134

125-129

<125

10016%

41068%

9716%

Heart FailureCirrhosisSIADH/other

By Serum Sodium Level (mEq/L)

By Underlying Etiology

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Tolvaptan’s development programs

Worsening heart failure indicationTolvaptan-treated subjects in phase 3 heart

failure trials (N=2063)

Subset of heart failure subjects who also happened to have hyponatremia

Hyponatremia indicationTolvaptan-treated subjects in phase 3

hyponatremia trials (N=223)

Hyponatremia due to SIADH/Other, Heart Failure or Cirrhosis

N=242

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Mortality in the phase 3 heart failure studies

47.5

24.1

42.7

24.4

0 20 40 60

Subgroupwith

hyponatremia

All treatedsubjects

Percent of subjects with fatalities

Tolvaptan Placebo

(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

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The Safety Database (N=3294)

Subjects with hyponatremia

Phase 3 hyponatremia trials

Phase 2 trials

Subjects with heart failure or hyponatremia

Subjects with hyponatremia

60718%

14223%

22337%

Phase 3 heart failure trials

24240%

268782%

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Mortality in heart failure subjects with hyponatremia

Other trials enrolling heart failure subjects with

hyponatremia

Subjects with hyponatremia enrolled in phase 2 heart failure

trialsTolvaptan: 13.2% (12/91) Placebo: 10.0% (4/40)

Subjects with heart failure enrolled in placebo-controlled

hyponatremia trialsTolvaptan: 11.5% (10/87)

Placebo: 7.6% (6/79)

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0 10 20 30

GI bleed orecchymosis*

Ecchymosis*

GI bleed

Percentage of subjects (%)

Placebo(N=57)

Tolvaptan(N=63)

*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)

9.5% (CI: 2.3, 16.7)

1.8% (CI: 0, 5.3)

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

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Baseline Serum Sodium (mM)Ste

ad

y S

tate

Se

rum

So

diu

m C

ha

ng

e f

rom

Ba

selin

e (

mM

)

110 115 120 125 130 135 140

01

02

03

0

Efficacy in tolvaptan’s phase 3 hyponatremia trials

Change in

Sodium (mEq/L)

Study 156-02-235 Study 156-03-238

Baseline Sodium (mEq/L)

110 115 120 125 130 135 140

010

2030

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Safety

Subjects with hyponatremia: N=607

Serum Sodium Level (mEq/L)

529%

13723%

41868%

130-134

125-129

<125

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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

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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

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Closing Comments

• Can we generalize these findings to a population with more severe hyponatremia?