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Efficacy of Testosterone Transdermal System (TTS) for Treatment of HSDD in

Surgically Menopausal Women on Concomitant Estrogen

Daniel Davis, MD, MPHDivision of Reproductive and Urologic Drug

Products

December 2, 2004

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Clinical Efficacy Issues

First application for this indication Clinical significance of small treatment effects

Small in satisfactory sexual events (SSEs) Small changes in secondary endpoints Strong placebo effect relative to TTS effect

Methodology for determining a clinically meaningful treatment effect

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Clinical Development Program

FDA Draft Guidance and advice followed 3 Instruments developed to assess

efficacy Two placebo-controlled Phase 3 trials

that evaluated efficacy over 6 months

Study to determine the magnitude of change that is clinically meaningful

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Key Inclusion-Exclusion Criteria

Surgically menopausal, on stable estrogen

Acquired HSDD diagnosed by answer to5 questions

Generally good health, without history of diabetes, cardiovascular disease

No specific entry testosterone level

Stable partner relationship

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Diagnosis of Acquired HSDD

Was your sex life satisfying before the surgery?

Have you had a meaningful decrease in sexual desire since surgery?

Have you had a significant in sexual activity?

Are you distressed by the changes?

Would you like to see an in desire for sex and sexual activity?

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Primary and Secondary Endpoints Primary endpoint

Change from baseline in satisfactory sexual events (SSEs) per 4 weeks

Secondary endpoints Change in personal distress score on the

Personal Distress Scale Change in sexual desire domain in the

Profile of Female Sexual Function

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Satisfactory Sexual Events(Mean Change from Baseline per 4 Weeks)

Study Treatment Baseline Change (TTS - P)

Placebo 2.9 1.0SM 1(N= 562)

TTS 2.8 2.11.1

Placebo 3.2 0.7SM 2(N=532)

TTS 3.0 1.60.9

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Personal Distress Score(Mean Change from Baseline)

Study Treatment Baseline Change (TTS - P)

Placebo 62.6 -16.3 SM 1 (N= 562)

TTS 64.8 -23.6

-7.3

Placebo 66.4 -18.3 SM 2 (N=532)

TTS 66.6 -24.3

-6.0

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Sexual Desire Score(Mean Change from Baseline)

Study Treatment Baseline Change (TTS - P)

Placebo 20.8 6.9SM 1(N= 562)

TTS 19.8 11.95.0

Placebo 23.4 6.2SM 2(N=532)

TTS 21.7 11.45.2

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Summary of Efficacy Findings(Change from Baseline)

SM 1 SM 2

Placebo TTS Placebo TTS

SSEsper 4 wk

1.0 2.1 0.7 1.6

Desire 6.9 11.9 6.2 11.4

Distress -16.3 -23.6 -18.3 -24.3

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TTS Treatment Effects Compared to “Normal” Values

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Number of Events or

Score

SSEs per4 wks

Desire Distress

HSDD BaselineHSDD Post-TTSNormal

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Determination of Minimal Meaningful Treatment Effects

Blinded exit interview of subset (n =132)

“Considering everything that we have talked about today, would you say that you experienced a meaningful benefit from the study patches?”

On TTS: 52% yes; On Placebo: 31% yes Analysis: Receiver Operating Characteristic (ROC) Results

SSE: ≥1.1 event per 4 weeks Desire: ≥ 8.9 change in score Distress: decrease of 20 or more in score

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SSEs - Percent Responders (Phase 3 Studies Combined)

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Percent Responders

>1 SSEs >2 SSEs >3 SSEs

Definition of Response

Placebo

TTS

Differences in percent of responders (TTS minus placebo) ranged from 12 to 14%

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Clinical Efficacy Summary

Small, statistically significant increase in mean number of SSEs

TTS - Placebo = 1 event per 4 weeks

Small changes in secondary endpoints Distress Score:

• TTS - Placebo = - 6.7 units Desire Score

• TTS - Placebo = 5.1 units

Small increase in SSEs responders TTS -Placebo = 14% (>1 event/4 wks)