Agenda

6/20/01


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Table of Contents

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Agenda

Experts Available for the Committee

Chemical Structure

Regulatory Overview

Recognition of Abuse

Proposed Indication

Prevalence of Narcolepsy in the U.S.

Narcolepsy - Medical Need

Narcolepsy - Cataplexy

Narcolepsy - A Disabling Disorder

Driving Effects and Accidents

Objective Measurement of EDS

Abnormal Regulation of REM Sleep

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Partial Efficacy of Treatments: MWT

Hypocretin Deficiency in Narcolepsy

Need for New Treatments

William Houghton, M.D. Chief Operating Officer & Medical Officer, Orphan Medical, Inc.

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OMC-GHB-2 Study

OMC-GHB-2 Efficacy Parameters

OMC-GHB-2 Inclusion Criteria

OMC-GHB-2 Overall Study Design

Cataplexy Attacks per Week

OMC-GHB-2 Primary Efficacy Total Cataplexy

OMC-GHB-2 Primary Efficacy Cataplexy (Median Percent Change)

Secondary Efficacy Epworth Sleepiness Scale

OMC-GHB-2 Secondary Efficacy Daytime Sleepiness (medians)

OMC-GHB-2 Other Daytime Sleepiness Parameters

Clinical Global Impression (CGI)

Clinical Global Impression of Change at Endpoint OMC-GHB-2 – By Dose Group

Post-Hoc Responder/Non-Responder Analysis

OMC-GHB-2 Secondary Efficacy CGIc

OMC-GHB-2 Other Variables

OMC-SXB-21

OMC-SXB-21 Objective

OMC-SXB-21 Study Design

OMC-SXB-21 Cataplexy Median Change from Baseline

OMC-SXB-21 Cataplexy Median Change from Baseline

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Scrima Cross-over Trial Study Design

Scrima Trial Number of Cataplexy Attacks / Week

Lammers Trial Study Design

Lammers Trial Cataplexy

Lammers Trial Other Measures

OMC-GHB-3

OMC-GHB-3 Cataplexy – Median Percent Change

OMC-GHB-3 Mean ESS for All Dose Groups

OMC-GHB-3 Dose Distribution – 6 & 12 Months

OMC-SXB-21 Supports Efficacy in OMC-GHB-3 Cataplexy Attacks / Week: OMC-GHB-2/3 Patients in OMC-SXB-21

Summary of Efficacy

William Houghton, M.D. Chief Operating Officer & Medical Officer, Orphan Medical, Inc.

Xyrem Pharmacokinetic Studies

Plasma Concentrations of Oxybate (GHB) After 4.5 Grams (2x2.25) or 9.0 Grams (2x4.5) of Xyrem to Normal Volunteers (Mean, Standard Error)

Plasma Oxybate (GHB) Concentration After an Oral Dose of 4.5 Grams of Xyrem to Normal Volunteers Following a High Fat Meal or after an Overnight Fast

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Xyrem Pharmacokinetics: Summary

Xyrem Pharmacokinetics: Summary

Polysomnographic Effects of Xyrem

Effects of Sodium Oxybate on Quantitative EEG Parameters in Narcoleptics

Scrima and LammersTrials Nocturnal PSG Data

OMC-SXB-20 Study Design

OMC-SXB-20 Study Results

Change in Slow Wave (Stages 3&4) Sleep Duration

Total Slow Wave (Stages 3&4) Sleep Duration

Delta Power

MWT Sleep Latency (Daytime)

Epworth Sleepiness Score (Daytime)

Correlation Between Daytime and Nocturnal Effects

OMC-SXB-20 Overall Conclusions

William Houghton, M.D. Chief Operating Officer & Medical Officer, Orphan Medical, Inc.

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Sodium Oxybate Exposure All Trials Including Scharf

Sodium Oxybate Exposure Updated ISS Excluding Scharf

Updated ISS Database Summary of Patient Exposure by Dose

Updated ISS Database Treated Patient Disposition

Updated ISS Database Summary of Adverse Events

Updated ISS Database Dose Distribution of Adverse Events

Updated ISS Database Most Frequent Adverse Events (n=399)

Placebo-Controlled Clinical Trials Most Frequent Adverse Events

OMC-SXB-21 Safety Summary

OMC-SXB-21 Possible Withdrawal Associated AEs

Scharf Trial

Adverse Events

Scharf Trial (16 years) Patient Disposition

Scharf Trial (16 years) AE Incidence

Comparison of Updated ISS Database to Scharf Trial (First 6 months) Most Frequent Adverse Event Incidence

Adverse Events of Special Interest

Incontinence

Incontinence

Incontinence Method

Urinary Incontinence

Fecal Incontinence

Incontinence Conclusion

Convulsions

“Confusion”

Summary of Adverse Events COSTART Coded as “Confusion”

Updated ISS Verbatim Terms for “Confusion”

Updated ISS Action Taken for AE of Confusion

Controlled Trial: OMC-GHB-2 Confusion as AE

Confusion -- Conclusions

Neuropsychiatric Events

Summary of Neuropsychiatric Adverse Events

Updated ISS Summary of Neuropsychiatric Events

Scharf Open-Label Trial Summary of Neuropsychiatric Events

Conclusions Neuropsychiatry and Confusion

Sleep Disorders Sleepwalking (Somnambulism)

Sleepwalking Summary of Events

Sleepwalking Differential Diagnoses

Sleepwalking in Controlled Trials

Sleepwalking -- Conclusions

Summary of Safety

Summary of Safety

Safety Conclusion

William Houghton, M.D. Chief Operating Officer & Medical Officer, Orphan Medical, Inc.

Benefit-Risk Assessment Proposed Indication

Narcolepsy - Overview

Benefits of Xyrem

Clinical Benefits of Xyrem

Safety of Xyrem

Somnambulism

Enuresis

Laboratory Measures

Tolerance

Withdrawal Phenomenon

Abuse Issues

Conclusions

Robert Balster, Ph.D. Medical College of Virginia

Abuse Liability of Xyrem

GHB and GHB-like Substances

Abuse of GHB-like Substances Results Primarily From Availability

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Scientific Data on the Abuse Potential of GHB

Conclusions From Abuse Potential Studies

Potential Sources of Abuse of Xyrem

Abuse Among Patients is Unlikely

Illicit Diversion of Xyrem Unlikely

GHB, GBL and 1,4- Butanediol Comparison of Production Quantities

Abuse Liability Summary

Patti Engel, R.N., BSN Vice President of Marketing & Sales, Orphan Medical, Inc.

Xyrem Success Program

Xyrem Success Program

Risk Management Through Risk Confrontation

Standard Pharmaceutical Distribution

Xyrem Closed Distribution System

Xyrem’s Distribution

Physician Promotion and Education

Physician Promotion and Education

Physician Success Program Materials

Prescription Process

Physician Verification

Patient Verification

Pre-Shipment Patient Counseling

Rapid Trac® System

Patient Success Program Materials

Post-receipt Contact

Benefits of Central Data Repository

Xyrem Success Program

Xyrem Closed Distribution System

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Xyrem® (Sodium Oxybate) oral solution

OMC-SXB-21 Median Change In Cataplexy Attacks by Dose

Updated ISS Database Summary of Patient Exposure by Dose

Updated ISS Database with Scharf Summary of Patient Exposure by Dose

Updated Integrated Summary of Safety Summary of “Confusion” Events

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