DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`FOOD AND DRUG ADMINISTRATION
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`CENTER FOR DRUG EVALUATION AND RESEARCH
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`PERIPHERAL AND CENTRAL NERVOUS SYSTEM DRUGS
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`ADVISORY COMMITTEE
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`Wednesday, June 6, 2001
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`8:15 a.m.
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`Holiday Inn
`Bethesda , Maryland
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`FOOD AND DRUG ADMINISTRATION
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`CENTER FOR DRUG EVALUATION AND RESEARCH
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`PERIPHERAL AND CENTRAL NERVOUS SYSTEM DRUGS
`
`ADVISORY COMMITTEE
`
`Wednesday, June 6, 2001
`
`8:15 a.m.
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`Holiday Inn
`Bethesda , Maryland
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`N
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`PARTICIPANTS
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`Claudia H. Kawas, M.D., Consultant and Acting
`Chairman
`
`Sandra Titus, Ph.D., Executive Secretary
`
`MEMBERS:
`
`Ella P. Lacey, ?h.D., Consumer Representative,
`LaRoy P. Penix, M.D.
`Richard D. Penn, M.D.
`Gerald Van Belle, Ph.D.
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`CONSULTANTS:
`
`Gustavo C. Roman, M.D.
`Jerry S. Wolinsky M.D.
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`XYREM CONSULTANTS:
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`VOTING:
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`Pippa Simpson, Ph.D.
`Carol Falkowski, Ph.D.
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`NON-VOTING:
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`Christine A. Sannerud, Ph.D.
`Jerry Frankenheim, Ph.D.
`Jo-Ellen Dyer, Ph.D.
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`ON PONE—LINK - NON-VOTING:
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`Ronald Chervin, M.D.
`Christian Guilleminault, M.D.
`
`FDA:
`
`Robert Temple, M.D.
`Russel} Katz, M.D.
`Ranjit Mani, M.D.
`John Feeney, M.D.
`Deborah B. Leiderman, M.D.
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`C O N T E N T 5
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`Call to Order and Introductions
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`Conflict of Interest
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`FDA Overview, Russell Katz, M.D.
`
`Orphan Medical Presentation:
`Introduction, David Reardan, Ph.D.
`Medical Need, Emmanuel Mignot, M.D.
`Efficacy, William Houghton, M.D.
`Polysomnographic Effects of Xyrem, Jed Black, M.D.
`Safety and Summary of Risk/Benefit Assessment,
`William Houghton, M.D.
`
`FDA Response to the Presentation, Ranjit Mani, M.D.
`Committee Discussion and Deliberations
`
`FDA Invited Speakers on Risk Management Issues:
`Epidemiology of GHB Abuse Issues,
`Carol Falkowski
`Adverse Medical Effects with GHB,
`Jo Ellen Dyer
`
`Sponsor Presentation on Risk Management and Abuse
`Liability, Bob Balster, Ph.D.
`152
`Risk Management, Patti Engel, R.N., BSN
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`Open Public Hearing:
`
`Sharon Fitzgerald, Littleton, Colorado
`Richard L. Gelulla, MSW, National Sleep
`Foundation
`Abbey S. Meyers, National Organization
`for Rare Disorders,
`Inc.
`Robert L. Cloud, Narcolepsy Network
`Cindy Pekarick
`Eric C. Strain, M.D., College on Problems of
`Drug Dependence
`Deborah Zvorsec, Ph.D., Hennepin County
`Medical Center
`Trinka Porrata, LAPD
`Matt Speakman
`Charles F. Ciehon, National Association of Drug
`Diversion Investigators
`Debbie Alumbaugh, Michael's Message
`Foundation,
`Inc.
`Brian A. Hunter, Young Adults with Narcolepsy
`Joe Spillane, Pharm.D., ABAT
`Mali Einen
`Sandra Jones
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`Continued Committee Discussion and Deliberations
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`P R O C E E D I N G 3
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`Call to Order and Introductions
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`DR. KAWAS: Good morning, everyone, and
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`welcome to the Wednesday, June 6, 2001 meeting of
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`the Peripheral and Central Nervous System Advisory
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`Committee. My name is Claudia Kawas, and I
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`think
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`we can begin with introductions, please, perhaps
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`over by Dr. Temple's side.
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`DR. TEMPLE:
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`Bob Temple,
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`I am the Office
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`Director.
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`DR. KATZ: Russ Katz, Division of
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`Neuropharmacological Drug Products, FDA.
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`DR. FEENEY:
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`John Feeney, neurology team
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`leader, FDA.
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`DR. MANI: Ranjit Mani, medical reviewer,
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`Neuropharm., FDA.
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`DR. LEIDERMAN: DebOrah Leiderman,
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`Director, Controlled Substance Staff, FDA.
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`DR. SIMPSON:
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`Pippa Simpson, University of
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`Arkansas Medical Sciences, biostatistician.
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`DR. FALKOWSKI: Carol Falkowski, drug
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`abuse researcher, Hazelden Foundation.
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`DR. ROMAN: Gustavo Roman, Professor of
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`Neurology at the University of Texas, San Antonio.
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`DR. WOLINSKY:
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`Jerry Wolinsky, Professor
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`U1
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`of Neurology, University of Texas, Houston.
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`DR. TITUS:
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`Sandy Titus, FDA,
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`the
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`administrator of the Peripheral and Central Nervous
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`System Committee.
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`DR. PENN: Richard Penn, neurosurgeon at
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`the University of Chicago.
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`DR. LACEY: Ella Lacey, professor emerita,
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`Illinois University, Carbondale, Tllinois.
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`DR. VAN BELLE: Gerald Van Belle,
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`Department of Bioetatistics,
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`from the University of
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`Washington.
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`DR. PENIX:
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`LaRoy Penix, Associate
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`Professor of Neurology at Moorehouse School of
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`Medicine.
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`DR. SANNERUD: Christina Sannerud, Drug
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`and Chemical Evaluation Section, Drug Enforcement
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`Administration.
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`DR. DYER:
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`I am Jo Dyer, with the
`
`University of California, San Francisco and the San
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`Francisco Poison Control System, Caiifornia.
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`DR. FRANKENHEIM:
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`Jerry Frankenheim,
`
`pharmacologist, National Institute on Drug Abuse.
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`DR. KAWAS; Today we have met to discuss
`
`the consideration of Xyrem, proposed to reduce the
`
`incidence of cataplexy and to improve the symptom
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`of daytime sleepiness for persons with narcolepsy.
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`DJ
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`The main focus of the deliberations will also be on
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`risk management
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`issues.
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`If we could ask Dr. Titus to begin with
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`the conflict of interest statement?
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`Conflict of Interest Statement
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`DR. TITUS: Before I begin the conflict of
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`interest statement,
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`I just want
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`to announce that we
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`have two people on line with us. Dr. Chervin and
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`Dr. Guilleminault.
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`They are both in a room
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`listening to us and will participate with us on the
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`mikes.
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`The following announcement addresses the
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`issue of conflict of interest with regard to this
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`meeting and is made a part of the record to
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`preclude even the appearance of such at this
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`meeting.
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`The special government employees
`
`participating in today's meeting have been screened
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`for interests in Orphan Medical's Xyrem and for
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`interests in the products and sponsors deemed by
`
`the agency to be competing. Based on the agency's
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`review of each participant's response to the
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`conflict of interest screening, it has been
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`determined that there is no potential for a
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`conflict of interest with regard to this meeting.
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`With respect to FDA's invited guests,
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`there are reported affiliations which we believe
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`should be made public to allow the participants to
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`objectively evaluate their comments.
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`Dr. Ronald Chervin would like to disclose
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`for the record that he has a contract with Cephalon
`
`to study Provigil, but not for use in narcolepsy.
`
`He is the principal investigator. however. no funds
`
`from Cephalon, present or past, have contributed to
`
`his personal salary and none have been made
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`available for his non-research related use.
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`Further,
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`in previous years Dr. Chervin was a
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`co investigator with Cephalon in a narcolepsy
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`clinical trial.
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`Christian Guilleminault has been the
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`administrator of the Sleep Disorder Clinic in Palo
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`Alto, California, where the study of Xyrem was
`
`performed by a team of researchers.
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`In the event that the discussions involve
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`any other products or firms not already on the
`
`agenda for which an FDA participant has a financial
`
`interest,
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`the participants are aware of the need to
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`exclude themselves from such involvement and their
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`exclusion will be noted for the record.
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`With respect to all other participants, we
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`ask in the interest of fairness that they address
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`any current or previous involvement with any firm
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`whose products they may wish to comment upon.
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`Thank you.
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`DR. KAWAS:
`
`Thank you very much, Dr.
`
`Titus.
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`We will begin with Dr. Russell Katz, of the
`
`FDA, who will give us the FDA overview of the
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`issues.
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`I want to point out to the committee
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`members that they have much of the materials that
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`they will be seeing during this meeting in front of
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`them.
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`FDA Overview
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`DR. KATZ: Thanks. Claudia. First,
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`I
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`would like to welcome the committee back.
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`You were
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`here just a few months ago so I appreciate your
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`coming back so soon.
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`We have a number of invited guests who are
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`augmenting the committee today, and many of them
`
`are experts in the evaluation of issues related to
`
`drug abuse, and I would just like to welcome them,
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`in particular Drs. Simpson. Sannerud and
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`Frankenheim.
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`We have two other experts who will
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`actually be speakers later this morning. Dr. Dyer
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`will speak on her experience with GHB use and
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`misuse in cases she has seen, and Dr. Falkowski
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`will talk about the epidemiology of GHB abuse in
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`the United States.
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`Finally, as Dr. Titus mentioned, we have
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`two acknowledged experts in sleep disorders who are
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`attending the annual sleep meetings in Chicago, but
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`who have agreed to sit in a hotel room for however
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`long this takes and participate by phone.
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`So, Drs.
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`Guilleminault and Chervin, wherever you are,
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`thank
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`you. Thanks for being here.
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`As you know and as you have heard,
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`today
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`we will ask you to discuss NDA 21—196, which was
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`submitted by Orphan Medical for the use of Xyrem,
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`gamma hydroxybutyrate or better known as GHB,
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`for
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`the treatment of cataplexy and excessive daytime
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`sleepiness in patients with narcolepsy.
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`GHB is a simple molecule and it is
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`ubiquitous in mammalian tissues,
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`its function
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`though is not really well known.
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`Its relevant
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`regulatory history goes back to about 1990, and
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`prior to that date it was freely available in
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`health food stores. But in 1990 the agency began
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`to receive reports of widespread recreational use
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`in a number of different types of folks,
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`for a
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`number of different types of reasons, or GHB and
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`[‘J
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`began to get numerous reports of serious adverse
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`events associated with its misuse.
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`It was not entirely clear that all of
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`these events were necessarily related to GHB.
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`Tt
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`was difficult to interpret some of these reports
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`because there were concomitant medications that
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`were unreported and it wasn't entirely clear
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`whether or how much GHB was in a particular
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`preparation that someone had taken.
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`Those sorts of
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`issues made it difficult to completely interpret
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`the reports, but many of the reports were of events
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`that were known to be consistent with GHB's effect
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`as a potent CNS depressant,
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`including things like
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`respiratory depression,
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`coma and other decreased
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`levels of consciousness.
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`So, it was reasonable to
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`believe that GHB was at least in part responsible
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`for some of these reports.
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`As a result of these reports,
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`the agency
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`withdrew GHB from health food shelves and made it
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`illegal to use. However, illicit use continued and
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`continues to this day. not only with GHB but with
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`two related drugs which are precursors, GEL and
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`1,4-butanediol, and there have been similar reports
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`of serious adverse events associated with the use
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`ll
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`of those products.
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`So, against this background of use,
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`the
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`investigation of GHB as a treatment for cataplexy
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`began. Based on the results of a single trial
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`performed by the sponsor and their commitment
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`to
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`perform additional trials,
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`the sponsor was granted
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`a treatment
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`IND in December of 1998.
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`For those of
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`you unfamiliar with a treatment
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`IND, it is
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`basically a mechanism to permit use of an
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`investigational drug outside the context of a
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`controlled trial for a serious disease for which
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`there aren't other available treatments.
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`It is
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`usually granted relatively late in the development
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`of a drug so that by the time you grant it you have
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`some reasonable idea, based on controlled data,
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`that the drug is probably effective and reasonably
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`well tolerated.
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`Just another relevant piece of history,
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`in
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`2000 Congress passed a law which placed GHB in
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`Schedule I and also placed it into Schedule III for
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`any approved uses that may be granted.
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`The NDA that we are discussing today was
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`submitted in September of 2000 by the company, and
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`it contains the results of four controlled trials
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`which the sponsor believes establish substantial
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`evidence of effectiveness for cataplexy and
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`excessive daytime sleepiness in patients with
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`narcolepsy.
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`It also contains, obviously, safety
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`experience.
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`I iust want to talk about the safety
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`experience for just a little bit. As you know from
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`the briefing documents, much of the safety data in
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`the application was not generated by the cempany
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`but by an individual investigator under his own
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`individual investigator IND. This is Dr. Scharf,
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`and he is an acknowledged expert in the use of GHB
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`and he has been treating patients under his IND for
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`about 16 years. His data comprise almost 30
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`percent of the patient safety database in the NDA.
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`If one looks at patient time, his experience
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`constitutes about 70 percent of the total patient
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`exposure.
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`As part of a routine investigation of
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`the
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`NDA to look at source documents,
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`the agency
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`investigators found that they were unable to locate
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`some critical sOUrce documents of Dr. Scharf's IND,
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`and it was difficult to confirm the sponsor's
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`submission of Dr. Scharf's data. However,
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`subsequent
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`to that. Dr. Scharf has made extensive
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`efforts to provide the additional source documents
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`and agency investigators have reinspected that
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`data.
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`I believe the conclusion of that
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`investigation is that we find that the records,
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`for
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`the most part, do support
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`the sponsor's
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`descriptions of Dr. Scharf's data. And, we believe
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`we can make certain statements about that data at
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`this point.
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`We were particularly interested in the 80
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`or so patients that Dr. Scharf treated that did not
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`move on into the company's treatment
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`IND.
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`He
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`treated a total of 143, or thereabouts. patients,
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`60 of whom went
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`into the sponsor's treatment TND.
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`So, we had a good idea of what was happening to
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`those patients but there were about 80 that didn't
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`and who were basically discontinued from treatment
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`under Dr. Scharf‘s own IND.
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`So. except for a handful of patients. we
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`believe we know why those 80 patients discontinued
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`and their status.
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`I believe we can say reasonably
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`comfortably say that nothing catastrophic that we
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`don't know about happened to those patients but,
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`unfortunately, we have relatively little
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`well—documented data regarding other less serious
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`adverse events in that cohort of 80. Other than
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`patient diaries. we have essentially no
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`documentation about exactly what dose those
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`Id
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`patients took and for how long.
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`I have gone into this at some depth
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`because the safety experience in the NDA is
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`relatively small as compared to a typical NBA. and
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`that is by agreement. This is an orphan product.
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`Based on the sponsor's estimated prevalence of
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`cataplexy of about 25,000, it received orphan
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`designation and one wouldn't necessarily expect
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`that a safety database of a typical size, which is
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`somewhere in at least 10000 to 2000 patients in the
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`typical NDA, would be submitted in an orphan
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`application.
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`50, we agreed with the sponsor that
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`about 500 patients treated for appropriate
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`durations, at appropriate doses would be
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`acceptable.
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`But, given the relatively small database
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`and some of these residual questions about a
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`reasonable proportion of it.
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`that
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`is to say Dr.
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`Scharf's data,
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`that may take on some additional
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`meaning and we would like you to think aoout that
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`as the day goes on.
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`in addition to the safety and the
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`effectiveness data which is required in an NBA of
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`course,
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`the sponsor has proposed a detailed risk
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`management program, and that has three goals:
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`to
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`N
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`inform patients and physicians about
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`the risks of
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`GHB;
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`to minimize the risks to those patients; and
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`also to minimize the likelihood that subjects for
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`whom the drug has not been prescribed will be
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`exposed to it. This latter point not only refers
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`to diversion and its use illicitly by folks who
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`shouldn't be taking it, but also to the accidental
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`use of GHB in the home, perhaps by small children,
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`and you will hear how GHB is administered and what
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`form it is prepared in, and We think that is a
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`potential risk.
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`So, we would like you to think
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`about that as the day goes on too.
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`As far as the risk management program, you
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`will hear about it in great detail from the company
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`but,
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`in brief. it consists ot a couple of sort of
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`major components. One is that the product will be
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`made available through a central pharmacy and will
`
`be shipped directly to the patient at home.
`
`Physicians and patients will also receive detailed
`
`materials about the risks and the appropriate use
`
`of the drug after the first prescription is filled.
`
`Actually,
`
`they will receive those materials
`
`initially and all subsequent refills of
`
`prescriptions will be contingent upon patients and
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`physicians documenting that they have read these
`
`materials, and they understand the risks and how to
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`take the drug appropriately.
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`_
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`All patients and physicians will be
`
`entered into a registry, and there will be close
`
`surveillance instituted to ensure that untoward
`
`events are minimized, for example,
`
`to ensure that
`
`patients don't go from doctor to doctor trying to
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`get refills of prescriptions that are
`
`inappropriate.
`
`So, with these data and against the
`
`background of misuse of GHB out
`
`in the population
`
`at
`
`large, we bring you today's application and we
`
`will ask you to formally vote on three questions.
`
`One is whether or not you think that substantial
`
`evidence of effectiveness has been submitted for
`
`the indications that the sponsor has proposed,
`
`that
`
`is to say, cataplexy and excessive daytime
`
`sleepiness in patients with narcolepsy.
`
`If you
`
`find that they haven't, we would he very interested
`
`to know whether or not you feel that substantial
`
`evidence has been submitted for either of those two
`
`indications.
`
`while you listen to the effectiveness
`
`data, we would like you to pay particular attention
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`to the question of dose and for which dose you
`
`think evidence of effectiveness has been submitted.
`
`If you find there is substantial evidence of
`
`effectiveness for a particular indication, we need
`
`to ask you whether or not GHB can be considered
`
`safe in use given appropriate labeling.
`
`Now, we
`
`are not going to discuss necessarily the specifics
`
`of proposed labeling but, nonetheless, we ask you
`
`to think of it in that context.
`
`Again,
`
`in assessing the safety of the
`
`product, we ask you to concentrate on at least the
`
`question of what dose you have found to be
`
`effective and whether or not there is sufficient
`
`safety experience at that dose for the drug to be
`
`approved.
`
`Finally, we want to take a formal vote on
`
`the question of whether or not you think it is
`
`required or should be required that the drug be
`
`approved only with the risk management program of
`
`some type, not necessarily the one specifically
`
`proposed by the company. Obviously,
`
`the company
`
`has proposed a risk management program but we need
`
`to know whether or not you think it is mandatory
`
`that it be approved with such a program in place“
`
`If you do, we have a number of questions that we
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`would like you to discuss -- not necessarily take a
`
`formal vote on but discuss with regard to a risk
`
`management program and some of the provisions that
`
`the sponsor has proposed.
`
`There are some aspects of the program that
`
`they have proposed that we would like you to pay
`
`particular attention to and discuss.
`
`For example,
`
`there is some considerable sympathy in the agency
`
`for including a provision in the risk management
`
`program that would restrict the use of the drug to
`
`patients with whatever indication you believe has
`
`been supported,
`
`that is to say,
`
`to restrict as much
`
`as possible off—label prescribing. That is one
`
`possibility.
`
`There is also some enthusiasm internally
`
`for physicians and patients to document that they
`
`have reviewed the relevant materials before the
`
`first prescription is filled.
`
`So. we would like
`
`you to think about that as well as we talk about
`
`the risk management program.
`
`So, as you can see from the agenda,
`
`the
`
`company is going to present the safety and
`
`effectiveness data, after which Dr. Mani,
`
`from the
`
`Division, will come up and present briefly some of
`
`our views about the data you will have just heard.
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`Specifically,
`
`I believe we have some different
`
`views about
`
`the evidence submitted for establishing
`
`a claim for excessive daytime sleepiness in
`
`narcolepsy, and there may be other additional
`
`safety issues that we would like to bring up at
`
`that time.
`
`in particular the question of an event
`
`that has been called sleep walking.
`
`I think with that as background,
`
`I will
`
`turn it back to Dr. Kawas.
`
`Thank you.
`
`DR. KAWAS:
`
`Thank you, Dr. Katz. Orphan
`
`Medical presentation is to follow. Dr. David
`
`Reardan, Orphan Medical?
`
`Orphan Medical Presentation
`
`DR. REARDAN: Hi. Good morning. Good
`
`morning,
`
`ladies and gentlemen, members of the
`
`committee and FDA.
`
`[Slide]
`
`My name is David Reardan. and I represent
`
`Orphan Medical as head of regulatory affairs.
`
`Orphan Medical
`
`is a small, 6D—person firm,
`
`dedicated to the development of orphan drugs. We
`
`have obtained marketing approval for six orphan
`
`products from FDA since we were founded,
`
`in 1994.
`
`The firm became involved with Xyrem when
`
`approached by FDA that same year. and Xyrem was
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`CBM of US. Patent No. 7,668,730
`Page 19 of 400
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`Page 19 of 400
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`designated an orphan drug in 1994.
`
`Today we will
`
`share with you the data that has been collected
`
`with respect to the efficacy and safety since our
`
`IND was submitted,
`
`in 1996.
`
`[Slide]
`
`Dr. Mignot, director of the Narcolepsy
`
`Institute at Stanford University, will present a
`
`picture of a narcoleptic patient and the serious
`
`medical need such patients have for new therapeutic
`
`treatments .
`
`Dr. Houghton is the chief medical officer
`
`and chief operating officer at Orphan Medical, and
`
`he will present next on the efficacy that has been
`
`collected. Dr. Houghton was chair of anesthesia
`
`and critical care in Australia.
`
`Dr. Black, director of the Stanford Sleep
`
`Clinic and an investigator for several trials, will
`
`share with you the EEG pharmacology of Xyrem. Dr.
`
`Houghton will then present the safety data and
`
`finish up with a benefit/risk assessment.
`
`Following presentations by two FDA invited
`
`speakers with respect to GEB abuse, Dr. Balster,
`
`director of the Institute for Drug and Alcohol
`
`Studies at the Medical College of Virginia, will
`
`share with you his views on abuse liability.
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`PAR1003
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`Page 20 of 400
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`Page 20 of 400
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`Since there is pubLic abuse of GHB and its
`
`analogs.
`
`the company has developed a risk
`
`management program for Xyrem that will be presented
`
`by Patti Engel, our vice president of marketing and
`
`sales.
`
`[Slidel
`
`In addition to those presenting today,
`
`the
`
`following experts are available in the audience to
`
`answer questions from the committee or FDA: Dr.
`
`Emsellem, Dr. Hagaman and Dr. Ristanovic are all
`
`directors of their respective sleep institutes, and
`
`have been investigators in our clinical trials.
`
`Dr. Okerholm is a consultant
`
`in the area of
`
`pharmacokinetics and drug metabolism; Dr. Reno in
`
`the area of toxicology; and Dr. Richard Trout, who
`
`is a professor emeritus in statistics from Rutgers,
`
`is here if there are any statistical questions.
`
`[Slide]
`
`This is the chemical structure of sodium
`
`oxybate, more commonly known as gamma
`
`hydroxybutyrate, or GHB. Notice that it is a
`
`simple 4-carbon hydroxy fatty acid and, as such,
`
`quite easy to synthesize.
`
`In fact, kits have been
`
`illegally promoted on the Internet for its
`
`manufacture.
`
`If an amino group were to replace
`
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`PAR1003
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`CBM of US. Patent No. 7,668,730
`Page 21 of 400
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`Page 21 of 400
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`this alcohol functional group at position 4, you
`
`would have GABA, gamma aminobutyric acid, another
`
`CNS active chemical. Oxybate is a natural compound
`
`in the human body.
`
`[Slide]
`
`Gamma hydroxybutyrate was first discovered
`
`in the 1960's by Dr. Labore,
`
`in France, and was
`
`investigated as an analog for GABA.
`
`It was found
`
`to have hypnotic properties and was first appr0ved
`
`in France. and later a few other countries of
`
`Europe, as an adjunct
`
`in anesthesia.
`
`It was used
`
`in labor and delivery for quite a few years.
`
`The
`
`injectable form is still available today in parts
`
`of Europe.
`
`In the 1970's initial work was begun in
`
`Canada to test its properties in narcolepsy.
`
`Following initial promise for use in patients with
`
`narcolepsy two controlled trials were conducted by
`
`independent investigators, one in the U.S. and one
`
`in The Netherlands.
`
`In 1994, due to the promising
`
`investigator trials, FDA Office of Orphan Products
`
`approached Orphan Medical to consider the compound
`
`for development.
`
`Since there was no patent protection and
`
`the market was very small, no other firms were
`
`17
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`DJP.)L--'[J
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`I“) .5:-
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`Id in
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`PAR1003
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`CBM of U.S. Patent No. 7,668,730
`Page 22 of 400
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`Page 22 of 400
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`
`
`willing to consider the development of GHB for
`
`w
`
`narcolepsy at the time. Orphan Medical agreed to
`
`sponsor this medication. Our new drug application
`
`was submitted in October of 2000 and was designated
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`by FDA for priority review.
`
`The clinical development has been fairly
`
`straightforward and all controlled trials conducted
`
`to date have shown sodium oxybate to be effective
`
`and safe for the treatment of narcolepsy. This
`
`project has been made more difficult because of
`
`the
`
`abuse situation.
`
`[Slide]
`
`Let me explain why Xyrem is not going to
`
`be a factor in the abuse of GHB and its precursors.
`
`Orphan Medical was aware abuse existed at the time
`
`the company agreed to sponsor development of Xyrem.
`
`At this same time, Internet was burgeoning.
`
`Due to
`
`its ease of synthesis and ready availability of
`
`precursor chemicals, GHB was initially an easy
`
`target for promoters of illegal drugs.
`
`But GHB is not
`
`the only problem.
`
`GEL and
`
`1.4-butanediol are precursor chemicals that can be
`
`easily converted to GHB and are,
`
`in fact. converted
`
`to GHB in the human body.
`
`These precursors are
`
`widely available as bulk chemicals and are being
`
`PAR1003
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`CBM of US. Patent No. 7,668,730
`Page 23 of 400
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`
`Page 23 of 400
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`
`
`.'L
`
`illegally used in the United States, and the abuse
`
`L.)
`
`problem is growing.
`
`Federal legislation, enacted in 2000,
`
`helped to control
`
`the availability of GHB and GEL
`
`but not 1,4—butanediol and other precursor
`
`chemicals that can be used for the same purpose.
`
`In many states, even with GHB schedules, GBL and
`
`1,4—butanediol are not controlled.
`
`We believe that approval of Xyrem for use
`
`by patients with narcolepsy will not add to the
`
`general abuse problem of GHB and its numerous
`
`precursors.
`
`[Slide]
`
`The proposed indication for which we are
`
`asking FDA for marketing approval
`
`is to reduce the
`
`incidence of cataplexy and to improve the symptom
`
`of daytime sleepiness in patients with narcolepsy.
`
`[Slide]
`
`Narcolepsy fits the definition of orphan
`
`disease in the United States, with less than
`
`200,000 patients. There are estimated to be about
`
`135,000 patients, of which 55 percent are
`
`diagnosed, with about 24,000 seeking treatment for
`
`cataplexy.
`
`[Slide]
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`Page 24 of 400
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`Page 24 of 400
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`
`
`I‘d
`
`I would now like to introduce you to Dr.
`
`Emmanuel Mignot,
`
`from Stanford. Dr. Mignot has
`
`been widely published in this area and is
`
`considered one of the premiere international
`
`experts on narcolepsy.
`
`He has not participated in
`
`any of our clinical trials.
`
`Medical Need
`
`DR. MIGNOT:
`
`It is my privilege to talk to
`
`you today about narcolepsy.
`
`I have been working on
`
`narcolepsy for about 15 years, both at the level of
`
`basic research as well as clinical care.
`
`I am a
`
`medical doctor and I see patients with narcolepsy.
`
`[Slide]
`
`I am going to try to summarize in a few
`
`minutes really a lot of data about narcolepsy and
`
`how it impacts people.
`
`[Slide]
`
`First.
`
`I would like to start briefly by
`
`reviewing the symptoms of narcolepsy. Narcolepsy
`
`is usually associated with 5 different symptoms.
`
`The most disabling and the most problematic in
`
`patients with narcolepsy is sleepiness. Patients
`
`with narcolepsy are sleepy all the time; tired;
`
`they have sleep attacks;
`
`they cannot stay awake for
`
`a long period of time. and it is usually why they
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`Page 25 of 400
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`Page 25 of 400
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`
`
`come to see the doctor.
`
`They just cannot
`
`live a
`
`normal life. Especially in work conditions, as you
`
`probably know,
`
`it is very difficult -- you have to
`
`be awake all day long and it is a major problem in
`
`narcolepsy.
`
`Now,
`
`it is not enough to diagnose
`
`narcolepsy. Narcolepsy is not just sleepiness and
`
`there are a lot of other medical conditions that
`
`are associated with sleepiness. Patients with
`
`narcolepsy also have a series of symptoms that
`
`correspond to the fact that they go very quickly
`
`into rapid eye movement sleep. As probably many of
`
`you know, rapid eye movement sleep is a stage of
`
`sleep that only occurs 1.5 or 2 hours after you
`
`fall asleep where you are actively dreaming but
`
`your body is completely paralyzed and you have
`
`these rapid eye movements.
`
`Patients With narcolepsy go into REM sleep
`
`extremely quickly, sometimes in a few minutes, and
`
`that leads to a series of symptoms where patients
`
`sometimes are half way through REM sleep, being
`
`still awake. Consequently,
`
`they may experience odd
`
`symptoms that we call the dissoeiated REM sleep
`
`event, abnormal REM sleep event. Those are
`
`cataplexy, hypnagogic hallucinations and sleep
`
`N
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`Page 26 of 400
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`Page 26 of 400
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`
`paralysis.
`
`An example is cataplexy. when a patient
`
`gets emotionally excited,
`
`typically when they are
`
`happy,
`
`they meet a good friend, sometimes when they
`
`are angry but most often when they are joking,
`
`in a
`
`nice environment and happy about something,
`
`they
`
`may feel suddenly week;
`
`they become paralyzed;
`
`sometimes they fall down to the ground, completely
`
`paralyzed and they cannot move.
`
`In very rare cases
`
`they may even go into REM sleep.
`
`We believe
`
`somehow being emotionally excited stimulates the
`
`paralysis of rapid eye movement sleep that every
`
`one of us experiences during sleep, except that in
`
`patients with narcolepsy it may occur in the middle
`
`of the day in response to emotion.
`
`Also, when they fall asleep they sometimes
`
`have hallucinations because they go so quickly into
`
`REM that sometimes they dream while they are still
`
`awake.
`
`I
`
`remember a patient, for example, who
`
`every night would fall asleep and he would see
`
`someone coming and strangling him. Or.
`
`they may
`
`hear people talking; or see people walking in the
`
`room.
`
`It can be very frightening and it can be a
`
`very terrible experience for patients with
`
`narcolepsy.
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`Page 27 of 400
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`28
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`Another symptom of abnormal REM sleep that
`
`patients with narcolepsy have as well is called
`
`sleep paralysis. When they wake up from a nap or
`
`when they fall asleep, sometimes they again go so
`
`quickly into REM and disassociated REM sleep events
`
`that sometimes they ma
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