`
`IN ATTENDANCE:
`
` LYNN A. DRAKE, M.D., Acting Chairman
`
`Professor and Chairman
`
`
`
`Department of Dermatology
`University of Oklahoma Health Sciences Center
`619 N.E. 13th Street
`
`Advisors and Consultants Staff
`
`
`
`
`
`
`
`
`
`
`Oklahoma City, OK
`73104
`
` TRACY RILEY, Executive Secretary
`
`Center for Drug Evaluation and Research
`
`
`Fishers Building, Room 1093
`5630 Fishers Lane, HFD-Zl
`
`Rockville, MD
`20857
`
`
`Members
`
` ROBERT E.
`JORDON, M.D.
`J. Josey Erofessorrofinermr& Ch
`7
`N
`,,rrmmrrm,w
`
` Department of Dermatology, MSB 1.204
`
`
`6431 Fannin
`
`
`
`Houston, TX
`
`77030
`
`
`HENRY LIM, M.D.
`Chairman, Department of Dermatology
`
`
`Henry Ford Hospital
`
`
`2799 West Grand Boulevard
`Detroit, MI
`48202
`
`
`
`
`Director, Department of Dermatology
`Geisinger Medical Center
`North Academy Avenue
`Danville, PA 17822-1406
`
` O. FRED MILLER, III, M.D.
`
`
`
`
`
`
`
`
`ROBERT S. STERN, M.D.
`Beth Israel Deaconness Medical Center
`330 Brookline Avenue
`Boston, MA
`02215
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`11923 Parklawn Drive, Suite 203
`Rockville, MD 20852
`
`(301)881-8132
`
`
`
`IN ATTENDANCE:
`
`SBecial Government Emgloyee Consultants
`
`ELIZABETH A. ABEL, M.D.
`
`Stanford University School of Medicine
`2500 Hospital Drive, Building 9
`Mountain View, CA
`94040
`
`SUSAN COHEN, B.S.
`
`9814 Inglemere Drive
`Bethesda, MD
`20817
`
`JOHN J. DiGIOVANNA, M.D.
`Dermatology Clinical Research Unit
`NIH Building 10, Room 9N228
`NIAMS/IRPH
`Bethesda, MD
`
`20892—1820
`
`JAMES KILPATRICK, JR., Ph.D.
`S.
`
`Prefessorgof—BiostatisticsiWMedical College of Virginia
`Virginia Commonwealth University
`1101 East Marshall Street
`
`10029-6574
`
`Sanger Hall, Room B-1-039-A
`Richmond, VA
`23298-0032
`
`PHILIP T. LAVIN, Ph.D.
`Boston Biostatistics Research Foundation
`615 Concord Street
`
`Framingham, MA
`
`01702
`
`JOSEPH MCGUIRE, M.D.
`Carol Herzog Professor of Dermatology and Pediatrics
`Stanford University School of Medicine
`Department of Dermatology
`MSLS Building, Room P-204
`Stanford, CA
`94305
`
`JOEL MINDEL, M.D., Ph.D.
`Director, Neuro-Ophthalmology
`Mount Sinai Medical Center
`
`Annenburg Building, 22-14
`Box 1183
`
`New York, NY
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`11923 Parklawn Drive, Suite 203
`Rockville, MD 20852
`
`(301)881-8132
`
`
`
`MARTIN M. OKUN, M.D., Ph.D.
`Medical Officer, Division of Dermatologic
`and Dental Drug Products (DDDDP)
`
`JONATHAN WILKIN, M.D.
`Director, DDDDP
`
`SEonsor ParticiEants, DUSA Pharmaceuticals
`
`Guidelines,
`
`fflPhiDin-w
`Inc.
`-
`
`DANIEL PIACQUADIO, M.D.
`Therapeutics,
`Inc. of California - San Diego
`Clinical Consultant
`
`SAMUEL SWETLAND
`
`Guidelines,
`
`Inc.
`
`IN ATTENDANCE:
`
`FDA ParticiEants
`
`SHAHLA FARR, M.S.
`Mathematical Statistician, Division of Biometrics III
`
`RICHARD FELTEN
`
`Expert Reviewer, Center for Devices and Radiological Health
`
`Regulatory Consultant
`
`STUART MARCUS, M.D., Ph.D.
`Senior Vice President, Scientific Affairs
`Chief Scientific Officer
`DUSA Pharmaceuticals
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`11923 Parklawn Drive, Suite 203
`Rockville, MD 20852
`(301)881-8132
`
`
`
`C O N T E N T S
`
`Call to Order and Welcome
`
`Lynn A. Drake, M.D., Chair
`
`Conflict of Interest Statement
`
`Tracy Riley, Executive Secretary
`
`Introductory Remarks
`
`Jonathan Wilkin, M.D.
`
`NDA 20-965 Levulan Kerastick
`Open Session:
`for Topical Solution
`
`Daniel Piacquadio, M.D.
`
`Sponsor Presentation by DUSA Pharmaceuticals
`
`Introduction
`
`Samuel Swetland
`
`Levulan PDT Therapy
`
`Stuart Marcus, M.D., Ph.D.
`
`Pharmacology and Toxicology
`
`Allyn Golub, Ph.D.
`
`Phase I and II Clinical Studies
`
`Stuart Marcus, M.D., Ph.D.
`
`Phase III Clinical Studies
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`11923 Parklawn Drive, Suite 203
`Rockville, MD 20852
`
`(301)881-8132
`
`
`
`Devices Review
`
`Richard Felten
`
`Statistical Review
`
`Shahla Farr, M.S.
`
`
`-, W , 7, Jonathanjilkin,_M-Di—WWWW ,
`
`C O N T E N T S
`
`FDA Presentation
`
`Medical Officer's Review
`
`Martin M. Okun, M.D., Ph.D.
`
`Questions for the Committee
`
`Committee Discussion
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`11923 Parklawn Drive, Suite 203
`Rockville, MD 20852
`(301)881-8132
`
`
`
`
`
`P R O C E E D I N G S
`
`take their seat and please assemble.
`
`solution.
`
`Harvard Medical School, Massachusetts General Hospital.
`
`I would like the panel to introduce themselves.
`
`
`
`DR. DRAKE:
`I would like to ask everybody to
`
`
`
`Welcome to the Dermatologic and Ophthalmic
`
`
`Drugs Advisory Board meeting number 51. This is an open
`
`session regarding NDA 20-965, Levulan Kerastick for topical
`
`
`The first thing I will do is identify myself.
`
`
`
`I'm Lynn Drake.
`I'm professor and chair of the Department
` of Dermatology at the University of Oklahoma Health
`
`
`
`
`
`
`
`I know you've done this before these last 2 days, but we
`
`
`have new players, so I would very much appreciate it if you
`
`would identify yourself by name and position, as well as
` what you do.
`
`
`
`
`DR. STERN: Okay.
`I'm Robert Stern.
`I'm a
`
`
`
`
`
`
`dermatology at Geisinger Medical Center, Danville,
`
`
`professor of dermatology at the Harvard Medical School at
`
`Dr. Stern, would you please start?
`
`the Beth Israel Deaconess Medical Center.
`
`DR. MILLER:
`
`I'm Fred Miller.
`
`I'm director of
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`(301) 881-8132
`
`
`
`
` 8
`
`
`
`
`
`DR. DiGIOVANNA:
`John DiGiovanna.
`I'm director
` of the Division of Dermatopharmacology at Brown University,
`
`
`
`
`and an adjunct investigator at NIAMS of NIH.
`
`
`
`MS. COHEN:
`
`I don't know what to say with all
`
`those things.
`
`I'm Susan Cohen.
`
`I'm a consumer member, and
`
`I also spend some time at the state attorney's office in
`
`
`
`
`
` DR. LIM: I'm Henry Lim, chairman of
`
`
`Montgomery County.
`
`dermatology, Henry Ford Hospital, Detroit, Michigan.
`
`DR.
`JORDON: Dr. Bob Jordon, professor and
`
`
`' WWWEOlOQY’; University Of Texas swim,
`
`,,
`
`dermatology and pediatrics at Stanford University.
`
`
`
`
`Medical School, Houston.
`
`
`
`I'm Joe McGuire, professor of
`DR. MCGUIRE:
`
`
`
`
` I'm Tracy Riley.
`
`MS. RILEY:
`I'm the secretary
`
`
`of the Dermatologic and Ophthalmic Drugs Advisory
`
`
`I'm with FDA.
`Committee.
`
`
`
`
`
`biostatistics at the Medical College of Virginia.
`
`DR. KILPATRICK:
`
`Jim Kilpatrick, professor of
`
`DR. MINDEL:
`
`
`Joel Mindel, professor of
`
`ophthalmology and pharmacology at Mount Sinai Medical
`
`
`
`
`Center, New York.
`
`
`
`DR. LAVIN: Philip Lavin, a biostatistician
`
`
`
`
`FRIEDMAN & ASSOCIATES. COURT REPORTERS
`(301) 881-8132
`
`
`
`Medical School.
`
`MR. FELTEN:
`
`I'm not on the panel.
`
`DR. DRAKE: That's all right. You're at the
`
`table.
`
`MR. FELTEN:
`
`I'm Richard Felten.
`
`I'm the
`
`device reviewer for the NDA.
`
`MS. FARR:
`
`Shahla Farr.
`
`I’m the biostatistical
`
`reviewer, FDA.
`
`DR. OKUN:
`
`I'm Marty Okun,
`
`the medical reviewer
`
`for this NDA.
`
`
`BR. WILKIN:
`Jon WilkinytbermatologiC‘and”
`
`Dental Division Director.
`
`DR. DRAKE:
`
`Thank you.
`
`I am going to announce a slight deviation in
`
`the order of business. Not
`
`in the order, but I want to
`
`announce the fact that we'll probably not take a formal
`
`break this afternoon in the interest of completing this
`
`deliberation in a timely manner.
`
`So for those of you that
`
`need a break, please feel free to just sort of slip out and
`
`take one.
`
`And I would like now to ask —— oh,
`
`I'm sorry.
`
`Dr. Abel just joined us.
`
`Would you mind identifying yourself and your
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`(301) 881-8132
`
`
`
`
`
`
`DR. ABEL: Elizabeth Abel, dermatology,
`
`clinical professor of dermatology at Stanford University.
`
`DR. DRAKE:
`
`Thank you.
`
`I'm now going to ask our executive secretary,
`
`Tracy Riley,
`
`to give the conflict of interest statement.
`
`announcement addresses the issue of conflict of interest
`
`with regard to this meeting and is made a part of the
`
`record to preclude even the appearance of such at this
`
`
`
`
`
`
`
`
`MS. RILEY: Good afternoon.
`The following
`
`
`
`
`meeting.
`
`the agency has determined
`provided by the participants,
`
`
`
`
`
`
`
`participants are aware of the need to exclude themselves
`
`
` for the record.
`
`
`that all reported interests in firms regulated by the
`
`Center for Drug Evaluation and Research present no
`
`potential for conflict of interest at this meeting.
`
`In the event that the discussions involve any
`
`other products or firms not already on the agenda for which
`
`an FDA participant has a financial interest,
`
`the
`
`from such involvement, and their exclusion will be noted
`
`
`
`With respect to all other participants, we ask
`
`in the interest of fairness that they address any current
`
`
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`(301) 881-8132
`
`
`
`
` products they may wish to comment upon.
`
`
`
`
`
`Thank you.
`
`DR. DRAKE:
`
`
`Thank you, Ms. Riley.
`
`I'd like to ask Dr. Jonathan Wilkin to give his
`
`opening and introductory remarks about our business today.
`
`
`
`The questions for this afternoon are largely
`The agency has already come
`directed to labeling issues.
`
`to the conclusion regarding the approvability of this
`
`
`
`product.
`
`
`
`this—time, but the committeerhaswhad"thESE"to review:
`
`
`DR. WILKIN:
`
`
`Thank you, Dr. Drake.
`
`So I'll not read these in the interest of time at
`
`DR. DRAKE: Thank you, Dr. Wilkin.
`
`
`
`
`the issues presented before them, so what I'd like to do
`
`The committee has the questions before them and
`
`now is go to the open public hearing. We've had no written
`
`
`
`
`open for anybody to approach the open mike that wishes to.
`
`requests for appearances today; however,
`
`the invitation is
`
`If so,
`
`I would like you to identify yourself and any
`
`conflicts of interest or financial ties to the issue being
`
`
`discussed today.
`
`
`
`
`(No response.)
`
`I think we'll move
`DR. DRAKE: Seeing none,
`
`
`forward,
`
`
`
`then, with the rest of the program, and I would
`
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`(301) 881-8132
`
`
`
`Pharmaceuticals, and are you Samuel Swetland?
`
`MR. SWETLAND: Yes.
`
`DR. DRAKE: Hi. Welcome.
`
`I would ask you to
`
`introduce yourself and all your fellow presenters, as well
`
`as your role.
`
`And first thing, would you tell me what D-U—S-A
`
`stands for?
`
`.MR. SWETLAND:
`
`D-U—S—A is DUSA, and that's the
`
`name of the company.
`
`DR. DRAKE: That is the whole name of the
`
`MR. SWETLAND:
`
`DUSA Pharmaceuticals,
`
`Inc.
`
`DR. DRAKE:
`
`Thank you.
`
`MR. SWETLAND: Thank you.
`
`I'm Sam Swetland of Guidelines, Inc.
`
`I am a
`
`regulatory consultant for DUSA Pharmaceuticals, and today
`
`NDA No. 20-965.
`
`we are here to discuss -- the first slide, please -- today
`
`we're here to discuss DUSA Pharmaceuticals' NDA for Levulan
`
`Kerastick for topical solution, 20 percent
`
`-—
`
`DR. DRAKE: Can you excuse me just one moment?
`
`We need to have that off. There you go.
`
`Thank
`
`MR. SWETLAND:
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`(301)881-8132
`
`
`
`
` 13
`
`
`
`BLU-U blue light photodynamic therapy illuminator comprise
`The primary mode of
`a drug/device combination product.
`
`action for the combination product has been determined to
`
`be that of a drug, and the Center for Drug Evaluation and
`
`Research has been given administrative jurisdiction over
`
`the combination product. However,
`
`the Center for Devices
`
`and Radiological Health has review responsibilities for the
`
`premarket approval application for the device component.
`
`
`
`
`
`
`
`
`This is a slide of an outline of the sponsor's
`I will present some housekeeping
`presentation today.
`
`-*A*ifi---w fissuesanckrbrief introductiorrtrr the ' Levulan""KerHst’i§k"”""’" ~
`
`
`NDA.
`
`
`Following my presentation, Dr. Stuart Marcus of DUSA
`
`
`
`Pharmaceuticals will present an overview of the Levulan
`
`toxicology information that was submitted as part of the
`
`Then Dr. Marcus will return to present the Phase I
`
`
`
`be Dr. Daniel Piacquadio of Therapeutics, Inc., and the
`
`University of California at San Diego. He was one of the
`
`
`
`
`
`photodynamic therapy. Next, Dr. Allyn Golub, also of
`
`
`Guidelines, Inc., will present the pharmacology and
`
`
`
`NDA.
`
`and Phase II clinical study. Our last speaker today will
`
`
`
`
` Piacquadio will present the Phase III clinical data for the
`clinical investigators in our Phase III program, and Dr.
`
`
`Levulan Kerastick.
`
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`(301) 881-8132
`
`
`
`
` l4
`
`some terms that will be used throughout our presentation.
`
`Levulan is the registered trademark for DUSA
` Pharmaceuticals' brand of the active drug substance,
`
`
` dosage form.
`
`
`
`
`refer to the endogenous form of aminolevulinic acid. And,
`
`finally, PDT stands for photodynamic therapy.
`
`The Levulan Kerastick for topical solution,
`
`plus blue light irradiation~usingathewBfiUrH~biue~iight
`
`photodynamic therapy illuminator,
`
` drug component of the combination product is the Levulan Kerastick.
` segregate the active drug powder from the topical solution
`
` rapid-add mixture of the two components just prior to its
`
`aminolevulinic acid hydrochloride, or ALA HCl.
`
`The
`
`Kerastick is the trade name for DUSA's topical applicator
`
`BLU-U is the trade name for DUSA's blue light
`
`photodynamic therapy illuminator.
`
`ALA will be used to
`
`treatment of actinic keratoses of the face and scalp.
`
`The
`
`is indicated for the
`
`
`
`
`The Kerastick was specifically designed to
`
`vehicle during distribution and storage, and to allow the
`
`use.
`
`
`Since this is a novel dosage form, we brought
` along a display containing the various components of the
` Kerastick, and we'll just pass a few of those around the
`
` room.
`In the meantime, this is a picture of the display.
`
`
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`(30]) 881-8132
`
`
`
`applicator tip and a flexible plastic applicator tube
`
`containing two sealed glass ampules.
`
`The glass ampules
`
`contain the appropriate amount of the active drug substance
`
`and the topical solution vehicle, when mixed together,
`
`to
`
`produce a 20 percent weight/volume topical solution.
`
`The
`
`glass tubes inside the applicator are shown over here on
`
`sleeve, with a cardboard cap that covers the applicator tip
`
`during shipping and storage.
`
`the right. This is placed within a protective cardboard
`
`The drug application is conducted in the ——————physieianisfieéfiiee~bywthewphysieianmor~healthaprofessional7~‘~——vrri
`
`and at the time of administration the two glass ampules are
`
`crushed through the applicator sleeve by pressing at the
`
`locations printed on the label, and the contents are mixed
`
`by shaking.
`
`Then the cardboard cap is removed, and the
`
`solution is applied to the target lesion by gently dabbing
`
`the lesion with the tip such that it wets the lesion, but
`
`does not drip or run.
`
`The second component of the drug/device
`
`combination is the BLU-U blue light photodynamic therapy
`
`illuminator. Pictured here is one of the clinical units
`
`that was used in the Phase III clinical trials.
`
`The BLU—U
`
`is a compact non-laser light source that was specifically
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`(301) 881-8132
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`
`
`16
`
`the patient's face or scalp at a nominal wavelength of 417
`
`nanometers and a power density of 10 milliwatts per
`
`centimeter squared.
`
`A premarket approval application has
`
`been submitted to CDRH and has been reviewed by that
`
`center.
`
`Now I'd like to turn the presentation over to
`
`Dr. Marcus to describe how these drug and device components
`
`will be used in Levulan photodynamic therapy.
`
`DR. MARCUS:
`
`Thank you, Mr. Swetland.
`
`I'm going to introduce the section of this
`
`—~presentation~dealing with~the~photodynamic therapy using'r '
`Levulan and blue light.
`The first part will discuss the
`
`is an extensive worldwide literature on photodynamic
`
`background mechanism and the pharmacokinetics, as well as
`
`dose administered and pharm/tox.
`
`The second part will
`
`discuss the Phase II clinical trials, which involved both
`
`drug dose ranging and blue light dose ranging. And,
`
`lastly,
`
`there will be discussion of the pivotal clinical
`
`trials utilizing the Levulan Kerastick and the blue light
`
`source.
`
`ALA, aminolevulinic acid,
`
`is an endogenous
`
`molecule, and it's not a new molecule, but in the form of
`
`Levulan, it is a new chemical entity and a new drug. There
`
`FRIEDMAN & ASSOCIATES. COURT REPORTERS
`(301) 881-8132
`
`
`
`as human models of chronic exposure to systemically
`
`there are two clinical conditions which may be looked upon
`
`
` l7
` hydrochloride, and this molecule is rather unique in that
`
`
`
`
`overdose ALA and protoporphyrin, acute intermittent
`
`
`porphobilinogen, and erythropoietic protoporphyria as a
`
` model for chronic lifetime overdosing of protoporphyrin—9.
`
`porphyria for chronic overdosing of systemic ALA and
`
`photochemotherapy, which is a two-stage process,
`
`in that
`
` Photodynamic therapy is a type of
`
`
`the photosensitizer is delivered and then activated by
`
`
`
`light. However7~phetedynamic therapy differs fromgotherw~4w
`
`
`forms of photochemotherapy by its requirements for oxygen.
`
`The therapeutic effects of photodynamic therapy are
`
`
`
`photosensitizer to ground-state oxygen.
`
` Levulan is taken up by
`
`cells, converted first to ALA and then to protoporphyrin,
` which is a potent photosensitizer. As it accumulates,
`
`cells such as precancerous, malignant, or fast-growing
`
`cells can be identified by a characteristic fluorescence of
`
`
`protoporphyrin-Q. And then if you expose those cells which
`
`
`thought to be due to the production of singlet oxygen
`
`through the transfer of light energy through the
`
`Using an endogenous photosensitizer such as ALA
`
`involves the following steps:
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`(301)881-8132
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`
`
` 18
`
`
`
`appropriate wavelength and energy,
`
`the PDT effect occurs,
`
`leading to cell death.
`
`In the case of Levulan PDT,
`
`the
`
`application,
`
`followed by the accumulation of
`
`protoporphyrin—9 in the target cells.
`
`selective therapeutic benefit occurs due to selective drug
`
`
`
`
`
`This is the heme pathway, showing
`
`aminolevulinic acid as the first committed molecule in that
`
`
`
`
`
`‘The control point for the pathway is the
`
`regulation of ALA synthesis through ALA synthase regulation
`
`pathway.
`
`
`
`
`by the molecule heme, which is above the screen. When ALA
` is,addedwexegeneuslyTsitflbypassesmthe control point; and~W-H
`
`enzymes which are constitutively present, represented by
`
`the red line, are converted to protoporphyrin-Q, which,
`
`non—photosensitizing molecule heme.
`
`
`
`through the addition of iron by ferrochelatase, becomes the
`
`
`
`This is a simplification of protoporphyrin—9
`accumulation, which we like to call the Levulan therapeutic
`
`pathway.
`
`It shows the Levulan Kerastick applying ALA
`
`hydrochloride to the skin surface, which then becomes ALA
`
`
`
`
`and enters the system after the control point.
`rapidly converted to protoporphyrin-Q. Protoporphyrin-9
`
`It's then
`
`builds up rapidly, exceeding the capacity of ferrochelatase
`
`to remove it, and,
`
`
`
`
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`therefore, accumulates within the system
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` 19
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`The therapeutic benefit occurs through the production of
`
`singlet oxygen.
`
`But one must remember that ferrochelatase
`
`provides an escape mechanism by which excess
`
`protoporphyrin-9 is rapidly converted,
`
`then,
`
`to heme, which
`
`effect,
`
`removing excess drug.
`
`I'd like now to introduce Dr. Allyn Golub, who
`
`
`
`
`
`the very active shining of
`
`is a non-photosensitizer. Also,
`
`light on protoporphyrin-9 for PDT produces a photobleaching
`
`
`
`will speak.
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`
`
`
`ADRTVGOLUB:
`
`
`Thank you, Dr. Marcus.
`
`,
`
`~*
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`
`
`My presentation today will be divided into two
`
`sections. First, I'd like to discuss the pharmacokinetics/
`
`
`bioavailability and how we estimate the dose of Levulan
`
`
`Secondly,
`
`
`that's administered topically.
`discuss the preclinical toxicology studies that were
`
`I'll briefly
`
`
`
`conducted with this compound.
`
`As Dr. Marcus indicated, aminolevulinic acid is
`
`
`
`
`
`a well-described endogenous compound that's found in
`
`virtually all living organisms as a precursor in the
`
`heme and chlorophyll.
`
`porphyrin biosynthetic pathway leading to the formation of
`
`
`
`For pharmaceutical purposes, we use the
`
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` freely soluble in water, slightly soluble in alcohol, and
`
` practically insoluble in most organic solvents.
`The drug
`
`
`
`
`
`Levulan. This is an odorless, white to off-white
`
`crystalline powder with a molecular weight of 167.59.
`
`It's
`
`completely dissociates in aqueous solution,
`
`leading to a
`
`solution with low pH.
`
`The primary degradation product in
`
`The vehicle for Levulan administration is
`
`solution is pyrazine 2,5-dipropionic acid that's formed by
`
` the autocondensation of two aminolevulinic acid molecules.
`
`
` comprised of common dermatological excipients and has about
`
`
`
`56 percent—aicohotwursww—r
`.
`,
`
`Studies were done in both humans and dogs to
`
`already well described in the literature.
`
`In this
`
`
`
` characterize the systemic bioavailability and
`
`
` pharmacokinetics of Levulan to basically confirm what's
`
`
`
`particular slide, we're showing the results from a study in
`
`six normal male volunteers who were administered 128
`
`
`milligrams of Levulan intravenously and orally, and the
`
`
`time concentration curve generated over a period of 8
`
`
`hours.
`The important information on this slide is that the
` drug is very rapidly cleared from the systemic circulation
`
`
`
`that occurs following both intravenous and oral absorption,
`
` and that the oral bioavailability is lower than the area
`
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`about 60 percent bioavailable in this particular study.
`
`This table summarizes the results from that
`
`human study as well as a dog study.
`
`The IV half-life here
`
`was about 50 minutes, very rapidly excreted.
`
`In the dog it
`
`was about 20 minutes.
`
`The P0 half-life was about 40
`
`minutes in both species. And the relative bioavailability,
`
`as I said, was 60 percent in the humans in that study, and
`
`about 40 percent in the dogs.
`
`I should mention that we also monitored
`
`protoporphyrin levels in this study.
`
`very lew,
`they wereverratie7wandebeyond 12 hours thetherE*W”
`
`The levels were very,
`
`undetectable at the limits of the sensitivity of the assays
`
`package insert.
`
`that we used.
`
`Based on the wealth of data that we've
`
`generated in our developmental process, we're able to
`
`estimate the amount of Levulan that would be administered
`
`topically using the Kerastick as directed in the package
`
`insert and its potential systemic availability.
`
`From in
`
`vitro studies, several that were done during product
`
`development, we've calculated that approximately 2
`
`milligrams per centimeter squared of Levulan will be
`
`applied in two successive applications as directed in the
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`carefully measured the AK lesion surface area that was
`
`randomly chosen for application of the drug. This turned
`
`out to be approximately half a square centimeter per
`
`lesion.
`
`In our Phase III studies, ALA-018 and -019,
`
`physicians were allowed to apply the drug to four to 15
`
`lesions per patient.
`
`Seventy—five percent of the
`
`applications were less than 10 lesions, but we're going to
`
`err on the high side and assume, let's say, 15 lesions are
`
`applied per patient. As a matter of fact, all of these
`
`values were chosen to be on the high side of the numbers
`
`
`
`that we—ealeulated.
`‘-
`W ‘
`
`So simply by multiplying the quantity of
`
`Levulan applied times the lesion surface area that it's
`
`being applied to,
`
`times the total number of AK lesions
`
`treated, we can calculate that approximately 15 milligrams
`
`of Levulan would be applied per patient, and that's
`
`described in the package insert for application in the
`
`equivalent to about 12 milligrams of ALA. You divide that
`
`for a 70-kilogram individual, and it indicates that less
`
`than .2 milligrams per kilogram of aminolevulinic acid
`
`would be applied to the patient.
`
`Now, we've done in vitro studies through
`
`cadaver skin, again, using exactly the methodology
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`cadaver skin,
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`in which the stratum corneum was removed.
`
`In
`
`23
`
`intact skin, we see about —— and this, again,
`
`is on the
`
`high side —— approximately 2 percent of the drug passes
`
`through the skin into the receptor fluid over a 16—hour
`
`dosing interval.
`
`In stripped skin,
`
`in which the stratum
`
`corneum is totally removed, we see upwards of 30 percent
`
`over 16 hours. However, even if we assume 100 percent of
`
`that 12 milligrams of ALA is absorbed systemically, we
`
`calculate that that would be only about 3.5 percent of this
`
`number, 350 milligrams per day, which is believed to be
`
`_synthesized—byethe human body to supporteendogenous~heme
`
`-transiently increased aspartate and alanine
`
`synthesis.
`
`With these numbers in mind now, let's turn to
`
`the preclinical toxicology program that was conducted for
`
`the drug.
`
`Acute toxicity studies were initially done in
`
`mouse, rat, and dog.
`
`In mice and rats, doses up to 300
`
`milligrams per kilogram were administered intravenously
`
`with no adverse effects. This was a standard battery of
`
`measurements that was used to characterize the -— these
`
`studies were GLP studies.
`
`In the dog, 100 milligrams per
`
`kilogram led to some excessive salivation and vomiting and
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`24
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`milligram-per—kilogram dose. These increases were judged
`
`to be mild to moderate and were very transient,
`
`lasted for
`
`a very short period of time.
`
`In the skin studies that were conducted with
`
`this product, we did subcutaneous administration of the
`
`drug up to 1,000 milligrams, a gram per kilogram, and found
`
`dose-dependent irritation and/or the formation of lesions
`
`at the site of injection. There were no other systemic
`
`findings made, and these effects were judged to be a result
`
`of the high ionic strength and low pH of the solutions that
`
`
`were administeredTW r-_W4lllu_m i,
`
`The skin was prepared by clipping
`
`the topical solution, because this is the product
`
`In rabbits, we have evaluated topically the
`
`effects of the topical solution and the topical cream.
`
`The
`
`results in both of these studies, up to 30 percent ALA
`
`showed slight to moderate dermal irritation with both the
`
`vehicle and the formulation.
`
`I'd like to focus a little bit further on this
`
`study,
`
`that's under consideration here.
`
`There were 20 male and 20 female rabbits in the
`
`study.
`
`The body weight was approximately 2 kilograms.
`
`The
`
`drug application area was over 180 square centimeters on
`
`the back of the animal.
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`25
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`allow penetration of the drug through the stratum corneum.
`
`As I indicated, doses up to 30 percent of the topical
`
`solution were applied.
`
`It was applied at a dose of 2 grams
`
`of the solution per kilogram of animal body weight under
`
`occlusion. There was no light exposure in the study, but
`
`the skin was completely occluded for a period of 24 hours.
`
`This table summarizes the results found in this
`
`study. You see even with vehicle there was slight to
`
`moderate erythema. That
`
`tended to increase to moderate at
`
`the highest concentration. There was some edema,
`
`-desquamatienT—afidseeriaesousness andwfissuring'actually
`
`occurred primarily at the highest dose.
`
`In general there
`
`was only slight to moderate irritation detected in the
`
`study under pretty stringent conditions, under occlusion
`
`for 24 hours.
`
`Finally, a battery of mutagenicity protocols
`
`I should mention this says, "with a
`
`has been conducted with the Levulan product. This includes
`
`the salmonella, E. coli, and mammalian microsome reverse
`
`mutation assay, which is also known as the Ames test, at
`
`doses up to 5,000 micrograms per plate, plus or minus
`
`metabolic activation.
`
`The end result of this study was
`
`that there was no increase in revertants.
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`in succession, a complete replicate of the study,
`
`just to
`
`26
`
`confirm the results obtained the first time.
`
`Similarly, an Ames test with solar light
`
`radiation to look for photoproducts of ALA during
`
`incubation was conducted up to 5,000 micrograms per plate.
`
`Again, no increase in revertants, with or without solar
`
`light radiation. Mouse lymphoma also was negative, plus or
`
`minus metabolic activation. There's no evidence in these
`
`studies that there is mutagenicity. And, finally,
`
`in the
`
`in vivo mouse micronucleus assay, not only was there no
`
`sin—indicating? low" or new potential for
`
`genotoxicity, but also the dose of 1,600 milligrams per
`
`kilogram was well tolerated by the animals in the study.
`
`So overall it showed a very comfortable side effect
`
`spectrum.
`
`Now I'll turn the program back to Dr. Marcus,
`
`who will describe the Phase I and II studies that were done
`
`support and define the Phase III pivotal study.
`
`with this compound.
`
`DR. MARCUS:
`
`Thank you, Dr. Drake, and thank
`
`you, Dr. Golub.
`
`I'll be starting off the clinical data summary
`
`with the controlled clinical trials that were used to
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`study using blue light and 20 percent topical Levulan
`
`solution. ALA-007's study design was of a randomized,
`
`vehicle—controlled, and investigator-blinded multicenter
`
`study in which the Levulan solution was applied to
`
`individual AK lesions on 36 patients. There were three
`
`clinical trial sites, and because two lesions were treated
`
`with either Levulan or vehicle,
`
`the complete patient
`
`response was judged to be as patients with 100 percent of
`
`AK lesions cleared.
`
`
`pgint,
`tHGEe-fl'rs—a—t—rendT—as—yetheafrsee; The biflefilig Win ,_ W, ,7
`
`At Week 8, which is the primary efficacy time
`
`In the safety profile, mild to moderate
`
`joules per square centimeter delivered at the highest power
`
`doses were 2, 5, and 10 joules per square centimeter,
`
`delivered at either 3, 5, or 10 milliwatts per square
`
`centimeter power density.
`
`If you look at the 10-
`
`milliwatts-per-square—centimeter bar, you see a trend
`
`toward a dose/response with a maximal dose/response of 80
`
`percent after a single treatment with light and drug.
`
`The summary of this study showed, again, up to
`
`80 percent of patients completely responded to a single
`
`treatment with topical Levulan and blue light, and 10
`
`density provided the best results in that study.
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`28
`
`treatment, and this will prove to be a constant throughout
`
`the studies you'll be seeing this afternoon. There were no
`
`treatment-related significant adverse events and no
`
`systemic photosensitivity observed.
`
`Another blue light dose ranging study was done
`
`as a safety study, ALA-016. Again,
`
`this was a randomized,
`
`vehicle—controlled,
`
`investigator-blinded multicenter study,
`
`with 64 patients randomized. Here the 20 percent Levulan
`
`solution was applied to a 25—square-centimeter area of skin
`
`containing three to seven AKs, photodamaged skin. There
`
`
`were three clinical sites, as beforeTaand~here7 because ofmri*~“
`
`single treatment with topical 20 percent Levulan and blue
`
`you look at the 10~milliwatts-per-square-centimeter bar, we
`
`the larger number of AKs treated, we were able to define
`
`the complete patient response as patients having greater
`
`than or equal to 75 percent of their lesions completely
`
`cleared.
`
`The results of this study show that, again, if
`
`saw 100 percent responses in all three doses of light, but
`
`the most consistent result was 100 percent response at 10
`
`joules per square centimeter.
`
`In this study, up to 100 percent of the
`
`patients, by our definition, completely responded to a
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`best result, and this, of course, was consistent with the
`
`29
`
`first blue light dose ranging study.
`
`In the safety results -— and this was done as a
`
`safety study -— there was stinging and burning during light
`
`treatment, and there were no treatment-related significant
`
`adverse events or systemic photosensitivity. However,
`
`the
`
`discomfort of stinging and burning was increased as a
`
`result of applying Levulan 20 percent solution to a larger
`
`area than single AKs,
`
`individual AKs, and in this study 6
`
`percent of the patients had PDT treatment terminated early,
`
`and.9vpercent~reduced the powerwdensity due to the
`
`the first study statistically sized to detect the
`
`discomfort of stinging and burning as a result of the
`
`larger-area application. We took that as support of the
`
`labeling statement to apply Levulan solution to individual
`
`AKS .
`
`A Phase II drug dose ranging study was carried
`
`out using blue light at 10 joules per square centimeter,
`
`delivered at 10 milliwatts per centimeter.
`
`In this study,
`
`we evaluated the safety and efficacy of Levulan topical
`
`solution at 2.5, 5, 10, 20, and 30 percent weight—to-volume
`
`solution. Again,
`
`this was randomized, vehicle-controlled,
`
`and investigator-blinded, and multicenter, but this one was
`
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`solutions. One hundred and twenty—four patients were
`
`accrued to this study f