`
`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
`
`
`
`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
`
`
`
`
` 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,
`
`
`
`
`
`therefore, accumulates within the system
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`(301) 881-8132
`
`
`
`
` 19
`
`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.
`
`
`
`
`ADRTVGOLUB:
`
`
`Thank you, Dr. Marcus.
`
`,
`
`~*
`
`
`
`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
`
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`(301) 881-8132
`
`
`
`
`
` 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
`
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`(301) 881-8132
`
`
`
`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
`
`FRIEDMAN & ASSOCIATES. COURT REPORTERS
`(30]) 881-8132
`
`
`
`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
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`(301) 881-8132
`
`
`
`cadaver skin,
`
`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
`
`FRIEDMAN & ASSOCIATES. COURT REPORTERS
`(301) 881-8132
`
`
`
`24
`
`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.
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`(301)881-8132
`
`
`
`25
`
`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.
`
`FRIEDMAN & ASSOCIATES. COURT REPORTERS
`(301) 881-8132
`
`
`
`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
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`(301)881-8132
`
`
`
`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.
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`(301) 881-8132
`
`
`
`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
`
`FRIEDMAN & ASSOCIATES. COURT REPORTERS
`(30]) 881-8132
`
`
`
`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
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`(301)881-8132
`
`
`
`solutions. One hundred and twenty—four patients were
`
`accrued to this study f
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
