Drugs in R&D.
`DUP -'- General Collection
`W1 DR893TC
`v.6,no.4
`2005
`
`2005, Vol. 6, No. 4 (pp. 189-252)
`ISSN: 1174-5886
`
`·
`
`Research Perspectives
`Policosanol
`Eslicarbazepine
`ixed-Dose Orphenadrine plus Diclofenac
`Po ethylene Glycol 3350 p1us Electrolytes
`
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`MYLAN PHARMS. INC. EXHIBIT 1118 PAGE 1
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`MYLAN PHARMS. INC. EXHIBIT 1118 PAGE 1
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`Timely information on
`emerging drug classes
`and new treatments
`
`I . . . ..... . . ..
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`.....
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`... ... . .
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`Drugs in R&D gives you rapid access to information on emerging drug classes
`and new treatments for specific disorders, allowing healthcare decision
`makers to keep up-to-date with clinically applicable knowledge about the
`likely place in therapy of new drugs.
`
`Drugs in R&D features:
`• Original research with a strong link to clinical practice from all phases of
`drug development
`• R&D drug profiles on new drugs from their first stages of development
`up to launch that summarise:
`- key drug properties
`- development phase by country and indication
`- analysis of commercial potential
`
`All arlicles undergo peer review by international experts.
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`Dmgs in R&D is indexed In: Index Medicus/MEDLINE, EMBASE/Excerpta
`Medica,
`the Chemical Abstracts Service (CAS) and
`International
`Pharmaceutical Abstracts (IPA).
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`MEDLINE INDEXED
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`MYLAN PHARMS. INC. EXHIBIT 1118 PAGE 2
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`

`

`Vol. 6, No. 4, 2005
`
`Dru™
`.,R&Dgs
`
`Contents
`
`Original Research
`Articles
`
`Short
`Communication
`
`Adls R&D Profile
`
`Comparison of the Analgesic Effects of a Fixed-Dose
`Combination of Orphenadrine and Diclofenac
`(Neodolpasse®) with its Single Active Ingredients
`Diclofenac and Orphenadrine: A Placebo-Controlled
`Study Using Laser-Induced Somatosensory-Evoked
`Potentials from Capsaicin-Induced Hyperalgesic Human
`Skin
`,
`K Schaff/er, P Reitmeir, A Gschanes, U Eggenreich
`Effect of Food on the Pharmacokinetic Profile of
`Eslicarbazepine Acetate (BIA 2-093)
`J Maia, M Vaz-da-Silva, L Almeida, A Falciio, P Silveira, S Guimaraes,
`P Graziela, P Soares-da-Silva
`Effects of Addition of Policosanol to Omega-3 Fatty Acid
`Therapy on the Lipid Profile of Patients with Type II
`Hypercholesterolaemia
`G Castano, L Fernandez, R Mas, J Illnait, R Gamez, S Mendoza,
`M Mesa, J Fernandez
`
`A Randomised, Controlled Comparison of Low-Dose
`Polyethylene Glycol 3350 plus Electrolytes with Ispaghula
`Husk in the Treatment of Adults with Chronic Functional
`Constipation
`H-J Wang, X-M Liang, Z-L Yu, L-Y Zhou, S-R Lin, M Geraint
`
`BG 12: BG 00012, BG 12/Oral Fumarate, FAG-201, Second(cid:173)
`Generation Fumarate Derivative - Fumapharm/Biogen
`Idec
`Clindamycin/Tretinoin: Clindamycin Phosphate/
`Tretinoin Gel
`Hexyl Aminolevulinate: 5-ALA Hexylester, 5-ALA
`Hexylesther, Aminolevulinic Acid Hexyl Ester,
`Hexaminolevulinate, Hexyl 5-Aminolevulinate, P 1206
`
`'
`
`'
`
`lcatibant: HOE 140, JE 049, JE049
`
`Lubiprostone: RU 0211, SPI 0211
`
`Rufinamide: CGP 33101, E 2080, RUF 331, Xilep
`
`189-199
`
`201-206
`
`207-219
`
`221-225
`
`229-230
`
`231-234
`
`235-238
`
`239-244
`
`245-248
`
`249-252
`
`Register for the free Adis Electronic Table of Contents E-Mail Alert Service today at www.adisonline.info
`Drugs in R&D is indexed in the following biomedical databases: MEDLINE/Index Medicus, EMBASE/Excerpta Medica, International
`Pharmaceutical Abstracts (IPA) and the Chemical Abstracts Seroice (CAS). Individual articles are available through the ADONIS®
`Document Delivery Service and online via the World Wide Web through Ingenta. Further details are available from the publisher.
`
`MYLAN PHARMS. INC. EXHIBIT 1118 PAGE 3
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`MYLAN PHARMS. INC. EXHIBIT 1118 PAGE 3
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`L~.
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`INTERNATIONAL
`
`International Editorial Board
`
`1
`
`'. 1 <t;,imsden, Cooperstown, NY, USA
`S.E. Belllbas, Nutley, NJ, USA
`E. Beghl, Milan, Italy
`S. Bloomfield, Cincinnati, OH, USA
`A. Bryskler, F'arill, France.
`E. Chrlstophers, Kiel, Germany
`M.J, Eadie, Brisbane, Qt;.D, Australia
`D. Furst, Seattle, WA, USA
`L.C. Graap, Malmo, Sweden
`F. Horak, Vienna, Austria
`• f ' a:o. Kahan, Houston, TX, USA
`R. Kawamorl, Tokyo, Japan
`M.G. Kris, New York, USA
`M. Lader, London, UK
`K. McCormeek/Leighton Buzzard, UK
`J. FldmDton•Mlller, Lon~n, l,TK
`T. Morgan, Melbourne,sVIC,A.Um'lllia•,;
`G. Morris Ill, Milwaukee, WI, USA
`G. Moyle, I-ondon, UK
`,. Nathan, Ue~ne. vrc,¥allil
`D.J. Nutt, Bristol, UK
`I!. Perucca, Pavia, Italy
`ac. Schachter, Boston, MA, USA
`M.A. Smith, Cleveland, OH, USA
`F. Vajda, Melbourne, VIC, AustntMa ·
`C.J. van a.tel, Amllterdam,
`The Netherlands
`w: ;van l.ewden, Oosterbeek,
`4'he Netherlands
`,t. )Wison, Shreveport, LA, USA
`V. Wong, Hong Kong
`N. Yuen, Apex, NC, USA
`
`Dru TM
`"'R&Dgs
`
`Alm and Scope: The aim of Drugs in R&D is to provide timely information on:
`(i) emerging drug classes; and (ii) new treatments for specific disorders. Original
`research from all phases of clinical development is included, with a strong link to
`clinical practi~e. Healthcare d~cision makers are thus provided with clinically
`applicable knowledge about th~ likely place in therapy of a drug.
`
`1 :
`
`Journal issues comprise:
`, • Original research, including clinical trials with an emphasis on optimum
`clinical use and pharmacokinetic and pharmacodynamic studies in patients and
`healthy volunteers.
`• R&D drug profiles including: (i) key drug properties; (ii) drug development
`phase by country and indication; (iii) analysis of commercial potential.
`All articles are subject to peer review by international experts.
`
`• \
`
`Publication Manager: Lorna Venter-Lewis
`
`Editorial Office and Inquiries: Adis International Limited, 41 Centorian
`Drive, Private Bag 65901, Mairangi Bay, Auckland 1311, New Zealand.
`Information on the preparation of manuscripts will be provided to authors.
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`E-mail: DrugsR&D@adis.co.nz ,
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`http://www.adisonline.info/rdd
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`1 Drugs In R&D (ISSN 1174-5886) is published bi-monthly by Adis International
`Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 1311,
`New Zealand. The annual 2005 institutional· subscription price for print and
`online ls $US735 and for online only is $US725 .. The personal subscription price
`for print and online is $US230 and for online only is $US225. All online
`subscriptions include access to online archived articles. Further subscription
`information is given at the back of each issue.
`Policy Statement: Although great care has been taken in compiling the content of
`this publication, the publisher and its servants are not responsible or in any way
`liable for the currency of the information, for any errors, omissions or
`inaccuracies, or for any consequences arising therefrom. Inclusion or exclusion of
`any product does not imply its use is either advocated or rejected. Use of trade
`1 names is for product identification only and does not imply endorsement.
`Opinions expressed do not necessarily reflect the views of the Publisher, Editor
`1 or Editorial Board.
`1 Copyright: (£) 2005 Adis Data Information BV. All rights reserved throughout the
`world and in all languages. No part of this publication may be reproduced,
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`that the fee of $US34.95 per copy Is paid directly to the Copyright Clearance
`Center Inc., 222 Rosewood Drive, Danvers, Massachusetts 01923, USA, for
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`This consent does .not extend to other kinds of copying such as copying for
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`MYLAN PHARMS. INC. EXHIBIT 1118 PAGE 4
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`

`

`La~.
`a 1S
`
`jNTERNATIONA.L
`
`Dru TM
`mR&Dgs
`Editorial Policies and Procedures for
`Submitted Original Research
`
`Alm of Submitted Original Research
`The aim of original research articles in Dntgs in
`J,?.&D is to emphasise the role of rational clinical
`pharmacotherapy in optimising outcomes. T~is is
`accomplished by rapid publication of submitted
`original research covering all phases· of clinical
`drug development and therapeutic use of drugs.
`I!I addition, short communications and case study
`reports that meet these criteria may be considered
`for publication, along with letters to the Journal
`Editor.
`
`Types of Submitted Original Research
`Specific types of original research considered_ for
`publication in Dntgs in R&D include clinical trials,
`outcomes research, clinical pharmacoeconomic
`studies, pharmacoepidemiology studies with a
`strong link to optimum prescribing practice for a
`drug or group of drugs, clinical pharmacodynamic
`and clinical pharmacokinetic studies with a strong
`link to clinical practice and, in some instances,
`pharmacodynamic or pharmacokinetic studies in
`healthy volunteers, but in which some established
`or purported implications for clinical prescribing
`are discussed.
`
`Potential Conflicts of Interest
`Independent internationally recognised experts
`are sought in the first instance when seeking
`referees for articles. However, it is not always
`possible- to determine the relationship between
`authors and the pharmaceutical industry in
`advance. Authors and peer reviewers are required
`to disclose potential conflicts of interest. Possible
`conflicts of interest are identified whenever
`practicable and this information is published
`prominently. Sources of article funding are also
`disclosed.
`
`Peer Review
`The aim of the peer review process is to ensure
`publication of unbiased, scientifically accurate and
`clinically relevant articles that reflect international
`consensus of current opinion. All articles are
`subject to peer review by members of the Journal's
`international Editorial Board and/or other
`specialists of equal repute before a decision on
`publication is made. Revised manuscripts may be
`
`reviewed a second time if appropriate. The final
`decision on acceptability for publication lies with
`the Journal Editor. The Editor of Dnigs in R&D
`endorses the Consolidated Standards of Reporting
`Trials (CONSORT) guidelines for improving the
`quality of reporting of randomised controlled trials.
`The CONSORT statement, checklist and flow
`diagram have been adopted by the Journal to guide
`initial selection and peer review of original research
`articles submitted to Drugs in R&D. For more
`information on the CONSORT statement, checklist
`and flow diagram readers can visit the relevant
`World Wide Web site (http:/ /www.ama-assn.org).
`
`Technical Editing
`All articles are edited by an experienced and
`technically qualified Adis International editor.
`This process includes: (i) assessment of scientific
`accuracy, balance and completeness; (ii) choice of
`optimum structure; and (iii) general publishing
`considerations, such as house style and clarity of
`expression.
`
`Duplicate Publication
`In general, material that has been previously
`published or accepted for publication elsewhere is
`not knowingly accepted for
`inclusion. The
`occasional decision to republish material in full or
`in part is made with reader interest in mind and
`requires the permission of the copyright holder.
`Prior publication is prominently acknowledged.
`
`Drug Nomenclature
`Brarid names or tradenames are generally not
`used, except in instances where the use of the
`generic name would be impractical or ambiguous.
`Appearance of a brand name or tradename does
`not imply endorsement of the product.
`
`Copyright
`All authors are required to read and sign the
`statement on copyright transfer to Adis Data
`Information BV that is sent to them prior to
`publication.
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`MYLAN PHARMS. INC. EXHIBIT 1118 PAGE 5
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`MYLAN PHARMS. INC. EXHIBIT 1118 PAGE 5
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`

`

`ADIS R&D PROFILE
`
`Drugs RD 2005; 6 (4); 229-230
`1174-5886/05/0004-0229/$34.95/0
`
`C> 2005 Adls Data Information BV, All rights reserved.
`
`BG 12
`BG 00012, BG 12/Oral Fumarate, FAG.;.201,
`Second-Generation Fumarate Derivative - Fumapharm/
`Biogen Idec
`
`Abstract
`
`· Fumapharm AG has developed a second-generation fumarate (fumaric acid)
`derivative, BG 12 [BG 00012, FAG-201, BG 12/0ral Fumarate], for the oral
`treatment of psoriasis. Biogen Idec is currently evaluating the product in clinical
`trials as an oral treatment for multiple sclerosis (phase II) and psoriasis (phase III)
`trials.
`·
`BG 12 has an immunomodulatory mechanism of action. It seems that this
`product has been developed to reduce the adverse effects associated with a first(cid:173)
`generation product containing fumaric acid esters (mixed dimethylfumarate and
`monoethylfumarate salts), Fumaderm®. Fumaderm® was approved in Germany in
`August 1994 and is currently the leading oral systemic therapy for moderate-to-.
`severe psoriasis in Germany: One of the problems associated with· Fumaderm® ·
`capsules has been its gastrointestinal adverse effects (including diarrhoea and
`nausea).
`In September 2003, Biogen (now Biogen Idec) licensed exclusive worldwide
`rights (excluding Germany) from Fumapharm to develop and market BG 12.
`Biogen plans to collaborate with Fumapharm to accelerate phase III development
`for psoriasis and the registration programme worldwide. Financial terms ofthe
`agreement were not disclosed. Development plans for BG 12 include other
`autoimmune and inflammatory disorders, such as multiple sclerosis.11-21
`In November 2003, Biogen and IDEC Pharmaceuticals merged to form Biogen
`Idec. Fumapharm completed phase II trials of this second-generation fumarate
`derivative for psoriasis prior to licensing of the product to Biogen,. also with
`positive results.1 11 _
`
`1. Profile
`
`1. l Adverse Events
`
`Clinical studies: The most common adverse
`events reported iri a phase II trial of BG 12 were
`flushing, elevations in liver function tests and com(cid:173)
`mon colds, which were generally transient and mild(cid:173)
`to-moderate in severity.Ill
`The most common adverse events reported in a
`phase III study of 175 patients with moderate-to-
`
`severe psoriasis were flushing and diarrhoea. In
`addition, one patient was hospitalised with pneumo(cid:173)
`nia and another was hospitalised with kidney
`stones.131
`
`1.2 Therapeutic Trials
`
`1.2.1 Skin Disorders
`In a phase II dose-ranging trial, patients with
`severe psoriasis who received BG 12 experienced
`greater improvement in their psoriasis ~han patients
`(n = 144) were
`receiving placebo. Patients
`
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`230
`
`Table I. Features and properties
`
`WHO ATC code
`
`EphMRA ATC code
`
`Originator
`Licensee companies
`Highest development phase
`
`Properties
`Mechanism of action
`Route
`Adverse events
`
`Table II. Drug development history
`
`Jul2003
`Sep 2003
`
`Oct 2003 ·
`Nov 2003
`Nov 2004
`Apr 2005
`
`D05B-X51 (Fumarlc acid derivatives, combinations)
`N07X-X (Other nervous system drugs)
`N7X (All other CNS drugs)
`D5B (Systemic Antipsoriasis Products)
`Fumapharm AG: Swl~zerland
`Biogen l~ec: World
`Phase II (Europe)
`
`lmmunomodulators
`PO
`Rare: Common cold, Diarrhoea, Elevated liver enzymes, Flushing
`
`Phase-I in Multiple sclerosis in Europe (PO) ..
`This second-generation fumarate derivative has been licensed to
`. Biogen worldwide (excluding Germany) for Psoriasis
`Phase-Ill in Psoriasis in Europe (PO)
`IDEC Pharmaceuticals has merged with Biogen to form Biogen Idec
`Phase-II in Multiple sclerosis In Europe (PO)
`Phase-Ill in Psoriasis In ·Germany (PO)
`
`randomised to either placebo or BG 12 (120, 360 or
`720 mg/day) for 12 weeks. At 12 weeks, 42% of
`patients who received BG 12 720 mg/day achieved
`at least a 75% improvement in their Psoriasis Area
`and Severity Index (PASI 75), compared with 11 %
`of patients who received placebo. The mean per(cid:173)
`centage reductions in PASI from baseline were
`71%, 52%, 31% and 6% for the 720,360; 120 mg/
`day and placebo groups, respectively. It was also
`noted that some patients began improving as early as
`2 weeks after BG 12 was administered.l 1•41
`Favourable efficacy and tolerability through to
`week 16 have been reported in a phase III study in
`Europe. In this multicentre, double-blind study con(cid:173)
`ducted by Fumapharm, 175 patients with moderate(cid:173)
`to-severe chronic plaque psoriasis were randomised
`to receive BG 12 240mg three times daily (n = 105)
`or placebo (n = 70) for 16 weeks. At 16 weeks, the
`median PASI was 5.8 in the BG 12 group and 14.2
`in the placebo group. The median percentage reduc-
`
`tions from baseline in PASI were 68% and 10% in
`the BG 12 and placebo groups, respectively.[3,51
`
`References
`. . ,
`I. Biogen Idec, Fumapharm AG. Patients Show Improvement in
`Phase II Psoriasis Study of Novel Oral Immunomodulator.
`Media Release: 29 Apr 2004. Available from URL: http://
`. · www.biogen.com
`2. Biogen Inc. Biogen Licenses Oral Psoriasis Therapy From
`Fumapharm AG. Media Release: I Oct 2003. Available from
`URL: http://www.biogen.com
`3. Biogen Idec. BG-12 Psoriasis Study Meets Primary Endpoint;
`Oral Compound Also Being Studied for MS in Phase II Trial.
`Media Release: 7 Apr 2005. Available from URL: http://
`www .biogenidec.com
`4. Langner A, Spellman MC. Results of a phase 2 dose-ranging
`and safety extension study of a novel oral fumarate, BG-12, in
`patients with severe psoriasis. Journal of the American Acade(cid:173)
`my of Dermatology 52 (Abstr. Suppl.): 193 (plus poster) abstr.
`P2787, No. 3, Mar 2005
`5. Mrowietz U, Spellman MC. Efficacy and safety of a novel
`formulation of an oral fumarate, BG-12, in patients with mod(cid:173)
`. crate to severe pl11que psoriasis: results of a phase III study.
`Journal of the American Academy of Dermatology 52 (Abstr.
`Suppl.): 182 (plus poster) abstr. P2743, No. 3'. Mar 2005
`
`e 2005 Adls Dota Information BV, All rights reserved.
`
`Drugs R D 2005; 6 (4)
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`MYLAN PHARMS. INC. EXHIBIT 1118 PAGE 7
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`MYLAN PHARMS. INC. EXHIBIT 1118 PAGE 7
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