,
`
`xpert opinion on investigational
`ugs( IM)
`9. no 12 (Dec 2000)
`eneral Collection
`II EX52M
`:eceived '12-0·1-2000
`
`Ashley Publications
`
`Vol. 9 No. 12
`
`December 2000
`
`ISS
`
`Roxane Labs., Inc.
`Exhibit 1011
`Page 001
`
`

`
`Senior Advisory Panel
`Chairman: Fitzgerald JD Materia MedicaUK
`Abou-Gharbia M: Wyeth"Ayerst, USA
`Arnaud J-C: Servier, France
`Baldwin JJ: Pharmacopeia, USA
`Barry DW: Triangle Pharm., USA
`Breirner DD: Leiden Or. Drug Res., NL
`Buckel P: B. Mannheim, Germany
`Campbell SF: formerly Pfizer, UK
`Coombes J: formerly Noechst. UK
`Drews J: Hoffmann-La Roche, USA
`Duncan WAM: RW Johnson PRI, USA
`Evans C: Chiroscience, UK
`Ganellin R: Univ. London, UK
`Gillis 5: Corixa, USA
`Harrap K: lnst. Cancer Research, UK
`Hayaishi 0: Osaka, }()pan
`Hoyer D: Novartis, Switzerland
`Humphrey PPA: Glaxo, UK
`Jack D: formerly Glaxo, UK
`Krogsgaard Thomsen M: Novo, Denmark
`Maeno H:. Japan Tobacco, Inc., Japan
`McCall J: Pharmacia & Upjohn, Inc., USA
`Moncada S: The Cruciform Project, UK
`Moos W: Chiron, USA
`Marich F-J: Bayer AG, Germany
`Okazaki H: Takeda Chemical lnd, Japan
`Paioni R: Novartis, Switzerland
`Paste G: SmithK/JneBeecham, USA
`Ringrose PS: BMS, USA
`Ross BC: Glaxo Wei/come, UK
`Setoyarna 0: Chugai, Japan
`Sugino Y: Takeda, Japan
`$vihovec J: Charles Univ, Czech Rep.
`Swales J: Univ. Leicester, UK
`Taylor JB : Rh6ne-Pou/encRorer, UK
`Timrnermanns P: Dupont Merck, USA
`Tobert J: Merck, USA
`Tomlinson E: GeneMedicine, Inc., USA
`Weston A: Univ. Manchester, UK
`Section Editorial Board
`Pulmonary-Allergy, Dermatological,
`Gastrointestinal & Arthritis
`Cochran FR, Ferro M, Garst ME, Handley D,
`Kaminski JJ, Morley J, Richards IM, SircarJC,
`. Warne P
`
`Anti-infectives
`Barrett JF, Blonaeau J, Bty.skier A. Buckheit R
`Chopra I, Clerici M, Marriott MS, Ryder N,
`Turik M
`Biologicals & lmmunologicals
`Connolly K, Crooke ST, Dalgleish A,
`Glassy M. Middaugh R, Salgaller M, Slade H
`Central & Peripheral Nervous Systems
`Gurwitz D, Heydotn WE, Hill RG, Kloog Y,
`Nagase H, . Palacios JM, Panetta JA, Saxena P,
`Schachter S, Sramek JJ, Temple DL,
`Williams M, Wood M
`Cardiovascular & Renal
`Danser AHJ, Gristwood RW, Holvoet P,
`Julian DG, Mellies M, Nicholson CD,
`Primeau JL, Ruffolo RR, Shebuski RJ, Siegl P,
`Winkelmann BR
`Oncologic, Endocrine & Metabolic
`Bell P, Brandi ML, Briggs MG, Colca J, Denny
`WA Dujovne C. Gibbs JB, Kelland L,
`Koutsilieris M, Kowluru R, Papavasslliou AG,
`Whitfield J, Zhang WW
`
`Expert Opinion on Investigational Drugs
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`Commissionin~ Editor: Anja Joha nsen-Bibby
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`atth e N LM a n.d rnay t>e
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`
`Expert Opinion on Investigational Drugs
`December 2000
`Vol. 9 No. 72
`
`Contents
`Monthly Focus: Oncologic, Endocrine & Metabolic(>>)
`
`Foreword
`
`Reviews and Updates
`
`Surviving the information overload
`2765
`» Farnesyltransferase and geranylgeranyllransferase l inhibitors in cancer 2767
`therapy: important mechanistic and bench to bedside issues
`SM Sebti & A D Hamilton
`» Antineoplastic agents from natural sources: achievements and future
`directions
`GM Cragg & DJ Newman
`» Cancer gene therapy: developments to 2000
`AR Bateman, KJ Harrington, AA Melcher & RG Vile
`» Novel chemotherapeutic agents for the treatment of brain cancer
`HB Newton
`» Novel strategies for systemic treatment of endometrial cancer
`L Elit & H Hirte
`» New therapeutic strategies for the treatment and prevention of head and 2855
`neck cancer
`MW Lingen, B Emami & .II Clark
`» Therapeutic potential of endothelin receptor antagonists in diabetes
`S Chakrabarti, M Cukiemik, S Mukhe1jee & S Chen
`
`2783
`
`2799
`
`28 15
`
`283 1
`
`2873
`
`,., Tirapazamine: a bioreductive anticancer drug that exploits tumour
`hypoxia
`WA Denny & WR Wilson
`» Flavopiridol , the first cyclin-dependent kinase inhibitor to enter the
`clinic: current status
`·
`LR Kelland
`>> Marimastat: the clinical development of a matri x metalloproteinase
`inhibitor
`AL Thomas & WP Steward
`» Modifyi ng histones to tame cancer: clinical development of sodium
`phenylbutyrate and other histone deacetylase inhibitors
`SD Gore & MA Carducci
`An assessment of iloperidone for the treatment of schi zophrenia
`KKJain
`
`40th Interscience Conference on Antimicrobial Agents and
`Chemotherapy (ICAAC)
`BRyan, H-T Ho, P Wu, M-B Frasco, T Dougherty & JF Barrett
`40th Interscience Conference on Antimicrobial Agents and
`Chemotherapy (ICAAC)
`NS Ryder
`
`Drug Evaluations
`
`Meeting Highlights
`
`Glossary & Indices
`
`Acknowledgements
`
`2889
`
`2903
`
`2913
`
`2923
`
`2935
`
`2945
`
`2973
`
`2977
`
`30 17
`
`This m aterial w as copied
`at the NLM and m ay boe·
`Subject US Copyright Laws
`
`Roxane Labs., Inc.
`Exhibit 1011
`Page 003
`
`

`
`http://www.ashley-pub .com
`
`Drug Evaluation
`Introduction
`
`1.
`
`2. Overview of the disease
`
`3. Market
`
`4. Products in d evelopment
`
`5. Details of the drug
`
`6. Concluding remarks and
`expert opinion
`
`. Bibliography
`
`An assessment of iloperidone for the
`treatment of schizophrenia
`
`Kewal K Jain
`
`Jain PharmaBiotech, Bltisiring 7, CH-4057 Basel, Switzerland
`
`lloperido ne (Novartis' Zoma riln~ is an atypical anti psychotic agent for the
`treatment of schizophrenia. Current trends in the treatme nt of schi zo(cid:173)
`phrenia indicate that some atypical anti psychotics are being recomme nded
`as first-line therapy. Atypical antipsychotics, in addition to being dopamine
`(D) receptor antagonists, are all relatively pote nt seroto nin (5-HT) rece ptor
`antagonists and are less likely than conve ntional dopamine antagonists to
`induce moveme nt disorders. However, all of these agents differ in their
`receptor profiles and clinical profiles. lloperidone, a benzisoxazole, is a
`mixed 5-HT2A/D2 antagonist. lloperidone was found to be more potent
`than its analogues w hen compared w ith halope rido l in antagonising
`climbing be haviour in mice . Ilope ridone is exte nsively metabolised and the
`main circulating metabolite is reduced iloperidone. In patients treated w ith
`iloperidone, a low incidence of extrapyramidal sympto ms and weight gain
`has been shown. Data from Phase II trials demonstrated efficacy in patie nts
`at doses of 8 mg/day a nd tolerability was good up to 32 mg/day . Phase Ill
`prospective, double-blind, rando mised trials w ith ilo pe ridone are in
`progress under the ZEUS (Zomaril,.MEfficacy Utility and Safety) programme
`involving 3300 patie nts. Iloperido ne, with a balance of activity at the
`dopamine rgic and seroto nergic receptors, has obvious adva ntages over
`clozapine and olanzapine, both of w hich have a similar receptor profile as
`they favour seroto ne rgic over dopamine receptors. Ilo pe ridone is likely to
`reach the market in 2001 and has favourable prospects in the atypical
`antipsychotic market fo r schi zophre nia, which is expanding from US$ 1.5
`billion in 2000 to US$ 3 billion in 2005.
`
`Keywords: atypical an.tipsychotics, dopamine receptors, extrapyramidal
`syndromes, iloperidone, psychosis, schizophrenia, serotonin receptors
`Exp. Opin. In vest. Drugs (2000)~ 12):2935-2943
`
`1. Introduction
`
`Iloperido ne, an atypical antipsychotic agent, is in Phase Ill trials by Nova nis
`fo r the pote ntial treatment of schizop hrenia. Atypical is the te rm used to
`describe antipsychotic drugs that produce minimal side effects, such as
`moveme nt disorde rs, which were a typical feature associated with the use
`of classical antipsychotic agwnts. Clozapine (Nova rtis) was one of the first
`atypical antipsychotic agents and several mo re have been introduced since.
`Clozapine has a reduced tende ncy to produce a ny movement d isorde rs, but
`is associated w ith agranulocytosis in ra re cases, wh ich requires blood count
`monitoring and restricts its use in some countries to patie nts \:vho do not
`respond to conventio nal antipsychotics. This article w ill evaluate iloperi(cid:173)
`done fo r the treatme nt of schi zophre nia . The disease and atypical
`a ntipsychotic agents w ill be described brief1y as this top ic has been cove red
`in a previo us art.icle [1].
`
`2935
`2000 © Ashley Publications Ltd. ISSN 1354-3784
`f hi.s materi a I w a.s copied
`atth.e· N LM and may be,
`Subject US Copyright Laws
`
`Roxane Labs., Inc.
`Exhibit 1011
`Page 004
`
`

`
`2936 An assessment of iloperidone for the treatment of schizophrenia
`
`2. Overview of the disease
`
`2.1 Current management
`
`Schi zophre nia is a severe and disabling psychiatric
`disorder that is characterised by delusions, hallucina(cid:173)
`tio ns, disorganised speech or behaviour and flatte ned
`affect. Suicide is commo n in schi zophreni c patients
`with 20% atte mpting suicide at some time and with up
`to 10% dying by suicide. Although the pathophysi(cid:173)
`ology of schi zophre nia has not been fully delineated,
`the pharmacological treatment has bee n dominated
`by the dopamine rgic theory, which states that certain
`do pamine pathways are ove ractive in the disease.
`Cloning of genes for certain dopamine receptors has
`added a new dime nsio n to research in this area.
`Evidence for the dopaminergi c hypo thesis is that
`a ntipsychotic drugs that block 02 do pamine receptors
`are clinically effective. The main reason that clozapine
`a ppea rs to be an exception to the 0 2 blockade
`hypothesis is
`that it has antipsychotic effects at
`dosages that do not cause the high levels of D2
`blockade (70%) seen with the rape utic dosages o f
`o the r atypical and typical agents [21.
`
`in th e
`Se ro to nin ha s a lso b ee n impli ca te d
`p a th ogen esis o f schi zophre nia as post-mo rte m
`mo lecular studies show abnormalities in the 5-HT
`syste m. The re are two c hanges in 5-HT recepto r
`expression that seem to characterise the disease:
`
`• An increase in 5-HT1A receptor binding sites in
`frontal cortex, which is not accompanied by an
`increased 5-HT1A recepto r mRNA
`
`• A loss of coni cal 5-HTzA recepto rs, which is
`paralleled by loss of its mRI\/A l3J
`
`One way to resolve th e conflicting information is to
`consider that bo th serotonin and dopamine receptors
`interact and play a part in the pathophysiology o f
`schizophrenia.
`
`Positron emission tomography (PET) has been used to
`study the role of brain receptors in schi zophrenia [4].
`Combination o f PET w ith in vivo binding tethniques
`provides information abo ut the dopamine recepto r
`distribution , numbe r of binding sites a nd their affinity.
`Antipsychotic drugs have been shown to occupy
`dopamine 02 receptors predominantly with some
`occupying D1 receptors. PET studies using selective
`liga nds have also visualised and quantified 5-HT
`receptors in the brains of schizophrenic patients [5].
`
`Worldwide, most schizophre nic patie nts still receive
`conve ntio nal do pa minergic drugs, su ch as chlorpro(cid:173)
`mazine a nd halo pe rido l, as first-line the rapy and
`atypical antipsychotics are a second-line the rapy. The
`trend is changing in Western countries a nd a ty pica l
`antip syc h ot ics (exce pt c lozap in e) a re b e ing
`recommended as first-line th e rapy in Canada. The
`American Psychiatric Association practice guidelines
`of 1997 suggest eithe r a high potency typical agent or
`an aty pical agent o the r tha n clozapine as first-line
`treatment.
`
`Atypical a ntipsycho ti cs introduced during recent
`in additio n to be ing do pamine
`years (Table 1),
`receptor antagonists, are all relative ly po te nt 5-HT2A
`antagonists and can be mo re appropriately described
`'serotonin-d o pamin e recepto r antagonists'.
`as
`However, all of these agents diffe r in their recepto r
`profiles and therefo re have diffe re nt clinical profil es.
`Atypical antipsychotics are claimed to red uce p ositive
`(hallucinations and de lusio ns) and negative (apathy,
`e motional withdrawa l) symptoms of schizo phrenia
`and are gene rally more e ffective than conventiona l
`a ntipsyc ho ti cs against th e nega ti ve symp to ms.
`Atypical a ntipsych o tic drugs have improved th e
`quality of life fo r people with schi zophre nia. The
`advantages of these over the conventio nal antipsy(cid:173)
`chotics a re that unlike conve ntio nal a ntipsychotics,
`they cause few moveme nt disorders and they impair
`cognitive functio n
`to a much lesser degree than
`conve ntional antipsychotics.
`
`Conve ntio nal antipsychotics can furth e r redu ce
`cognitive fun ctio n, which is already impaired in most
`patients with schizophre nia du e to a redu ctio n in
`dopamine activity in th e prefrontal cortex. Anticho(cid:173)
`linergic drugs used to treat extrapyra midal sy ndromes
`or antipsychotics with anticholinergic activity also
`impair cognitive fun cti o n. Atypical se roto nin(cid:173)
`dopamine antagonists have less adverse effects o n
`cognitive fun ctio n than conve ntional antidopamin(cid:173)
`ergic antipsychotics and they also reduce th e need to
`use anticholinergic drugs [6].
`
`Remoxipride, which had been available since 1984,
`has been w ithdrawn from the market clue to adverse
`effects of aplastic anaemia, but it is still ava ilable fo r
`compassionate use in some patients. Sertindole has
`been restricted in som e co untries due to its cardiotox(cid:173)
`icity. In 1998, Lundbeck Ltd. , the manufacture rs of
`sertindole, voluntarily susp e nded the availability o f
`
`© Ashley Publication s Ltd. All ri ghts reserved.
`
`Exp. Opin. lnve.l'/. Dmgs (2000) 9( 12)
`
`Roxane Labs., Inc.
`Exhibit 1011
`Page 005
`
`

`
`Table 1: Atypical antipsychotics used for the treatment of schizophrenia. © Jain PharmaBiotech.
`
`•
`
`Jain 2937
`
`Drug
`Ciozapine
`
`Olanzapine
`
`Risperidone
`Sertindole
`
`Quetiapine
`
`Zotepine
`
`Eli Lilly' s Zyprexi'M
`
`Janssen's RisperdaJ1'M
`Lundbeck7Abbott' s SetdolecfrM
`
`Comments
`Company/trade name
`~------~--~~--------------~--- .~~~~~----------
`Novartis' ClozatillM or LeponexTM
`This was the first atypical antipsychotic. Itshows greater affinity for
`S-HT1c and S-HT2 receptors than other receptors. It is associated with
`agranulocytos'is in about 1% of the patients
`The receptor affinity of this drug is similarto that of clozapine, but it has
`more potent anticholinergic effects
`This is a dualS·HT2 and dopamine receptorantagonist
`1t has .~ 1 adrenergic blocking activity, whkh may cause hypotension. It is
`associated with prolongation of cardiac conduction. Withdrawn pending
`safety reassessment
`This is considered to be more selective fofS-HT2 receptors than D2
`receptors
`It is a dopamine anntgonist and claimed to :be particularly effective 'for
`negative syinpto1ns. Available only in Japan and a few Eutot>ean
`countries
`
`Zeneca's SeroqueJTM
`
`Fujisawa
`
`the drug du e to concerns abo ut cardiac arrhythmia
`and sudden cardiac d eath associated with its use.
`Sertindole was therefore w ithdrawn from the market
`pending discussio n w ith the European Regulatoiy
`Autho rity over cardiac safety .
`
`Clozapine still re mains the most w idely prescribed
`atypical antipsycho tic agent. According to the
`Cochrane Database of Systematic Reviews, the equal
`effectiveness and tole rability of new atypical drugs in
`comparison with clozapine has no t been proven as
`yet [7].
`
`New drugs are usually started at as low a close as
`possible and then increased over several weeks in
`respo nse to changes in symptoms and side effects.
`Treatment is usually continued for one to two years.
`Those patients who have had only o ne acute
`psychotic e pisode and who have had a good response
`to drug treatment may b e suitable fo r a trial of time
`witho ut drug treatment. Fo r those patients w ho have
`had two o r mo re acute e pisod es, treatment is
`continued for at least five years.
`
`3. Overview of the market
`
`Schizophre nia affects about 1% of the general po pula(cid:173)
`tio n and imposes a huge financial burden on society.
`lt affects mo re than 2 millio n people in the US alone
`and of these about 330,000 are hospitalised each yea r
`because o f this disease . At any given time, more than
`half of schi zophrenic patie nts are under some fo rm o f
`treatment. ln the US, the cost of care fo r schi zophrenia
`exceeds US$ 85 billion pe r year in direct as well as
`
`indirect costs [8]. Financial rewards for improved
`dru gs fo r the treatme nt will be conside rabl e .
`Worldwide market for atypical antipsychotics, w hich
`is expected to be US$ 1.5 billio n in the year 2000
`(about half of the total antipsychotic market of US$ 3
`billion), w ill cross the US$ 3 billion mark by the year
`2005 , when the total antipsychotic market will be
`about US$ 5 billion [8].
`
`Conventional antipsychotics still constitute a majo r
`portion of the antipsychotic drug market worldwide .
`During the past few years, most of market for atypical
`psychotics was held by clozapine, but it is now being
`shared by several new entries . In calculating the
`market size fo r antipsychotics, one should consider
`that schizophrenia comprises only about 38% of it.
`The rest of the market fo r antipsychotic medications is
`made up of manic depression (21 %), dementia (11 %)
`and other disorders (30%), which include conditio ns
`such as Tourette's syndrome, aggressive behavio ur,
`mental retardation, personality disorder and psychotic
`e pisodes [8]. There is also off-label use. For example,
`clozapine is used for psychosis of Parkinson's disease .
`The markets fo r antipsychotics are thus much bigger
`than what is anticipated fo rm the number of schizo(cid:173)
`phrenic patients.
`
`4. Products in development
`
`A selectio n o f the drugs in late stages of clinical
`d evelo pment for schizophrenia is shown in Table 2.
`These, alo ng with the atypical antipsychotics in
`clinical use, will be considered in competitive evalua(cid:173)
`tio n of iloperidone.
`
`<D Ashley Publications Ltd. All ri ghts reserved .
`
`Exp. Opin. lnvesr. Drugs (2000) 9( 12)
`
`This m•at .erial w as copied
`at the NLM an.d may be
`Subj&t US Copyright Law s
`
`Roxane Labs., Inc.
`Exhibit 1011
`Page 006
`
`

`
`2938 An assessment of iloperidone for the treatment of schizophrenia
`
`Table 2: Drugs in .late stages of development for schizophrenia. © Jain PharmaBiotech.
`
`Drug
`
`Amisulpride
`
`Mode of action
`Company
`Sanofi-Synthelabo Selective antagonist of D2 and D 3
`
`Status
`
`Available in some European coumries
`and awaiting registration in oihets
`Phase 1li
`
`Phase llb
`Phase TTl
`Phase II
`
`Approval recommended by the US FDA
`in July 2000. Launched in Sweden in
`September2000
`
`lloperidone (Zomaril™) Novanis
`
`SR-46349
`M-100907
`ORG-5222
`
`Ziprasidone (Zeldox™) Pfizer
`
`Inhibits both dopamine and ser? tonin
`receprors
`Sanofi-Syrnhelabo S-HT2 receptor antagonist
`Aventis
`Selective S-HT2 rec9ptor antagonist
`A combined a 5-HT2A• D2 and a1
`Organon
`receptor antagoni st
`Blocks 5-HT2A· S•HT2c and 5-HTm
`receptors as well as D2 receptors
`
`Figure 1: Structural formul a of il operidone.
`
`Some of the ideal properties o f an atypical antipsy(cid:173)
`cho ti c that sho uld be take n into evaluation o f a new
`drug are:
`
`• Effect o n bo th pos itive as we ll as negative
`sympto ms o f schizophrenia
`
`• Sho uld not produ ce any movement disorders such
`as ex tra pyra midal s yndro mes a nd ta rdi ve
`dyskinesia
`
`• Good safe ty and to lerability profile, parti cularly
`w ith
`rega rd
`th e ca rdi o va sc ul a r a nd
`to
`haemo poietic systems
`
`patent fo r this drug in 1990 and started Phase I clinical
`trials in 1995 . 1-loechst Mario n Ro ussel licensed it to
`Titan Pharmaceuticals in 1997. In 1998, Nova rtis made
`a deal fo r worldwide develo pment (exce pt Japan) of
`iloperidone with Titan and is condu cting Phase Ill
`clinical trials. Novartis predicts a filing in 2001, w ith a
`possible launch in 2002.
`
`5.1 Chemistry
`Iloperido ne is a mixed 5-I-IT2A/D 2 antagonist. Its
`chemical name is 1-(4-(3-( 4-(6-fluo ro-1 ,2- be nzisoxa(cid:173)
`zol- 3-y I) pi pe ridi ny l) p ro p ox y )-3- me th oxy phe n y I)
`ethano ne and its structural fo rmula is shown in
`Figure 1. Ilo peridone does no t have the tricyclic
`structure o f ()[her atypical ne uro le ptics such as
`is
`o lanza pine, cloza pine and qu e tiapine, but it
`stru cturally related to risperidone . It was selected for
`furth er develo pment because of its greate r affini ty for
`the 5-I-IT 2 over D2 receptors.
`Syno nyms of iloperido ne are as fo llows:
`
`Sho uld not produ ce impa irment o f cognitive
`fun ctio n
`
`• HP-873 (research code)
`
`• IL0-522 (research code)
`
`• No gain of weight as a side effect
`
`• Sho uld not raise prolactin levels
`
`• Cost-effectiveness
`
`• Improveme nt of the qu ality of life
`
`s. Details of the drug
`
`Jl o p e ri do n e , a be nz isoxazole, was o ri g in a ll y
`develo ped for schi zophrenia by Hoechst Mario n
`l{oussel ( now Aventis), who fil ed for a European
`
`© Ashle y Publicati ons Ltd. All ri ghts reserved.
`
`• ZomariJTM (trade name, Novartis)
`
`5.2 Pharmacology
`
`5.2.1 Pharmacodynamics
`Although the acti on of atypica l antipsychotic agents
`has been ascribed to 5-I-IT 2/ d o pamine D2 antagonism ,
`the exact pharmacological mechanism underlying the
`effi cacy is unknown. Most o f the aty pical antipsy(cid:173)
`choti cs also block seroto nin, adre nergic, histamine
`and acetylcho line receptors, w hich may be involved
`in th e a ntipsycho ti c e ffec t. A study o f d opa
`
`Exp. Opin. ln vesl. Drugs (2000) 9( 12)
`
`Roxane Labs., Inc.
`Exhibit 1011
`Page 007
`
`

`
`Table 3: In vitro and ex vivo studies of pharmacology of iloperidone.
`
`Jain 2939
`
`Results
`Experimental model ____ .
`Ref.
`Effect studied
`-----·
`[3H]spiperone displacement Rat frontal cortex and stri atum
`High affinity for the S-HT2 over D2 receptor
`[1 3]
`High ·affinity for the 5-HT 2 over D 2 receptor
`Dopamine/5-.HT receptor
`Rat frontal cortex and striatum
`[12]
`affJnity
`Affinity of iloperidone to a
`variety of human and rat
`homologues of dopamine
`and 5-HT receptor subtypes
`
`Jloperidone displayed higher affinity for the D3
`receptor than for the D4 receptor. lloperidone
`displayed high affinity for the 5-HT 6 and 5-HT7
`and was .found to have higher affinity for the
`S-HT2A than for the S-HT2c receptor
`
`[20]
`
`Receptor binding assays using
`membranes from cells stably
`expressing human dopamine Dt , D2s,
`D 2L• D3, D 4 and D 5
`and S-HT2A and S-HT2c receptors and
`rat
`5-HT<i and 5-HT 7 receptors
`Binding of [3H]spiperone to Ex vivo receptor autoradiography
`studies
`receptors
`
`Pretreatment with iloperidone inhibited the
`binding of [3H]spiperone to cortical and
`subcortical S-HT2 receptors by 42 - .94%, in
`contrast to only 1 - 15% ihhibition of
`(3H]spiperone binding to Dgeceptors in the
`nucleus accumbens and striatum
`
`[9]
`
`accumulatio n in the b rain as an index o f dopamine
`turnover in response to 0 2 rece pto r blockade has
`shown that ilo peridone is a 5-HT and dopamine
`receptor antagonist w ith weak activity at presynaptic
`dopamine autorecepto rs [9).
`llo pe rido ne displays
`high affinity fo r a 1 , 0 3 and 5-HT2A rece pto rs,
`moderate affini ty fo r 0 1 , 0 2 , a 2c and 5-HT1A receptors
`and low affinity for a 2A, 5-HT zc, histaminic H1 and
`muscarinic M1 recepto rs [10). Antagonism o f 0 3, Uzc
`and 5-HTzA can lead to increase o f do pamine and
`glutamate re lease in the frontal cortex. In conclusion,
`iloperidone displays targeted modulation of multiple
`ne urotransmitte r syste ms including do paminergic,
`noradrenergic, seroto ne rgic and possibly glutama(cid:173)
`te rg ic e ffec ts . Th ese ex plain th e e ffi cacy o f
`iloperidone against positive , negative and cognitive
`symptoms o f schi zophre nia w ith reduced possibility
`o f mo ve me nt disorde rs [11.1. Low a ffinity fo r
`histaminic H 1 minimises adverse effects such as
`sed ation and seizures , w he reas low affinity fo r
`mu sca rini c M1 recepto rs is like ly to minimi se
`cho linergic adverse effects. Low affinity binding to
`5-HT zc rece pto rs correlates with low potential for
`weight ga in.
`
`5.3 Preclinical studies
`
`5.3.1 In vitro and in vivo studies
`The in vitro studies are shown in Table 3.
`
`Antipsychotic activity o f ilo perido ne has been studied
`on apomorphine-induced climbing behavio ur in mice
`
`in vivo, w hich is antagonised by ilo pe rido ne [1 2].
`Iloperidone was found to be the most pote nt of the
`a n a log ues o f il o p e rid o n e as co mp a re d w ith
`haloperidol in antagonising climbing behav io ur in
`mice [13!.
`
`5.3.2 Pharmacokinetics
`
`Metabolism of the new er antipsychotic agents has
`b ee n reviewed e lsew he re [1 4]. Ilo p e ricl o ne · is
`exte nsively metabolised by rats, clogs and man by a
`numbe r of metabolic p rocesses, including 0-dealkyl(cid:173)
`a ti o n , hydroxy la ti o n and re du c ti o n o f t h e
`acetopheone ring structure w ith quantitative differ(cid:173)
`ences between species [1 5]. The primary metabolites
`are furth er oxiclisecl/conjugatecl w ith glycu ronic acid.
`Oxidative N-dealkylation also occurs and leads to the
`fo rm a ti o n o f 6 -flu o ro -3-(4- pip e ric\in y l)- 1 ,2-
`b e nzisoxazo le a nd th e acid d e ri va ti ve o f th e
`remaining part o f the ilo perido ne mo lecule. Other
`pathways commo n w ith rispe riclo ne include the
`opening of benzisothiazole ring, w hich is apparently
`mediated by liver enzymes rathe r than gut fl ora as
`postulated for rispe ridone. In humans, the main
`circulating metabolite is reduced ilopericlone , which
`is prod uced mainly by cytosolic enzy mes altho uoh
`CYP1A2, CYP2El and CYP3A"f may also ; lay a n;;e
`[16]. Liquid chromatography/ mass spectro metry was
`used in the initial studies to confirm the ide ntities o f
`the metabolites.
`
`© Ashley Publications Ltd . All ri ghts rese rved.
`
`Exp. Opin. Invest. Dmgs (2000) 9( 12)
`
`Roxane Labs., Inc.
`Exhibit 1011
`Page 008
`
`

`
`2940 An assessment of iloperidone for the treatment of schizophrenia
`
`Table 4: Clinical trials of iloperidone.
`
`Trial design
`
`Results and evaluation
`
`Phase I study of safety, tolerability and effect of food on
`the phatmacokinetics of iloperidone in healthy volunteers
`
`fn a Phase JI clinical trial, iloperidone was administered in
`a fixed dose regimen (4 and 8 mg daily) over a 6-week period after
`being titrated to maximal dose over 3- 10 days .. Patients included I 04
`hospitalised men and women with acute or relapsing schizophrenia
`according. Efficacy and safety were assessed at weekly intervals
`Phase 11 prospective, randomised, double-blind, placebo-controlled,
`11exible dose, parallel group, single-centre study to evaluate the safety,
`tolerability and efficacy of iloperidone (0.5 - 6 mg/day in two divided
`doses) compared with placebo in treating psychotic and behavioural
`symptoms in elderly patients with dementia
`Phase Tll prospective, double-blind, randomised trials with iloperidone
`are being conducted by Novanis Pharmaceuticals Corporation under the
`ZEUS (ZomariJTM Efficacy Utility and Safety) programme name. This
`programme will enrol over 3300 patients in eight Phase IJl studies at
`208 sites in 24 countr.ies. ZEUS is designed to assess the safety and
`efficacy of three 1i xed doses of ilioperidone in patients with
`schizoaffective disorders or schizophrenia
`
`lloperidone was found to be well-tolerated .
`The adverse effects were Jess pronounced
`when it was taken with food
`All three treatment groups showed
`improvement from baseline, with iJoperidone
`8 mg/day reaching statistical significance at
`end-point
`
`lloperidone, up to and including 6 mg/day,
`was safe and well-tolerated by elderly
`patients with psychotic and behavioural
`symptoms associated with dementia
`
`Pour of the seven planned trials are ongoing.
`Efficacy in these trials will be evaluated
`using Positive and Negative Syndrome
`Scales, Clinical Global Impression of
`Improvement Scale, Calgary Depression
`Scale, Psychotic Anxiety Scale, cognitive
`function tests and quality of life scales
`
`[22]
`
`[23]
`
`[24]
`
`In the rat, ilopericlo ne and metabolites were fo und to
`pene trate extensively into the brain. Protein binding is
`91 , 87 and 93% in rat, clog and man, respective ly, over
`the concentration range 5 - 500 ng/ ml (17]. The
`majority o f ilo peridone administered either o rally or
`intrave no usly is recovered in the faeces within 24 h,
`suggesting a biliary excretion as the principle route of
`eliminatio n.
`
`The pharmacokineti cs of ilopericlone (3 and 5 mg)
`we re studi ed in three groups of nine healthy, male
`vo lunteers in a placebo-co ntrolled , ranclomised
`design. The drug was well-absorbed afte r o ral admini(cid:173)
`stratio n, reaching peak concentration 2 - 3 h after
`administratio n of a single close [18].
`
`5.4 Clinical trials
`
`Clinical trials for sa fety and effi cacy of iloperido ne are
`sho wn in Table 4.
`
`5.5 Drug safety
`Ilo pe rido ne has undergone extensive tox icology
`studi es (teratoge ni city, mutagenicity and carcinogen(cid:173)
`icity), in which no unexpected adverse findings were
`observed. In over 300 patie nts treated with ilo peri(cid:173)
`do ne prio r to the Phase lli clinical tria ls, ilo peridone
`incid e nce o f extrapyramidal
`ha s sho wn a lo w
`
`sympto ms and weight gain , proble ms that effect some
`of the curre ntly marketed antipsychotic drugs .
`
`In a study using a daily titratio n schedule o f daily dose
`increases, doses up to 24 mg we re found to be
`well-tolerated (1 8]. Some of the adve rse effects o