(magma ‘
`
`MMUA
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`438
`
`(cid:3) (cid:55)(cid:75)(cid:76)(cid:86)(cid:3)(cid:80)(cid:68)(cid:87)(cid:72)(cid:85)(cid:76)(cid:68)(cid:79)(cid:3)(cid:80)(cid:68)(cid:92)(cid:3)(cid:69)(cid:72)(cid:3)(cid:83)(cid:85)(cid:82)(cid:87)(cid:72)(cid:70)(cid:87)(cid:72)(cid:71)(cid:3)(cid:69)(cid:92)(cid:3)(cid:38)(cid:82)(cid:83)(cid:92)(cid:85)(cid:76)(cid:74)(cid:75)(cid:87)(cid:3)(cid:79)(cid:68)(cid:90)(cid:3)(cid:11)(cid:55)(cid:76)(cid:87)(cid:79)(cid:72)(cid:3)(cid:20)(cid:26)(cid:3)(cid:56)(cid:17)(cid:54)(cid:17)(cid:3)(cid:38)(cid:82)(cid:71)(cid:72)(cid:12)(cid:3)
`
`Rivastigmine Novartis AG
`Jose Javier Miguer-Hidalgo
`
`Address
`Department of Psychiatry and Human Behavior
`University of Mississippi Medical Center
`2500 North Stat& University
`Jackson
`MS 39216-4505
`USA
`/
`f Email: jmiguel-hldalgo@psychiatry.umsmed.edu
`
`'
`
`Current Opinion In CPNS Investigational Drugs 2000 2(4):438-453
`C PharmaPrass Ltd ISSN 1464-844X
`
`Rioostignzim: is all acetylclwlitzesterase ( AOz£) inltibitor develuped
`and launched by Navarlis for
`tire symptrmwtic treatment of
`Alzheimer's disease (AD). By April 2000, tlze dmg lUJd been
`launched in more than 65 countries, i11cluding the member states of
`tire EU, atuf had bee11 approved in tire US {363944]. 111 }u11e 2000,
`tire dntg was lauucl:ed in tire US [371704].
`
`In May 1999, the company received an approvable letter from tire
`FDA. nud at this time approval was expected before tire end of
`1999 {324671}. However, i:Jy September 1999, N<r.;artis had be~1
`asked to provide more infomwlioll on 4000 patients in lcmg-term
`studies, hence approual in the US was tlot expected before Morclz
`/11 April 2000, the FDA granted markding
`2000 /342651 }.
`clearance for ri-oastigmine in tire US for the treatmmt of mild-ttr
`moderate AD /3638241, [363843/, [363944]. Rivastigmiue is due
`to enter tlu: mild-to-moderate AD market, nrhich is domiuated i:Jy
`Pfizer/Eisai's donepezil (Aricept), in May 2000; Novartis lUIS
`plans to initiate a comparative trill! of the two dn1gs in tlris patient
`populatiou by the end of2000 {364802].
`
`Itr May 1998, Nouartis received marketi11g approval from tire
`European Commission 12885641. and i:Jy july 1998, tire dmg had
`been cleared for marketing i11 over 30 countries {292661].
`However, i11
`tlzc same montlt, tile company received a non(cid:173)
`approvable letter because of a pote1rtial relatiolfslzip betwee11 lziglr
`doses of the dmg and deatlzs reported during clinical tritlls
`/3126451.
`
`Originator Novartis AG
`
`Status Launched Extensively
`
`Indication Alzheimer's disease, Cognitive disorder,
`Dementia
`
`Action Acetylcholinesterase inhibitor, Enzyme inhibitor
`
`Synonyms ENA-713, SDZ-212-713, SDZ-ENA-713,
`Exelon, rivastigmin, Prometax, rivastigmine tartrate, Exelon
`IDS, Exelon Solution
`
`CAS Carbamic acid, ethylmethyl3-[1-(dimethylamino)ethyl)
`phenyl ester, (S)-
`. Registry nos: 123441-03-2, 129101·54-8
`
`r·
`
`0/(N'-../'CH,
`
`0
`
`CH,
`
`N
`I
`CH,
`
`H,C
`
`Tire results of a pooled a1wlysis of three plwse 1li studies i11
`patients with mild-to-moderate AD, lws demonstrated
`that
`patients treated witlt rivastigmine experienced less decli11e in
`activities of daily Jiving (ADLJ tlza11 pntieuts treated witlr placebo.
`Approximately 50% more patients showed a cliuically significant
`improvement from baseline ADL compared to tlzose 011 placebo.
`The data were presenJed at the 52nd An11ual Meeting of the
`Gerentological Society of Anlerica (San Frmzcisco, CA. November
`1999) /348202/.
`
`Tire associated paten!, DE-3805744-B, discloses rivastigmi11e in its
`optically active form. Howroer, an older patent, EP-00193926,
`lteld i:Jy Yissum Research Development and Proterra, discloses tire
`stereochemically unspecified compound.
`
`In july 1998, the US FDA requested additional analyses of dJzta
`submitted in tlte NDA, filed in April 1997, in order lo conjirn1
`rivastigmirre's safety at high doses /291307}, [292661]. Tire
`additional do/a were submitted to tlu FDA in December 1998
`[319561].
`
`In September 1998, Merri!J Lynclz predicled peak sales of SFr 750
`million [300257]. In April 1999, Lehman Brothers commented
`_ tlwt rivastigmine, due to be launched in /Ire US in 1999, would
`Tile first nwrketing approval of rivasligmine, i:Jy ·tlte Swi~ .. face competition_fronr donepezil_nnd could also [ace competition
`regulatory authority IKS, was ill August 1997, for the trealmetrf
`from gnlan_tamme
`(Sarzoclrerm'! Plwr?wzeufllca AG!Janssen
`of mild-t0-nwderate AD. 71ze a rovnl, conducted i:Jy tile fast-track
`Plwrnwceutzca NV) and metrifonate .111 2000 [336750}.
`In
`,
`. · l
`_ .. ·
`pp
`d
`September 1999, Lehman Brothers predtctcd peak sales of $400
`a· ed 1
`ror~Je, was based 011 the largest AD clmtca program C01l uctw /11
`"11"
`[342651] l A
`"[ 2000 M
`"11 L
`J
`·
`,
`. d
`( 1-' .
`,. 1 mt ton
`pn
`ern
`~prcr pre ret
`twt
`.
`11
`.
`.
`d ·
`Europe nrrd
`the US, ADENA A 411e1mer s
`enrentw ul11
`l
`ld
`fr
`J CHF 6S
`.11.
`corztmue to nse om t re
`. ...
`.
`.
`.
`.
`.
`.
`.
`sa es wou
`mr 1011 eanze m
`nvastrgmme) winch mvolved more tlum 3330 palzents With Tmlu-
`1999 t CHF 480
`· 2004 [J649741
`-11 .
`mr 101111r
`0
`to-moderate AD [259187].
`-
`
`Rivastigmine is a twice-daily oral fommlation; some rival
`products, notably donepezil and metrifonate (Bayer Corp), are
`once-daily fommlatious [2871881- By tlze end of 1998, Novartis
`was also developing a transdennal fommlatiou of rivasligmine,
`E:relo11 TDS, and au oral solution of the compound, Exelon
`Solution {319337}. AI the elld of 1999, Exelon TDS was ill pfUISe
`11 trials, wit II an estinwted ftli!l& date of 2002 [364082].
`
`Introduction
`Rivastigrnine
`is an inhibitor of AChE that has been
`approved recently
`in Europe, USA and several other
`countries for the treatment of mild to moderate AD. Deficits
`in cholinergic transmission were identified early in the
`pathophysiological research of AD. Since disruption of
`cholinergic transmission in animals was found to produce
`
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`

`-4 AUG2000
`AND BliSiiJES5
`
`Rlvastlgmlne Miguel-Hidalgo 439
`
`memory deficits comparable to those in AD patients it was
`postulated that enhancement of cholinergic transmission
`may ameliorate cognitive disturbances in AD patients. In
`fact, AChE inhibitors have been the first widely used drugs
`for the treatment of AD. Tacrine (Warner-Lambert Co/First
`Horizon Pharmaceutical Corp) was the first AChE inhibitor
`to be approved for AD treatment although the hepatic
`toxidty that it causes in some AD patients has limited
`greatly its widespread use. The quest to find ot.'ler AChE
`inhibitors with an improved safety profile has lead to the
`development and approval first of donepezil (Eisai Co Ltd)
`and more recently to rivastigmine.
`
`Synthesis and SAR
`Although AD was first described in 1907, it was not until the
`mid-1970s that it became possible to think in terms of a
`rational hypothesis for designing drugs against AD. The
`observation that there is a selective loss of cholinergic
`neurons in the cortical and hippocampal areas of patients
`with AD led to the so-called 'cholinergic hypothesis' and
`made it possible to embark upon synthetic programs to
`design drugs that would enhance cholinergic function in the
`central nervous system (CNS). Much effort has gone into
`designing CN5-se!ective AChE inhibitors since many AChE
`inhibitors in medicinal use hav.e quaternary nitrogens and
`do not penetrate the CNS. A 1986 publication from the
`Hebrew University of jerusalem describes eight analogs of
`miotine,
`a
`neutral monomethylcarbamate of 3-[1-
`(dimethylamino)ethyiJphenol used clinically as a miotic
`(2410801. Although not the best inhibitors in vitro, three N,N(cid:173)
`disubstituted analogs displayed the best combination of
`brain selectivity, long-lasting in vivo activity, and good
`tolerability
`in mice. Of
`these
`three,
`the N-ethyl-N(cid:173)
`methylcarbamate (RA7) was chosen by Sandoz for clinical
`de\·elopment
`and was
`designated
`SDZ-ENA-713
`(rivastigmine}. While the original activity was reported for
`the racemic compound, the enantiomers were synthesized
`by recrystallization of the di-p-toluoyi-L-tartrates [241087}
`and the R(+) ertantiomer was found to be 5-fold weaker in
`vitro.
`
`Pharmacology
`Rivastigmine is an AChE inhibitor also able to inhibit
`butyrylcholinesterase {BChE) (in normal brain only AChE is
`abundantly represented). Reversible and non-competitive
`inhibition of AChE by rivastigmine has been called 'pseudo(cid:173)
`irreversible' to stress the fact that rivastigmine is actually
`cleaved by AChE and the resulting carbamate is bound
`covalently to the enzyme. However, this binding is transient
`due to
`the rapid metabolism and
`the rapid rate of
`decarbamylation, which regenerates AChE {372436]. At a
`difference with other AChE inhibitors, rivastigmine shows a
`preferential inhibition of AChE in brain areas such as the
`hippocampus and the neocortex while the inhibition is much
`lower in peripheral organs. For instance,
`it increases
`salivation at doses over 6-fold higher {6.4 mg/kg ip) than
`those where alert non-mobile behavior is induced (0.5
`mg/kg ip) and produces a 50"/o ex vivo inhibition of cortical
`and hippocampal AChE at a dose {3.0 }.1/kg sc), 10-fold
`lower than that which inhibits heart AChE (30.0 JlffiOI/ kg sc)
`[162923J. When examined ex vivo in rats, rivastigmine is 10-
`fold less potent than physostigmine in the brain, compared
`
`to 100-fold less potent ill vitro. These effects may be due to
`preferential inhibition of the G1 form of AChE, which is
`present in relatively higher concentrations in cortex and
`hippocampus.
`
`Rivastigmine demonstrated a number of properties
`in
`animals that indicated its potential in the treatment of AD. It
`appears to readily penetrate the CNS since a dose of 0.75
`mg/kg po produces a long lasting(> 6 h) EEG activation. In
`rats with closed head
`injury (CHI} 1
`to 5 mg/kg
`rivastigmine produced 40 to 80% inhibition of AChE in the
`cortex
`and
`hippocampus
`[289316). Microdialysis
`measurements of acetylcholine (ACh) in the hippocampus
`shows an increase of available extracellular ACh produced
`by rivastigmine. In rat hippocampus rivastigmine at doses
`of 0.625, 1.25 and 2.5 mg/kg po produced maximum
`elevations (190, 346 and 480%, respectively) of ACh at 0.5 h
`after administration as measured by microdyalisis, while
`maximum increases were attained with donepezil and
`tacrine at 1.5 and 2 h, respectively [3724381. Rivastigmine
`(0.1, 0.2 mg/kg po) also was able to prevent the reduction of
`choline acetyltransferase (ChAn in the frontal cortex of rats
`with their basal forebrain lesioned by ibotenic acid [37Z442].
`
`Rivastigmine improves memory impairments in different
`animal models. Rivastigmine (0.5 mg/kg ip) attenuated
`significantly the working memory impairment produced by
`scopolamine in the delayed non-matching to position task
`given to rats [367020]. At doses between 0.05 and 0.10
`mg/ kg/ day it improved acquisition and retention in basal
`forebrain-Iesioned rats tested in a step-down avoidance
`paradigm [1935041. In rats with the same lesions tested in
`the water maze task rivastigmine (0.1, 0.2 mg/kg po)
`ameliorated
`the
`impairment in acquisition
`in a dose
`dependent manner (372442]. In a rat model of memory
`impairment induced by scopolamine in a delayed non(cid:173)
`matching
`to position
`task
`rivastigmine significantly
`attenuated the working memory deficit.
`
`rivastigmine
`Since
`is aimed at aging populations,
`experiments with aging animals are especially relevant In a
`study by Ohara eJ al [2591391 in aged rats rivastigmine (0.2
`mg/kg) significantly shortened the time to reach a hidden
`platform and also at 0.1 and 0.2 mg/kg inhibited aging
`induced decreases in AChE activity in the frontal cortex. In
`senescent rats, chronic administration of rivastigmine
`blocked aging-induced reductions in ACh and in choline
`acetyltransferase
`(ChAT)
`levels
`in
`frontal
`cortex,
`hippocampus and striatum and in B...,. of muscarinic M,
`receptor binding sites in frontal cortex [193505}.
`
`A number of studies indicate that rivastigmine may be
`useful in the treatment of cerebrovascular dementia. In
`ischemic gerbils, administration of 0.2 mg/kg
`ip
`immediately after 5 min of bilateral carotid artery occlusion,
`and again after 6 and 12 h, resulted in a significant decrease
`in pyramidal cell death in the hippocampus (230733). In
`another study, gerbils receiving 0.2 mg/kg ip, 2 h prior to
`transient ischemia, were protected against ischemia-induced
`reductions in hippocampal ACh levels and in the maximum
`number of muscarinic ACh receptors (B_) {162883].
`Administration of 0.2 mg/kg ip 30 min before transient
`ischemia in this same model blocked ischemia-induced
`decreases in brain ACh, dopamine and 5·HT [162929). In
`
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`
`Page 4 of 18
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`

`440 Currant Opinion in CPNS Investigational Drugs 2000 Vol2 No 4
`
`to 0.5 mg/kg iv ri\'astigmine,
`hypertensive rats, 0.05
`administered 10 min before cerebral ischemia, protected
`against reductions
`in cortical and hippocampal ACh
`{230734J, similar to the results in gerbils. In line with the
`neuroprotective effects is the report of a reduction in edema
`and in disruption of the blood-brain barrier in rats with CHI
`treated with rivastigmine at doses of 2 and 5 mg/kg. These
`improvements were accompanied by a faster recovery of
`motor deficits [289316]. In mice with the same type of injury
`rivastigmine (2 mg/kg sc) improved memory performance
`in the Morris water maze. It also reduced by at least 50%
`cerebral edema 1289264].
`
`Recently, gender differences in the effect of rivastigmine on
`brain cholinesterase {ChE) activity and cognitive function
`have been described in rats [372445]. Rivastigmine {0.75 and
`1.5 mg/kg) caused significantly greater ChE inhibition in
`females than in males in the cerebral cortex, hippocampus
`and striatum, although not in the periphery. Rivastigmine
`also antagonized more effectively scopolamine-induced
`spatial memory impairment in female than in male rats.
`Male testicular factors appear to account for the differences
`since these differences were abolished by orchidectomy, but
`not by ovariectomy.
`
`Some new experiments suggest that rivastigmine might
`have application as a
`topical agent
`that may lower
`intraocular pressure (lOP) in glaucoma therapy [372437}. In
`rabbits, topical application of 1, 2 or 5% rivastigmine on the
`eye produced maximal lOP reductions of 15.2, 19.6 or 23.2%,
`respectively, without signs of local toxicity.
`·
`
`Toxicity
`In the rat, cat and squirrel monkey, rivastigmine exhibits no
`significant effects on cardiovascular parameters at doses at
`which dear central effects can be demonstrated [162923). To
`achieve a similar pressor effect rivastigmine must be injected
`at doses 2-fold the dose of tacrine and 40-fold the dose of
`physostigmine in rats (372440}.
`
`Results of a phase 1/ll trial in AD patients showed a bid and
`tid treatment regime to be safe and well tolerated up to 12
`mg/day, although side effects were similar
`to
`those
`experienced in previous trials [190327).
`
`Rivastigmine shows some selectivity for brain AChE,
`suggesting that it may have a greater margin of safety than
`other nonselective
`cholinesterase
`inhibitors. Studies
`conducted in healthy volunteers showed rivastigmine to be
`centrally active, long lasting, and well tolerated over a
`moderate dose range. Side effects,
`including nausea,
`vomiting, diarrhea, dizziness and headaches were evident at
`high doses, although these did not include hepatotoxicity
`!304019}.
`
`Metabolism
`Orally administered rivastigmine in healthy subje<ts (3 mg)
`was rapidly and almost completely absorbed {> 96% of the
`administered dose) with T_ being 1.1 h, C.., 7.7 ng/ml and
`AUC 18.6 ng.h/ml (367022]. It was converted with a t112 of
`1.5 h to the principal metabolite, the decarbamylated phenol
`(C..., 6.1 ng/ml, AUC 35.4 ng.h/ml), which was eliminated
`
`with a t,11 of 3.5 h. In AD patients the pharmacokinetic
`profile of rivastigmine (3 mg) is similar, showing rapid
`absorption with a T_, of 1.67 h, C_ 5.07 ng/ml, AUC 15.4
`ng.h/ml and a t11: of 1.23 h [289261]. In these AD patients
`dose dependent inhibition of cerebrospinal fluid {CSF)
`AChE was significantly correlated with plasma drug and
`In spite of
`its complete
`metabolite concentrations.
`absorption, rivastigmine undergoes extensive saturable first(cid:173)
`pass metabolism, which
`leads
`to bioavailability of
`approximately 35%. The principal metabolite of ri\•astigmine
`is at least 10-fold less active then the parent compound.
`Unlike tacrine, donepezil and galantamine, rivastigmine is
`not metabolized by the cytochrome P450 liver enzymes.
`Rivastigmine is metabolized via esterases and is then
`rapidly se<reted in the urine [229292], [372435), [209139).
`This is probably the reason for its safe hepatic profile.
`
`The bioavailability of rivastigmine is higher in aged subjects
`that in young healthy volunteers. However, studies with AD
`patients between 50 and 90 years old did not show evidence
`of bioavailability changes with age (BIAM monograph on
`rivastigmine}.
`
`In ten renally- and ten hepaticaliy-impaired patients, the
`AUCs for rivastigmine were 2.3-fold and 1.4-fold higher,
`respectively, and the AUCs for the metabolite were 0.8-fold
`lower and 1.5-fold higher, respectively, as compared to
`healthy subjects. The conclusion was drawn that dose
`to the usual clinical
`titration
`adjustment in addition
`appeared unwarranted in these patients [234634).
`
`(rivastigmine) was
`r'CJ·SDZ-ENA-713
`In mm1p1gs,
`iv (0.1 mg/kg), orally (1.0 mg/kg} or
`administered
`topically (18 or 54 mg with a dermal patch) [367021]. Oral
`of 0.83 h.
`doses were efficientlv absorbed with a T
`Bioanilability was lo~ (0.5%} due to exten;ive first-pass
`metabolism. Excretion was mainly renal (roughly 90%) and
`t.,1 was 56 h, higher than 46 h after the iv dose. Dermal
`administration produced a lower absorption (no larger
`than 19%), but bioavailability was 20 to 40-fold higher
`since most of the absorbed drug reached the systemic
`circulation without. suffering first-pass metabolism. The
`metabolite of I"CJ-SDZ-ENA-713, ZNS-114-666 was rapidly
`formed, but accounted only for less than 4% of the total
`drug-related material in the systemic circulation.
`
`In rabbits, rivastigmine administered orally (1.09 mg/kg)
`was completely and rapidly absorbed (T,_
`::: 1.3 h}.
`Following iv administration at the same dose, rivastigmine
`was extensively distributed (Vss = 3.1 1/kg) and rapidly
`cleared (CI = 2.7 1/h/k.g). The radioactivity corresponding to
`the labeled rivastigmine was mainly excreted through the
`kidneys (86% of dose) [367023j.
`
`Clinical Development
`
`Phase/
`Extensive testing of rivastigmine in healthy, young, old and
`· renally /hepatically impaired patients has been conducted.
`Data on the safety, tolerability, pharmacokinetics and
`metabolism of rivastigmine are presented above [367022),
`[289261}, [229292}, [372435), (209139], [234634].
`
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`
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`

`Rlvastfgmlne Miguel-Hidalgo 441
`
`· Phasell
`There is clinical evidence for the central selectivity of
`rivastigmine. A single 3 mg po dose produced 30 to 40%
`inhibition of AChE in human CSF but minimal inhibition of
`either erythrocyte AChE or plasma BChE {241060}. In a study
`in healthy subjects preferential inhibition of AChE in CSF {as
`compared to plasma or erythrocyte AChE) was found after
`treatment with 3 mg of rivastigmine po [367019}. In a related
`study in which AD patients were titrated -in 1 mg bid/week
`increments to target doses of 1, 2, 3, 4, 5 or 6 rng bid
`rivastigrnine, it was further found that inhibition of CSF
`AChE is dependent on the dose of rivastigmine {289261]. The
`6 mg bid treahnent group showed a maximum mean
`inhibition of 62% at 5.6 h post-dose. In a study of sleep quality
`in young male volunteers, effects on REM sleep density at 1,
`1.3 and 2 mg indicate rivastigmine is centrally active [3157].
`
`In a phase H efficacy study of rivastigmine in 402 AD
`patients, the completion rates were 87 and 85% for doses of 4
`and 6 mg/day, respectively (2292921. In a second study, in
`which 114 patients with mild to moderate AD were dosed
`bid and tid in the range 6 to 12 mg/day, 12 mg/day was
`tolerated, but completion rates were 64% in the bid group
`and 76% in the tid group. In a similar study in 50 patients in
`which drug was given after food 1209139], 12 mg/day was
`also well tolerated. The principal adverse effects at 12
`mg/day were typical of excessive peripheral cholinergic
`stimulation, ie, headache, nausea, dizziness and diarrhea.
`
`Phase Ill
`The phase III ADENA program comprised four separate,
`multicenter, placebo-controlled, 6 month, double--blind trials
`in patients with mild to moderately severe AD. The selection
`criteria also allow older patients. patients with significant
`physical illnesses and those taking concomitant medication
`[241060}. Results are available in published form from two
`of these trials [372434], [372444].
`
`In a US trial (6352}, 699 patients were randomized to either 1
`to 4 rng/day bid, 6 to 12 rng/day bid, or placebo for 6
`months and were evaluated on scales of cognitive function
`(ADA5-Cog), global functioning {CIBIC+) and activities of
`daily living (PDS) (372434]. Of the high-dose group, 25%
`showed improved PDS, ADAS-Cog, and CIB!C+ scores
`compared to 15%, 7%, and 16o,'o of the placebo group for the
`respective outcome measures (372434}. The minimum
`effective dose is suggested to b€ 6 mg/day. 25% Of the drug(cid:173)
`treated patients withdrew because of the side effe<:ts dted
`above, versus 16% of the placebo group.
`
`In the phase III study 8303 725 patients from 45 centers in
`Europe and the USA received either 1 to 4 mg/day (low
`to 12 mg/day (high dose group)
`dose group) or 6
`rivastigmine, or placebo, over 6 months [372444]. The doses
`were increased over the two fixed-dose ranges during the
`first 12 weeks and assessed during the subsequent 14 weeks.
`During the trial period, patients treated with placebo
`deteriorated according to measures of cognitive function,
`global functioning and ADL. In this study 24 to 4lo/o of the
`high dose group were full responders in all three measures
`and 50 to 60"/o were partial responders. Scores of the ADAS(cid:173)
`Cog improved in patients in the higher dose group when
`compared with patients
`taking placebo. Modest, but
`significant improvements were found in global function and
`in the progressive deterioration scale.
`
`the American Academy of
`the meeting· of
`During
`Neurologists (May 1998), Novartis presented results of a
`meta-analysis of three double-blind, placebo-controlled, 26-
`week phase III studies (designated 8303, 8351 and B352}
`[289815]. In more than 2000 patients rivastigmine had
`significant beneficial effects on measures of cognition
`(ADAS-Cog scale), global functioning and ADL. In a study
`with 100 weeks of treatment, the mean change on the AD AS(cid:173)
`Cog scale following rivastigmine was 3.8 points better than
`placebo treatment [297099]. In an open-label extension
`phase, patients who had originally received placebo (n =
`145) or rivastigmine (n = 136) received rivastigmine for a
`further six months. At the end of the six months, patients
`who had originally been on the placebo scored nearly three_
`points higher on the ADAS-Cog scale. Between 44 and 52
`weeks all patients experienced a decline in cognition scores,
`although this was more modest in patients who were
`originally on rivastigmine {287188). Factors affecting patient
`responses to rivastigmine, using pooled data from the same
`studies (8303, B351 and 8352), were discussed in the Sixth
`International Conference on Alzheimer's Disease and
`Related Disorders (Amsterdam, The Netherlands, July 1998).
`In total, these trials encompassed 1843 patients {293335}.
`Analyses were performed on the effects of rivastigmine (6 to
`12 or 1
`to 4 mg/day) or placebo upon cognitive
`improvement after 26 weeks of treatment. Patients were
`divided into subgroups according to age, race, gender,
`baseline disease severity, concomitant medications, co(cid:173)
`morbid
`illness and Hachinski
`score. Response
`to
`rivastigmine was determined by an improvement in ADAS(cid:173)
`Cog score of 4 points, and a CIBIC + score of < 4 at the
`endpoint [293335}. In general. response to rivastigmine is
`most effective at doses between 6 and 12 rng/day, in
`patients with moderate AD. Lower body weight enhances
`reduces
`response.
`responsiveness, and nicotine use
`Insufficient patient numbers prevented meaningful analysis
`of the influence of comorbid illness, race or concomitant
`medication on rivastigmine treatment, although in the latter
`no differences were seen with NSAIDS or estrogen.
`
`Since rivastigmine shows neuroprotective properties in
`some animal models, clinical trials have started to apply
`rivastigmine to other neurodegenerative diseases. Recent
`data from a multicenter study showed that rivastigmine has
`efficacy in improving the behavioral and psychological
`symptoms of dementia and cognition in patients with Lewy
`body dementia (LBD). 120 LBD patients in Italy, Spain and the
`UK, with a mini-mental state examination (MMSE} score of at
`least 10 were enrolled. The study used 3 to 12 mg/day of
`rivastigmine or placebo for 20 weeks with a fixed titration
`every 2 weeks. Significant improvements over placebo were
`achieved on ail neuropsychiatric inventory (NPI) items and
`attention, but not MMSE scores {337485).
`trials of
`In
`ri\•astigmine in AD greater cognitive benefits were observed
`in cases with vascular risk factors, like hypertension than in
`cases without [364146]. Some data presented this year at the
`Congress of the European Society for Clinical Pharmacology
`suggest that rivastigmine might be of value in the treatment of
`cognitive dysfunction in Parkinson-plus·dementia {369737}.
`
`A recent study has analyzed the efficacy and safety of
`rivastigmine in AD patients with concurrent vascular risk
`factors [372439]. Patients were randomized to placebo (n =
`235), low-dose rivastigmine (1 to 4 mg/day, n = 233), or
`high-dose rivastigmine (6 to 12 mg/day, n = 231) for 26
`weeks and efficacy assessed with ADAS-Cog, CIBIC+, PDS,
`
`Noven Ex. 1018
`
`Page 6 of 18
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`442 Current Opinion rn CPNS Investigational Drugs 2000 Vol2 'No 4
`
`GDS, and MMSE. Additionally patients were categorized
`into two groups (with or without vascular risk factors) by
`the
`for
`baseline modified Hachinski
`Ischemic score
`determination of vascular risk factors. The
`treatment
`difference between high-dose rivastigmine and placebo was
`larger in the group with vascular risk factors than in the
`group without vascular risk factors. The conclusion of the
`study was that rivastigmine is effectiye in both categories of
`patients, although
`those with vascular
`risk
`factors
`experience greater clinical benefit.
`
`Side Effects and Contraindications
`Studies in phase ll and III have revealed that rivastigmine is
`well tolerated with doses up 12 mg/day [372434), [372444).
`Adverse events were predominantly gastrointestinal, of
`mild-to-moderate severity, transient and occurred mainly
`during the escalation of the dose. The most common side
`effects were cholinergic and included nausea, vomiting,
`diarrhea, abdominal pain, and anorexia. In the lower dose
`group of study 8303 (1 to 4 mg/day) only the incidence of
`nausea (17%) was significantly higher than in the placebo
`group {10%) [3724441. These cholinergic adverse effects can
`be reduced by slowing the rate of titration or lowering the
`dose by as little as 1 mg/day. No clinically relevant
`differences were observed between groups in vital signs
`(blood pressure, heart rate, body temperature), ECG,
`physical examination, hematological or biochemical analyses
`(including the levels of hepatic enzymes). Discontinuation of
`treatment in trials for any reason was significantly higher in
`the high-dose group (33%) than in the low-dose (14%) or
`placebo groups (13%) 1372444].
`
`rivastigmine with
`of
`administration
`Concomitant
`med ications belonging to 22 different therapeutic classes did
`not reveal significant increase of adverse events that would
`have indicated a drug interaction [367018}. In contrast, the
`pharmacokinetics of AChE inhibitors tacrine and donepezil
`have been reported to be altered by drugs like theophylline
`and cimetidine [327826].
`
`Patent Commentary
`in EP-
`The basic molecule of rivastigmine is claimed
`00193926, filed in March 1986 by Yissum Research and
`De\•elopment Co. The application was assigned to a Swiss-
`
`based company, Proterra AG in 1987 and granted in 1990.
`Sandoz filed a German priority case, DE-03706914 in March
`1987 claiming the(-) enantiomer (rivastigmine). This formed
`the basis of a patent family which includes GB-02203040 and
`US-05602176.
`
`Current Opinion
`The ability
`to produce modest improvements . or just
`arresting temporarily the decline in behavioral and cognitive
`functions that characterizes AD is of paramount medical and
`social importance. Inhibitors of AChE have been the first
`pharmacological compounds to demonstrate that ability in
`the clinic. Although the cholinergic treatment is called
`is supposed not
`to
`interrupt
`the
`symptomatic and
`underlying processes causing AD evidence is appearing
`which suggests that procholinergk agents, like rivastigmine,
`may significantly delay the progression of AD symptoms
`beyond one year in mild-to-moderate AD patients.
`
`Since rivastigmine does not interact with many of the
`medications which are prescribed to the often heavily
`medicated aged AD patient group, it might have an
`advantage over donepezil or tacrine in long-term use.
`However, new studies are revealing that the responses to
`ri\•astigmine may vary in different groups of AD patients
`depending at least on their gender or on the presence of
`vasc-Ular risk factors.
`It is possible, that a particular
`population of AD patients may benefit preferentially with
`different doses of rivastigmine. This possibility dearly calls
`for further basic and clinical research. Furthermore, the
`mechanisms of action of rivastigmine and donepezil are
`different and consequently they might also be directed to
`different populations of AD patients. The extent that the
`putative different populations of AD patients are going to
`benefit from differential dosage or from the use of an
`altemati\'e drug
`treatment will depend on careful
`the side effects and
`monitoring of
`the degree of
`improvement observed in a particular population.
`
`Finally, it is significant that trials with rivastigmine in
`patients with other neurodegenerative diseases (eg, LBD) in
`which cholinergic mechanisms play an important role have
`already started. They will provide important information on
`putative neuroprotective properti