The Cyciosporlns
`Jean F. Borel
`
`I T WAS to years ago, at the Seventh International Con-
`
`in
`
`in
`of the
`from the
`that a few papers,
`group and retating to cyclosporine (CS), Were presented in
`what was
`to be an
`work(cid:173)
`lml:lltluicOOfi:tc R.esponsi.venesl!: Pbarma-
`However, it
`obviously been
`would be disclosed, since
`rumoured that sensational
`tbe Imall room was overcrowded and miDY more
`stood in the haIlway,listl'lning to results obtained with CS in
`The climax waS
`transplantation
`reacbed when Sir
`on a handful of cHnieal
`cases, cada.ver lddney
`who had been started on CS
`since the end of June 1978.405 It became clear to "vf>r"hnrlv
`of thOle results was like rainfall on r---"-
`that the
`land.
`The main interest in Sandimmunel\
`in organ
`focused on its
`almost
`as Ii
`transplantation. With its selective and reversible inhibition
`of the immunocompetent T lymphocytes, SIM can indeed be
`I'Cg!Al'fled as the
`of a new
`immuno·
`I:'l'i.F'I>lIlClll its immediate
`in this
`life-saving indication and perhaps the raising of dispropor-
`of severe side effects sllch
`tionlte
`The
`as
`OVcr the
`years, to mas.sive dose reduction and to a fundamental
`oftbeSIM treatment
`The
`of
`these further and thus
`both in
`transplantation and in the newly
`autoimmune disorde1'l> remain rea,$OIlab,lj O1~nnr"''''''
`as the first-line treatment
`assess the optimal use of a drug we need to !mow its
`mechanism of action, It should be stressed that CS plays an
`in buic research,
`im.,..,n""t fole as an
`
`has
`in an immune
`UIH1V1f'" the different
`response in
`roles of cell
`the
`and
`interactions and of mediators in lymphocyte
`for analysing the cell regulatory mechanism of the genes,
`Time
`hfn'1I on the mode of
`action
`
`THE CYCLOSPORINS: THEIR STRUCTURE-ACTIViTY
`RELATIONSHIP
`
`A, tne
`number of
`lh~ same structural type. At least 25 of these natural
`have been isolated and their chemica.1 eornrx>SI-
`t10n cnamelerised,ll
`I amino acidll
`and seldom ditrer by mOre than one
`The
`exchange of amino acid units oceurs in most
`the
`
`exceptions so far being position :3 (ss'n;!OIine) and POSition
`(D·alanine). Of interest are variations at position 1:
`f and Ie contain a~;ox1~-\"~-aJmulo
`
`from the biotrans-
`about 24 metabolites
`formation of CS have been isola.ted from urine and bile and
`I.iU~'U"''''''''.r characterised.16 Tbe metabolic pathways of as
`show that
`in man and M·l in
`as weD as tbe
`N·dimethylated derivative M-21, should be tXIns!dered as
`metabolites of CS. Funher oxidations of M·l Of
`and
`di.~,vdjroxvlated derivatives
`to further ~1U'[J.~.!I;r"LIl:1
`-16, which in turn
`The major metabolites (M-l'. -1,
`are clearly less
`imlnwlosllpp,r=sive lhan CS itself and may not contribute to
`of
`some el'lfltl'l1lVersial
`Toxicologic studies in tbe rat have conclusively sbown
`their
`is mlnimal
`cannot
`CS-induced nephrotoxicity, Moreover,
`account for
`when the metabolism is increased, the nephrotoxicity iJ,
`is inhihited,
`and when the
`creat.i.nine levels
`In spite of OUf incomplete knowledge of the pharmaco}Q,II-
`iced
`of all tbese
`the following four
`main conclusions CIUl be drawn:
`L Surprisingly, none of the natural
`
`or the
`pharmacological
`
`PrecliniCal Research, Sandol; Ltd" Ballel, Swlizenall.d
`Address flprln! requesls to P~Olessor Jean F. Boral, PrecU"*
`ca.1 Researoh, San dot AG (PostfI'lCh). CH.4002 Basel, 5 ..... 111(1,.
`
`1Itl 1989 bV Appleton" Lang&. Inc.
`0041·134IlIS91$3.00f +0
`
`i M. ;
`
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`
`

`
`1
`I
`I
`
`I]
`0-
`as
`A
`
`oe
`lid
`Vi,
`ler
`
`ni·
`in
`:nt
`Ib-
`
`,.
`nd
`:S
`,he
`as
`or
`lid
`
`!!lIli
`to
`ld(cid:173)
`W'Il
`:tot
`'eI',
`is
`
`the
`cal
`
`Un1·
`
`S15
`
`model of eye'osporll'l A
`Fig 1..
`MH
`TIt.llldu6e. (From: V Que8nleux, R
`11 amIno
`Schreier, .t II: Prog Allergy 38; 108, 19Se. By p.rmillilon of
`Karger, Be8el,)
`
`a few natural ""1.!t!In;:n<'\I·ifl~
`and
`have been found to exert strong in vivo
`severnl derivatives do elicit !UUlf!'!t:iAIl,le
`Differences in the
`Il.nd
`these congeners mll.y be responsible: for this
`macokinetL~
`lack of correlation between ill vitro and in vivo activity.
`3. It is evident that the unusual MeBmt chain (~.arnino
`acid) is
`involved in tbe
`effects of the CS
`molecule but that it alone is not sufficient for lIrunullolup·
`
`of
`includes amino acids 1,2,3,
`the CS structure that
`9, 10, and 11; these ate clustered on the surface of the
`molecule.
`
`PHARMACOLOGIOAL PROFIL.ES Of
`IMMUNOSUPPRESS&VE CYCLOSPOAINS
`Pb:I!.nl:ta",:oIelJlcal studi~ on IlrIl.Clunl-a.C:tlv'itv
`started in the Sandoz Laboratories in the mid- t970s
`the following three major goats! (1) to search for derivatives
`with mucb hisher biological actMty than CS; (2) to detect
`c;yciosporins with a more selective spectrum of activity, for
`example, inhibition restricted to
`cells or
`sitic
`and
`to find so-called B01Ulevln"otctlQC
`lives that
`to CS.
`The results
`in this intensive and
`the structure of the
`effort are sOIl'u:what
`biologically active part of the molecule has been character(cid:173)
`ised successfully as just mentioned, hut despite extensive
`in
`relationship. it seems
`than CS itself will
`that CS derivatives more
`be discovered.
`CS has a
`On the second
`of
`activities;
`large spectrum of
`antibody- and cell- mediated responses, inhibition of chronic
`inflammatory reactions, fungicidal and antiparasitic activi(cid:173)
`ties, and reversal of multidrug resistance (Fig 2). The search
`for a
`derivative
`one of tbese effects
`and
`without the otbers has been rel~:mtl.essIY
`but SQ.rar
`is very limited.
`
`The first attempt was the preclinical development Qf
`(ThrI)dihydro-CS (DH-CS-C), walch was equipotent to CS
`"HI""''' ..... cell-mediated
`but in contrast to
`a
`<'>Il the II'm .. IUUllY
`resPOflSe,."'" Much bter it WIlS dis«lvered that
`when administered in certain
`COiJIlP<Ineltit wouLd
`!ruppr~s
`(IF
`unpublished data) ..
`The most interesting pharmacological profile is tha.t of
`vi"Ifn.C:S (DH-eS-D), which has been ""'''1'1#1'1'1
`derivative dQeS not inhibit humorallmlllUlllity
`
`a
`~ limiW to CS
`resloon:ses, as demonstrated in seVera! DTH
`of chronic infiammation and in the
`reactions, In
`localised GvH assay. (VaI1)dihydro-CS was selected for the
`treatment of autoimmune disease:!I because it proved remark(cid:173)
`ably active in acute experimental
`(EAE) in the tat and
`in the Rhesus rnn'''<'''''"~
`interesl arc tbe res.ults obtained in the new
`EAE in Lewis rats.W<Ii Wbereu both CS
`ebronic
`and
`are
`the analogue etfe:cti'lclv
`well as 5uppres.sfng ongoing
`prevented a relapse in therapeutically treated rats
`in comparison witb ...... ",u,,"",
`cessation of treatment,
`CS-treated rll!S suffered a marked ~acerbatiall of
`an discontinuation of treatment,21 PaJrad'\1xjicallly,
`little effect in !l'uf,l1re!lc'lj'l'l
`tive
`in rats.lt.29 This
`was also tes.ted ill ilt
`murre
`limited Ilumber of rheumatoid patients, but clinical
`could not be conclusively established,lo Of major interest Was
`the observation that this
`had no obvious
`toxic
`thus
`that
`may not
`and
`becal.l.3e of other side effects
`further clinical
`the best-known deriv-
`Third, the reduced
`ative (Nva2).CS (CS·G), as demonstrated on the basis of
`numerous animal experiments. raised hopes that this would.
`followup to CS.a:1Jl Its
`be lluccessful as the
`pil~unlaCOLO:(!:I(:al spectrum is
`identical to that of
`been «Inlirmed
`
`be linked, Hm"ew!/'.
`
`IMMUHotIUel!llEHIQN
`(HUMQAAJ. /\Nfl CIi!U.-
`MEDIA'l"m IMMUN'I't'I')
`
`Flg 2, Phaf1McOlogl.eal apecttum of c,dcsllofin A and
`"me derivatlYM.
`
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`

`
`812
`
`BORa
`
`Its l:mnnlnclSuppres,sive
`of
`in exl)erlm;~ntlll
`and heart in rats,)4 of
`and
`fUrther, been tested
`heart in primates.'s This compound
`sll~llfully in several autoimmune models such as Freund's
`adjuvant arthritis (HU Gubler.
`communication),
`EAE (Borel, unpublished
`experimental autoim-
`the fat and
`autoim·
`In aU these in vivo
`
`dog,
`to CS in the majority of Uwiie.!l
`monkey;"') compared with those reporting the opposite
`(rat,4$ dog,oIoi primate"). Toxir;ity studies have yielded even
`more confusing results, the
`reasons being. on the one
`the lack of standardised methods and the use of
`
`in
`Ol1stre.ted that the derivative more ll!;:lJl\~iU~U~I'{,;
`the rat,41 the dog,l',JI; and tbe
`other stlldies
`showed that both drugs are bot.b nephrotoxic and hepatotoxic
`in tats.'l.o,$O All these perplexing results illustrate the diffi·
`culties in finding parameters and
`to predict reliably
`the
`toxicity of a
`cvc:losoorin aruiIIDgui~. We bllve been
`years, to find an answer to
`is:
`further "'''Il,IUIl,~''''
`
`CVClOSPORINS WITH OTHER
`BIOLOGICAL ACTIVITIES
`CS has been reported to exhibit a rather narrow spectrum of
`antifungal activity that includes It few species among the
`
`yeasts and wine
`il'n1llel'lfecltL" Growth inhibition
`most cyciosporins, but does not correlate with immuna..
`suppressive activity (Table" in Wartburgl )). Two groups
`have published the anticoccidloidel activity of CS in "ivo as
`well as in "itro in experimental murine coccidioidomyco·
`Three antifungal CS derivatives that are etjtllp(>tertt
`but with negligible imlIllUnO!,Uppre'$$i1~e
`the doses Ulied in the above
`Fierer and Kirkland
`begirutJing, CS
`as T
`used in
`agent in order to find a solution to Ute
`involvement ofT celh or antibodies in several
`systems of
`infections,s4 Unexpectedly,
`it was discovered that
`had an intrinsic antiparasitic; effect
`in the rodent models of malaria,''''' leishmaniasis/"s, schis(cid:173)
`tosomiasis,1IO-64 filiariasis,6UT IItrongyloidiasis,61 and trichino-
`sis (A, Perrudet-Badoux,
`ootnmunication;
`There is some
`' al'! lIntitO;(l)(cid:173)
`but Ii ne~tatt've
`model
`tenderlC]i' was shown in a rat iruection
`doses CS had
`and wit.h
`ma,rginaJ effects in Giardia muris.n In contrast, clear
`eXl!I.eerbation was demonstrated wher!
`cruzf·
`infected mice were treated with
`Depending On the
`model and the parasite used. the compound has preventive
`and/or therapeutic actMty, which may be directed agllmst
`both immature and adult
`CS preferentially
`aft'ects female worms,
`and its
`effects often seem to be host-mediated rather tban dir~
`as can be demonstrated in vitro. It
`the
`not understood how the
`effects of CS are
`mediated7s
`It is difficult to ""vu ......
`its
`evidence
`nti:nar'Q.,itic drug. Since there
`sitic properties are not linked to its immunosuppressive
`activity, the search for CS derivatives with antiparasitic
`
`Table 1. Fun;lcldaland Parasitic Effects o.f OS and Some Derlvatlvee In eXperlmlilnill1 Models
`Species
`Expefimel!!al Model
`D4IIlVII:llves IActlve)
`EfOOl
`Positill8
`ptev/tl'lar
`piev I thar
`Pfev
`prev
`prBvlther
`prevllher
`prevlther
`prey
`
`HN~4
`Be>'49, C5-34. H7-94
`H7 -94,. C5-34
`&5·49
`B5·49, 05-34
`BS·4 iii , G7·53
`
`Cocddioidomycosia
`Meilida
`Cerabral mailiria
`Leisl'tmenllU!11s.
`Schlalosomiaaia
`Filariasis
`Strongyloidosis
`Trichinosis
`
`mouse
`mouse
`mouse
`mOlllls
`mouse
`mastomys
`rat (dog)
`mouse
`
`Toxoplasmosis
`Giardiosis
`
`Poollmoc:yatis
`leillhliWllas!s
`
`mOllse
`mouae
`
`fat
`moose
`m(lUSC8
`
`NOMJ
`pre'll
`prllv/ther
`
`Ex.l1:ceftlation
`proyoc
`toor
`
`way, T
`antimal
`dozen
`better
`d.erivat
`e,valual
`
`Sch(
`inhibit.
`d'l'tsw
`
`CSanl
`was pr
`treate<
`but die
`loms,
`
`resism
`somet
`mhed
`The
`schist<
`also b
`tive (
`uudie
`cx.bib
`aclea
`lIubth
`Rued.
`FiI
`CJides
`
`depel
`drug
`mar~
`or m
`uteri
`efrec
`tiled
`Tl
`be
`reve;
`
`cens
`cyto
`om!
`COUI
`mod
`non:
`moe
`imn
`utili
`t
`bas,
`
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`

`
`THE CVCLOSPORINS
`
`a13
`
`is under-
`nroner'llies but without
`way. The
`were screened for
`the Raile
`and the top
`antimalarial
`were further selected for signifi.carlUy
`dozen
`tban CS. Several
`these
`better
`deri .... atives were sent on request to outside laboratories to be
`evaluated. in their
`assays and some of the
`results have been tlut)iiStled.
`the in
`have
`SClleii)el, et
`of two CS deriva-
`ooflcentration for
`tives was at least three times lower than that of CS it:3elf. An
`was that a sbart cour:>e
`low dotes of
`and
`
`sur·
`of the
`Overaccumulation of hundred· fold or
`face P·glyooprotein (170
`which occurs in normal liver,
`colon,
`and adrenal
`and which func-
`tions as II,
`system for cytn!Il,Tic WlllPU'UH~IIJ,
`observed in
`cells. MDR
`increased rate of eftlux of anticancer
`the p.g1ycoproteins
`mollecllles out of cells.
`been found to act
`et
`''"''''''1-'''''''''' with
`the suggested ex.pbinations for this phenomenon are contra-
`and must await further
`evalua-
`for
`tion of the tberapeutic fIIrv .... 'nll'l ..... ,"""'"" ...
`
`were effective in enltlall)ClI!)g
`resistance to Leishmania
`infected mice but caused
`some exacerbation when administered to animals with estal>(cid:173)
`·llshed lesions.51
`
`murine
`has
`and later
`also been reproduced with the dihydro-CS (B5-49) de.riva-
`live
`Edensive
`studies
`showed tbat
`exhibited similar
`aclear
`
`of both CO(npclunl:is
`
`CONCLUSIONS
`
`series of two doze!!
`number
`biotransforrned
`aniliottues" Ii
`rnetablOlites, and many hundreds of semi- or
`relationship studies have
`is linked with a
`111\;11.1\;1'1::1 the MeBrnt chain. CS
`pnllrrrlaOOlOl~lau f'ilrl\n.~Ttii"'" and it
`
`tbe uu!~relmllig
`effects as well
`in
`the
`to act as a resistance
`some experimental tumours, Nepnrotolticity might also be
`coRsidered a separate
`the inhibi-
`to
`the
`potency
`whole im:munOI~UllPre:ssi'\I'e ~fll1'!"'li"nn
`have cotlsisteTiltIy
`Whether future
`
`!L
`
`Q(cid:173)
`nt
`in
`
`:0-
`ve
`lei
`
`z{·
`he
`
`an
`
`tic
`
`in cancer .. 111.111,,,,,""1
`interest. Recent
`potenttatl!ll!. the effect of some cvtost~IUC
`both in vitro and in vivo in both tumour and normal
`of
`n01Ne\rer. a clear
`
`their sellsitive
`resistance, or
`c()unterpatts!3~7 Hence CS may have a role as a'resistance
`modifier in MDR tumours. Since a number of
`or
`nOil\1l11mUl'I!l!lIUPPires:sive CS
`also act as resilltance
`the
`for
`imlrnu,nOSuPI)rel~ion and rC5istance
`appear to
`differ!6.37
`
`known about the me<::ha.nistic
`cellular
`levels.
`
`mU.lat(~G Iy'm"tb~::vtj~ release a "'<J",",un-
`etfect and wbich is
`aceta te·stimu(cid:173)
`"it
`of
`
`NOVARTIS EXHIBIT 2004
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`
`

`
`814
`
`BOREL
`
`the
`
`ACKNOWLEDGMENTS
`(or her kind and compelent aSliistanoe in
`1 wisb to thank M .8,
`IU1!,r~rilll.'! the ImlJI;lWil,;n~IL I am alsio indebted to II numbero(
`collllall,UelI both ror
`data
`lIS yet
`their colDtl'll<:tive disI:)lSSl.OTl5.
`
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