The macrofil chemotherapy project, 1996-1999

t-7 fts IJORLD HEALTH ORCA.I.I I ZATION ORGANISATION MONDIALE DE TA SANTE ONCHOCERCIASIS CONTROL PROGMI.{HE IN WEST AFRICA PROGRAI{HE DE LUTTE CONTRE L'ONCHOCERCOSE EN AFRIQUE D8 L'OUEST E(PERT ADVISORY COHXITTEE Stxceench sesglon Or.ragadougou. 5-9 June I995 ocP/E^cL6.6 ORIGINAL ENGLISH THE I{ACROFIL CHEI{OI}IERAPY PROJECT. 1996.99 I. BACKGROUND Ttre Independenc Con'-lsslon, reporti.ng ln I981 on che long tertr prospecrs for the Onchocerciasls Control Programe ln l.Iesc Afrlca (OCP) recoruended chat che Onchocerclasls ChenoCherapy ProJect (OCT) be seE up to develop a safe and effecttve nacrofllarlcidal drug, whlch would boch help OCP to brlng irs progrA'me co an end nichln the allocaEed 20 year cime period, and Eo naintain disease concrol thereafcer. OCT began operacions tn 1982, and pursued a uultldlsclpltnary drug dtscovery and development prograpme, iniEially wich che collaboracion of cuo uultinaclonal pharmaceutical companies (l.Iellcome and UpJohn). In Ehese early years of OCT, l{erck and Co iniciaced hu.man clinical crlals of Lvernectln (Hectlzanr) as a oicrofilaricidal drug for onchocerclasls, and in collaboraclon ulch OCT, successfully registered Hectlzan as a Crearnent for onchocerciasis in 1987. triEh a very safe drug avallable for control of morbldlcy, nainly in prevencing blindness and skin changes, the OGT agatn turned lts full resources Eowards developoent of a oacrofllariclde co kill che long-Iived adulc Onchocerca worns (oean Iifespan of a feuale noro is I0-12 years). A fully effecclve and safe rnacrofilaricide would replace Ehe need for elCher the 14 years of veccor concrol ess€ntial Eo reduce lnfectlons to a level where recrudescence is unlikely, or Ehe conElnuous.dlsCribution of lveruectln if this drug alone is used for onchocerciasls concrol. (ltrere ts norr some evtdence Ehac veccor conErol and lver:nectln used ln opctual conblnations vill. allow disease concrol in L2 years). The OCT has always been based in Geneva, and has operat,ed in the same way as TDR Steertng Connitcees, and scientific work has been under che day-co- day concrol of Dlrector, TDR, although funding for the projecc cn-e from che OCP budgec. Reporcing and revlew of the work of OCT was chrough the Experc Advlsory CounlCtee (EAC) and Joinc Prograrnrne Comrniccee (JPC) of OCP. OCT had always collaboraced closely wtch the Ftlariasis Steering CommitEee of TDR, whtch also had a drug developoent componenE for both onchocerciasis and lymphatlc fllartasts. A Jol.nt Precllnlcel Drug Developnenc Tean (PDDT) enabled Che yofk of the two prog,rames Co be coordinated, and !^ras successful enough for tt co be suggested thac alI r'rork on drug developmenc for onchocerclasls should be carrted out wlchtn one programme, Thus in l99l , OCT became che !{acrofLl Chemocherapv Projecc (}'IACROFIL) and che drug developrnetrt proJecCs of TDR-FIL were Cransferred Lo the ttr'w project, rogt-ther witlr sufftclenc TDR funds (approxlmacely US $1100,00t) ircr' nnnlmr\ Lo cottt itrut' rlrt'ir ,) supporc. MACROFIL has conrlnued as a Jotnt proJect slnce chac clme, wlch lcs or.rn Steerlng CommlCCee, and ls located wlChln Ehe Product Development Area of TDR. Since 1991, HACROFIL has Cherefore also been revle!,red annually by STAC of TDR, ln addltton to EAC of oCP. The OCp was planned co come co an end tn 1997, and ln anElclpaclon of chls a Hid-ceru (Phase IV) Prospecclve Evaluatlon of OCP was carrled out by EAC in June 1994, and 1Cs recommendatlons dlscussed by Che JPC of OCP ln Deceuber, 1994. HACROFIL, as a conPonenC of OCP, vras lncluded ln Chese revlews, and Ehe outcor1e uas as follows. (Extracts taken from Ehe ReporE of JPC, 15ch Sesslon, 29 Noverober-1 Decetrber, 1994)' ,5.42 professor Holyneux, Chalruan of EAC, noEed EhaE a macroftlarlctde aroenable Eo large-scaIe fleld-appllcacton trras noc 1lkely to become avallable slChln the nexE ferr yeare. In the neanllme Macrofll ehould concengragc on sEudles of Chc tuo cotrPounds mosE llkely to provlde a drug wlch proven nacrofllerlcldal effect rrhlch, even lf lE would need co b" gtven under oedlcal suptrvtslon, could Play a role ln such slcuacions as Ilolted recrudoacance control t{acrofll should also conEtnue tts scudy on Ehe potenttal nacrofllsrlcldal effecc of hlgh- dose tvermecttn Cr€aEDenc es Ehts provided Che best hope at present for a drug whlch k[l}ed adulC uorEa and whlch dld noE regutre expenslve develoPnent cosEs. 5.43 In rhts connectton the Chalrnan of EAC scressed that a fleld- appllcable uacrofllartclde was unllkely co uacertallze before Che end og OCp operaCions tn ttme Eo reduce Ehe duraclon of veclor control and chac hls ConnlcCee had Cherefore recounended the cessatlon of OCP fundtng of !{acroftl by Ehe end of 1997. Several delegatlons emphaslzed tn thls connectton Ehe luporcancs of contlnulng Ehe search for a fleld- appltcable nacrofLlarlclde beyond 1997' 5.44 Dr Hans Reume, speaking on behalf of Dtrector, TDR, and referrlng Eo che EAC recomnrendaElon thaC OCP ceas6 lts fundlng of Macrofll by che end of 1997, tnforoed the CouutCtee thac Dlrector, TDR, lntended to supporE contlnued search for a macroftlartctde to control onchocerclasts and lymphaclc ftlarlasls. Proposals would be made ln thac respecE co rhe TDR Governlng Body wlchln a 1996-1999 four-year plan. " ,9.15 Concern nas also expressed abouc Ehe recommendaElon thaE OCP c€eso funding of Hacrofll by Eha end of 1997 glven Ehat a fLeld' appltcable oacrofllartclde would be of caplcal lmporcance for onchocerclasis control outslde Ehe OCP area as well as for recrudegcence conErol. It uas explatncd that !f none of the tuo candldate compounds or htgh-doao tveruecttn fulfllled expeitatlons by end of 199? any drug found aftcr chaE date would become avalleble too lacc co have any tnpect on ocP reachtng tts obJ€cclve. 9.17 Houever, tha scarch for e uacrofllartclde for the control of onchoccrclarlt rnd lynphetlc ftlartaslr uould conttnue, ae explatncd prcvlouslY, ulch tDR fundt'nt.' l]. RESPONSE TO EAC AND JPC RECOH}'IENDAIIONS As requesced tn rhe Htnuces of JPC- I5, Dlrcccor TDR rcquesLcd HACR()l'I l. co prep;rre a (-year plan (BIennia 1996-9/ and 1998-99) which would covcr Lht: cransiclon pcrlod when OCP fundi.ng ended in I997, and TDR alone would nct:d Lo firrance the ProJecc. Ac ics Iasc meeclng (22-2t February, 1995) Ehe HACROf-lL Sreering, Cornnltree revieved che sclenElftc plans and budget requlremenrs of che Projecc up co Che year f999, and Chey are sullrDarized in this document. The Scienclfic and Technlcal Advisory Cornrn!ccee of TDR (STAC) reviewed che 6-year plan ar tcs 17ch Heettng held on 6-8 March, I995, and reporLed as sho',m belou (quocaCions caken frorq Che Draft Reporc of 27 Harch). - STAC consldered the developoenc of an lnexpensive and effeccive macrofllarlclde to be a useful tool for (1) use ln the OCP area afrer OCP itself has flnlshed should recrudescence occur, or 1n existlng problem area.s such as Slerra Leone, Arl area of Grana and east.ern Benln, (il) use in the African Prograooe for Onchocerclasls Control shere cheootherapy vlII be supported by olnloal vector control, and (111) deflnltlve trertment of the lymphatic fj.Iarlases. STAC recoonended the contlnued developmenr of a candidase oacrofllarlclde by fDR after OCP fundlng is slt.hdravn in I997. TDR gtll have co tdentlfy sourcea of nev funds to suPport thls sctlvity." In lcs revieu of 1994 acElvlctes by disease, STAC-17 commenced as fo I Iovs : four-year planning docunent, "The HACROFIL CheooCherapy ProJect, 1996-99-, uas clrculaCed Eo STAC neobers 8C che requesE of Dlrectors TDR and OCP, and urs revfeued by Che STAC sub-group covering che ProducE Reseerch and Developuenc are8.' .STAC considered thac an effecclve and affordable oacrofllarictdal drug would be of PoCenEiaIly treat imporcance in oalnCainlng concrol in Che OCP area afcer vecEor control efforcs are disconglnued and ln che expanded Afrlcan Programoe for Onchocerciasis Concrol ln vhlch lvermectln vlll be eoployed ulth oinloal veccor control. STAC also consldered thac the avallablllcy of a uacrofilarlclde, tn addltlon co lveroecrln, can be expecced to be a vlcal tool tn fucure efforcs to reduce trorbtdlcy tn lyophacic filarlasls.' ]. IJORKPI.ANS AND PRIORITIES OF HACROFIL Durlng Ghe period 1995-I997, I{ACROFIL wiII pursue che objectives ourlined by EAc of ocP, namely co brtng co fleld use, as quickly as Possible, che Chree drugs viCh poCenClal oacrofilaricldal activicy, arrd co srudv Ehe possibiliCy of r""lsCance Co lvernectln ln onchocerci'asIs. l.l tlhen che scandard dose of lveroecctn (150 p8,/k8,) tras given elctrer annually for 5 yeersr. 3 nonChly for uP to 2 L/2 yearsr, oonthl-y for up to I yeirr. 6 tr;ecments gtven ovory-2 veeks', 9.-6 tronthly for 2 years!,to onchoccrclasts petlenis, rnd edult uoros elcher exantned dtreccly', or by cotrpu3gr onalysls of parastCologlcal data', there rras etther nn ('\\:r.:,:, tn()l-(.tl rtv Itl .t(ltllL felnale w()flns o[ ,ll)pl()\iln:lLcIy .]07. ,or 'ltr apl).-rl'.r1t l'r.duct ion irr tlrc fccundicy of wortns o{ ,r similar ortl<:r of magt.tiLtrde'. As ic was also observed chac ctre rrurnber of male worms found r.rir6i11 rllc 6odule lrfls rcducedz. rhls 302 reductiotl in fecundi'cy mi6hr also be clrre to lack of ferCtllzatlon of females by absent or ilc.rp:rcitatc( rnale ',,rortns. (For dtscusslon sct: l)laisicr, A.l'. ct aI'). f'rom sCudles of Onchocerca gtbsonl ln catEle, iC ls known Ehat a verv lrigh dose of ivermeccin (5000 pglkg) only kills about 40I of che adtrlt f6maIe urorms of this specles, ahd Ehus compLete macrofllarlctdal acCiviCy from any accepEabLe lvernecEtn CreaEmenE ln man ls not anticipaced. However, any effecE on Ehe long-1lved adulC Onchocerca uorms reduces che tlme needed to brlng severe onchocerctasls down Eo IeveIs ',rhen lE ls no longer a Publlc healch problem. Herck and Co cherefore approved a safety study tn onchocerclasls patlencs ln whlch slngle dosec of lvermecttn uP to 8OO Pg/kg rreregiven. The onseE, evoluElon.and reeoluElon of the llazzoltL reacElon, and Ehe clratng of acute phase reacttons uere not altered by hlgh dosage. Ocular reacclons were mlntmal, and there were no prevtously unreporEed severe adverse effeccs. As slngle htgh doses of lvermect,ln were knoun co be safe, a further grouP of onchocerclasls patlenEs received cwo doses of 800 yE/kE wlth a 13-day tnterval. Agatn there were no addlclonal reacttons to treacment. Hacrofllarl.cldal effects of these hlgh doses of lvermeccln wlIl be measured ln ctro trays: a) In vicro assay of moclllty and btochemlcal acclvttles ln L,orms obcatned by noduleccomy at 6 months posE-creacment. b) HlstopsEhologlcal exanlnatlon of flxed and stalned nodule materlal In vlcro assays have been coapleted frou che slngle, hlgh dose srudles, buE deflnltlve results EusE awatt' etandard hlstopathologlcal studies. and flnal lncerpretattgl o.f the q+&1e results. As macroftlarlct'daI'actty(tY of tve'rnectln has always prevlously been seen in rnultlple -ddslng ectr'e'a.tfe",' fi. lg now proposid to Creec sIarger populitlon of onchSCeritasli t'utlents tn the communlty, comparlng a practlcal "spaced' craatmenE (4 treaEmentEiP€r year 8t 3 monChly lncervals), wtth . !_ ugre . concentraEed couras 'of treaEment employlng the same cotal 'd<isri' (4'.treatrnenEe glven every two weeks over 6 r,reeks). Nodules rrtll be removed 6 uonths afcer Ehe last treatxnent co examlne vtabtltty of adulc 't orns. ' '; . 'j.-i: 3.2 Clba Getgy have now terrulnated all rcork on Amocarztne (GGP 5140), and by fornal- feldf -igreendnE'tiave traiif6rred all documentrtlon relacing to the drug,-,and:aII- avallable supplled of bulk drug and cablt-cced nateilal Eb .qHb:-. hlf: flture devef6pment of Aroocarzlne slll rhe-refbre need coip'e. cgr5lcd o.ut .9y ctre uailbifr Proiect'. ' l'. r-.* All exteclng precltnlcal ,'rto "rrr,rcal dara r.rere recently revlewedac a IOCROFIL-sponsored neetlng, and lc was concluded chat cllnlcal trlals should be contlnued for both onchocerclasls and lynphatlc fllartasle. Clba-generated precltnlcal data lndlcaced that Anocarzlne could be safely glven to paElents at a level of 1Omg/kg/day. Pregnant feoalea should not be troated. However, exlsltng cllntcal daEa from over 2000 patlents nlth Anocarztne tn Afrtca and l-atln fuuerlca, showed that above a toEal dose of 20 ng/kg, reverslble cencral nervous system effects beco-e llultlng, and che opttmal dose schedule, developed in Ecuador, u8s 3r9/kt. b.t.d., for 3 days, l.e. a EoEal dose of l8mg/kg. The neetlng developed proEocols for future cltnlcal 'crlals ln onchocerclaslg (see Developnent Plan 2) and lymphactc fllarlasls (see Developoenc Plan 3). The Onchocerclasls Cheuotherapy Research Centre ln Hohoe, Ghana vtll carry ouc a Phasa II scudy ln onchocerclasle paElenta to exaol.ne Ehe safeEy and efficacy of the optlnun doslng schedule on a "forest' sEraln of O. volrnrlus. In order co separaEe the sdverse effeccs of che HazzotEl reactlon fron any tnErlnslc toxlclty of the drug, a eubgroup of patlents ulII be precreaced ulch che- gtandard dose of lvermecEln(I50 Fe,/tg) one ueek prlor to doslng nlth Aoocarzlne. 6 oonths Posc'treacnCntl nodules vlll be reooved frou Anocarzlne-treated patlenEa, and frorq a control troup Erested only vlth Ehe standard lvemect,lndose, snd rnacrofllarlcldal actlvlcy deEerroined by both ln vltro blocherolcal paraneEers, and by standard hletopathologlcal examlnatton. If reasonable efflcacy (70I ktll of adult worms) ls shown ln the t,rlal,(uhlch vlll be revlaued at lhe Sepcernber, 1995 meettng of I{ACR0FIL), chen further developnenc rr111 proceed by uay of a nultlcentre Phase III crlal durlng 1996-97. Key lssues vlch Anocarztne relace to lts efflcacy agalnsc Afrlcan stralns of onchocerclasts, and tts narrow Cherapeuttc tndex. If all lceros of safecy and efflcacy are resolved ln the nulEicentre cllnlcal CrlaIs then a reglstratlon dossler wlll be prepared durlng L991-98, for subuisslon, and hopefully approval durlng 1998. For lyuphattc fllartasis, where optlual doslng schedules are unknown, the recoronendatton (see Developnent Plan 3) uas co tnlclace a Phase I safeCy and pharnacoktneclc study ln Indta, Prlor to Phase II sEudles agalnst Brugtan and Bancrofctan fllarlasls tn the sane country. The Phase I study wl,ll begln as soon as Sovernmenc approval [s rece.l.ved, and hopefully a raport wlll be avallable by the end of 1995. Phase 11 studleg tn lnfected pactents nould chen begln ln lace 1995 or early 1996 (dependant upon Indlan toverruent approval). Hultl-c€ntre crlals vould then take place durlng 1997 and Ehe ftrsc half of 1998. If good cllntcal resulCs are avallable by the end of 1998, PreParetlon of che regletratlon dosster could begln, and a subrotaaton roade durlng 1999. Thus the carllesB approval of Anocarztne uae for lynphaClc ftlarLasts uould be Ehc cnd of 1999. - (Developtrent Plan 4.) i "Jr of rerearch, coopound, la an trrltanc shown Ehat, Thls drug, ihtch ca^nc -ftrou a TDR.Supporced ProgranEsts a derlvatlvi"oi qfuUgnd;pb1e rwhlctrl:'irnrlke ths' P;rlnt stgnlflcantly btilivltfaUfS''vta the o?al roucs, and 1s hot when glven by the parenc6r'al'toute:' RecenE assayr have !'e t, . ,, . drrr.L , , 6unlike other benzlmldazole carbamaEes, lc ls noE mutagenlc ln the Ames cesC. Houever there ls a chtral centre ln Ehe molecule, and UMF 078 exlsts as Clro enan!lomersr uhlch may have dlfferenC efflcacy or CoxtclCy proflles. All work to date has been done wlth a racemic mtxcure. AC Ehe presenc Clme lC ts preferable Eo develop a new drug as a slngle enantlomer and thus the Cwo enantlomers are currently betng produced by chlral colu,ran Cechnology to study Ehe tr blologlcal properCles. Uork durlng 1995 '.rt11 concenErace on precllnlcal coxlcologlcal sCudles such as the acute CoxtctCy ln raCs !o augmenc that already obCalned froo nice, and Che ouscle lrrlEancy sCudy to allow a ftnal declslon to be made on profarred rouges of admlnlsCraElon. Effl.cacy and doslng reglnens of tHF 078 were worked ouE ln the Br.rsla,/dog model, and thus durlng 1995, Ehe eff tclency agalnst Onchocerca ochene.l u111 be scudled ln che cattle model- If all studles have a successful ouccome, chronlc toxlclty studtes ln rac and dog wlll be lnltlaCed tn 1996, and plans made for a phase I srudy ln man. The earllest date for cllnlca1 trlals vould be lare 1995, conclnutng into 1997. Phase II studles ln lnfected patlents(onchocerclasls and lynphaclc fllarlasls) could then take place ln 1997 and Phase III tn 1998. Analysls of cllnlcal data and assembly of a reg,lscraclon dossler would Chen take place ln 1998 and 1999. gtvlng 2000 as the earllssE Posslble ttoe for approval. 3.4 The oosstbllltv of lvermecctn reslstance ln onchocerclasls As lveruacEtn ls the only drug currently used for conCrol of onchocerclasis, appearance .of reststance nould be a maJor problem both for OCP, and che recenEly creaced Pan Afrtcan Onchocerclasls Control Prograume, whlch ls based on.the use of lveroecEln. IvermecEln resistance has already occurred ln sevcral gastrolntesctnal parastClc nematodes ln the veEertnary fleld uhere ivernecCln has been ln nldespread ulto slnce 1981. Macrofll rras Cherefore asked by EAC of OCP, to study the mechanlsm by whlch nematodes becane reslstant to lvermecEtn, and lf posslble to develop a dtagnostlc uethod Uy uhtch reslstance genes could be ldentlfled ln Onchocerca before resfstanca had become a problem ln the fleld. Inlttal work has uttllzed reslscanE trutants of the free-1lvlng neuaEode Caenorhabdltls elegans, and the antnal paraslte of sheep Eaemonchus contortus. Several reslstance genes have now been cloned and sequenced froo these parasltes, and the nechanlsms pf mutatlon scudted. Addlttonally. supporc has been glven to the RoEterdau grouP vho havc developed Eha robust and prcdtcclve model of onchocerclasts 1n Ean - ONCHOSIU. Conputer stuulatlons ovsr a 50 year Etme span have been developed to nodel the eprcad of donlnant or roceasLve reststance tonos Chrough the uoru populrCton under varlous Progralruroe oftveruecctn dl.atrlbuclon. A HACROFIL-sponsored ueeElng on tvernecttn rcstscance ulII take place ln 1995, to determtno the most producctve way to contLnue these lnvostlgattons. DRUG DISCOVERY HACROFIL, as parc of che TDR Producc Developmenc Unlc, collaborates wlch the tr.ro mal or chemoEherapy programmes (CHEHAL and I -CHEH) via the 1n-house CHEHCORE group. The same scracegy ls folloved; i. e. poEenciatly IerhaI molecular cargecs are ldencifled, and Ehen the genes for chese are cloned and expressed, wich che obJectlve of generaElng a screenlng assay capable of htgh- throughput screening of molecules obcalned from collaborators. Recencly a centrallzed compound holdlng and shipping laboracory has been escabllshed 8E RCC, BasIe, and a cent,ral compuEer daca base of chemlcal andbiologlcal information has become operative. Thls wiil allow TDR to invescigaEe the currenE technologles of robocic drug screening, and chus che cescing of comblnacorlal chemlcal Itbrarles. Work Ln thls straceglc research area trusc no!, be funded by TDR as a Iong Eerm lnvestmenE in potenEial macrofllaricides. AddicionaIIy, compounds obtalned froo pharmaceutlcal companles and elsewhere are cesEed ln che varlous ln vlcro and ln vlvo models avatlable EoMacrofll: 0 . vo lvulus ll_lllSlg, B. lahanel and A. vlEeae ln gerbtls, B. pahangl ln dogs, and O. ochengi ln cat,Ele, Successful compounds go on to precllnlcal development lnvolving scale-up chemiscry, uetabollsn, coxtcology, assay developmenc, formulaclon eEc as approprlace, and laboracorles must, be ldentlfted able Eo carry ouc such workto lnEernatlonal sEandards. Four such lead compounds have been ldentlfted, and are under developnent. FINANCIAL SUPPORT FOR HACROFIL 1995.99 Prior co 1991, OCT/MACROFIL uas fully funded by OCP, and funds were earmarked for che full cosc of the proJect 1.e, salarles of personnel, cosc of meeclngs, duty cravel etc rrere all co be patd from the funds allocated, tn addiclon to che operaclonal cos!s of che research and developmenE of oacrofllaricidal drugs. In 1986, Jusc prlor to regiscraclon of lvermeccin for onchocerclasls, OCT coscs peaked co Just over US$ 3 mtIIion. In the lace1980's wlth struccural changes caklng place utthtn the proJect, annual cosEsfell co about US$ I.5 nllllon. In che 1990's JPC requested an acceleraglon of drug developrnent and che annual budgets u,ere Lifred Eo US$ 2,5 co $3uilllon. wtthln the Fourch ftnanctal phase of OCP budgers were planned copeak tn f99l-% and co fall sceadtly chereafEer to Ehe termtnaEion of OCT/OCPin 1997. Stnce 1991, TDR has contrlbuEed co the operarions budget ac a leveI of approxlmately US$ 400,000 per annu!. STAC-17 recomrnended rhac chts be increased co US$500,000 per annwr for che blennlurn 1996-97. Thus (see Tablet - !{ACROFIL PROJECT - FIrNDING 1995-99) che total budger of HACROFIL for 1995ils Jusr below UsS 3 mtllton, bur wtll fall co abouc US$ 2.3 mllllon by Lgg7,If TDR wtshes to conElnue Eo operato the ilacrofll Chemocherapy ProJect beyond 1997 at even that nlnlnal levsl Lt ul,ll need to meet the Eotal annual coscs of SZ.2-2.3 rallll.on. Thts allows for approxlnately g0.5 mllllon per annum for adulnlscratlve coscs, and gtves an operactonal budget of $1.7-1.8 mlllton il r..rl o'xerr rlourr .rs irtrlic.iLt'tl irr tlrt, l;udg,et t-.11)i(' l'joLc t lr;rL l'i)R funcl irrl; lo:- yiCROI lL <lulinii Llre 19q(r-97 bicrlrlium is set at USS569,0{t() [)er annum J'<> <]at-rr TDR has nor needed co supply ftrnds for clinical trials of new drug,s in l,r.rnplr.rtic fil.rri:rsis. trrrL tlris year Amocarzlne wlll ent-ct'into such clinical trial.s in lndia. Ic is hoped chac iniciaI cllnical trials in t995 may be funded ctrrough che Filariasis F'ield TrlaLs Task Force of AFR of TDR, buc -spec i f ic f trnds need co be earmarked f or t,his purpose ln the nexE biennium. Tlrrrs i t can be seen thaL che Hacrof lI Chemothcrapy ProJecL tras a prograrnne of rsork vich ldencified cllnlcal and Precllnical candldaces, whlch uill carry iE co 1999 and beyond. Ic is cherefore hoped thac as recommended by pnrcicipating and donor counErles at JPC-1.5, TDR can conElnue to support a programme of macrofl Iarlde development,, for both onchocerc las ts and l-ymphatlc filarlasls, wlclttn lcs overall chemocherapy prograrune. Re fe rences I. 2. 3. 4. 5. Plaisier, A.P. ec. al. In Press. J. Infect. Dis. Duke, B.O.L. ec. aI. Ar!. J. Trop. lled, Hyg,.46 189'194 Duke. B.O.L. ec. al. An. J. Trop. Med. Hyg. L7 657'664 Duke, B.O.L. eE. aI. Bull. W.H.O.69 163-168 (f991) Chavasse, D.C. et. aL Trop. Hed. Paraslcol. lf 256-262 ( 1992 ) ( 1ee0) ( r992 ) DeveloPment Plan 1A CRITICALPATHANALYSISFoRHIGHDoSEIVERHECTIN DEVEI'PXENT FOR ONCTIOCERCERCIASIS AND KEY DECISION POINTS: AS AT 24 FEBRUARY t995 CRITICAL PATH ACTIVITY Nodules removed for ossessmong APR 95. Report avallable JUL 95 JUN 95Phase 2 for safetY, !olerance, efflcacY To be gtven co OCP, MAR 95 FEB 95Proposal for follow uP s trudle s Asssssuonc of resulcs and communlcatlon to EAC, CTD' OCPt, Herck, Donatlon ConmtEcee O oac39 Eo EE NI : E:gE (J2 Ul H(a 4HUfr EIU otl .l.(, 2o I2H E{U frltdH H EI ut oa I troH tr Eco e ut ur eo N t Eooo6 ul ot odl o a Ea o E oo cr N aaaEc E oo oE oo Ec a o o ai Eo q o: :z DeveloPuent PIan 2A' ONCHOCEBCIASI8 AIID XEY CB.ITICAL PATE AIIALISIS rOB NOCARZINE DEVEI"oPT{ENT TOR DECISION POINTS: AS -AT 24 EEBRT'Af,I 1995 _ REilARX^SBECIN. let of END-Llrt dey ofCRITICAL PATB ACTIVITY a. FEB 95 [eecing Geneva 20/21 Feb 1995. Agreement to Droceed reached' Protocol flnal Lzed ilturrrutc of Precrintcal and .i-i"i".r daca ' Flnallzaslon .;';;;;;'ol for Phase 2 FEB 95 Safety and Eolerance knoun-end JUNE 95' ReoorE on shole itloy avallable DEC qq SEP 95 SEP 95 APR 95 Phase 2 fot safetY ' tolerance rnd efflcacy aE 3r,g/kg' bld' X 3 PP (Auadzl) SEP 95 Ac SEP SC oeerlng' If Jusctfied, aE SEP sC meeElng r+ Ar 5 p II-"f" of Arradzl Phase 2 "i.ir-""0 Eolerance daca' ."ii'",i".tY drafctng of Phase Ar FEB SC meeCing'if lusctftea, at' FEB SC neeclng +FEB 96 J -s L\re, *rrris of Phase 2 eff lcacY daEa, ;i;ilzaclon of Phase 3 ..^-^^^'l FEB 96 Because of 6 nonch follow uP for efficacY, PaEienE ' enrollmenE uould I h".r" Eo be conPlete I uv nen 97. RePorc onLi ot" study I avallab1e DEC 97 ' APR 96 SEP 97PrvLvv-- Phase 3 nulcicencre oPen .;;;; l,' P'cl"''ts ulch .rl"L....r (IvH) aining Eo ".,rt11 5oo'looo .a- FEB 98 ComPletc rr FEB SC -oor{n[ ll JN{ 98 ! AnalYs ts Dossler I ..^ . -..L, of Phase 3 daca assembly and edltlng ,{ cc{ofl HAR 97 APR 98 APR 98 Could be uP co 6 ,o.Eht--]"td + OCT 98I\lVl suv'"---- Earllest aPProval -dg44 + crlclcal declsion Polnc 3oc39 Clo NI -o .9Z= :Eo2 (,l H Ul( H U& frlU otrU zo & oh BI zH N n4U oEd ozo 3 6.,' '9QO€ ::i Ugo9;o,o c o 6 ! E .o)! a a! GI oaaf ! c 5 alE CI oaa o- a co ! C\ E ag, a .g a G' a aaf I o 't o ar o aa G' aaaf ! ot ot( CRITICAL PATH FOR LYI{PTIATIC ' DeveloPment Plan 3A' NIALYSIS FOR N{OCASZINE DEVEI'PI{ENT EIIARIASIS AND KEY DECISION POINTS: AS AT 24 FEBRUARY 1995 REI{ARI(SCRITICAL PATH ACTIVITY BEGIN.lst of END- lact day of FEBg5 l{eeclng Geneva 20/2L Feb 1995. Agreement to proceed reached. Protocot flnallzed for Phase 1 (. Assessroenc of Precllntcal and cllntcal data and ftnallzaclon of Prococol for Phase 1 FEB9 5 SEP9 5Phase I for safecY, toleranca JUL9 5 NOV95 fAssessment of Phase I'Deslgn of Phase 2 for safeEY' -^l^vonno rnd afflcacv Nov9 5 JAN96 MARg5 Efftcacy SEP 96Phase 2 MAY96 I{AY96 If Justlfl'ed + Analysls of Phase 2 safetY and colerance daca' PreIlmlnarY drafctng of Phase 3 scudy Analysis of Phase 2 efflcacY aata. Flnallzacion of Phase 3 ocTg6 ocT95 If Jusclfled + Y JAN97 JT'N98 Because of 6 monthfollow up for ef f lcacy, Pat,lenE enrollment nould have to be couPleEe by DEC 96, RePorc on who etudy avellable SEP 9E. Phase 3 roulclcentro oPen scudy alming to enroll 500' 1000 pattents ulth comParacor ( IvH) NOVg8 +Analysls of Phase 3 data ocTg8 JNI99Dossier assemblY and cdtctng DEC98 JN{99ltAA eubnlaslon JULg9 Could be uP to 6 nonthe leter +Earllesc aPProval f crtclcal declslon Potnt Devclopment Plan -rB. J. ort (oul oQ(rt ; ..!o.. .qo9;do ql H ut( H H4 FfH F. UH Fl $At}{}] Hotr ftlzH N &( UoE( O o5C3e EDoO= il E G: :EUZ= ,R 3 3 : : :3iN .6| ln ft,6 I E:6loi I t o ca D a\l t UI rO ! rno !: I : I a> -g 'B ri i- : li:r l. : iE ri i; iE i: iEf ra la i{ 3'i F > o lo Il ; 6 -a! $ 3:: i < -:laa>'t{iiao!<c .ia-[ar]<a >l Gl al -l "rl .lttrlBa ooo o o G' I l=lalalaIG - lrB lg G! c o C o o o; o 't o cr a c\a Eo o o g o osc Development Plan 4A. CRITICAL PATII ANALYSISI FOR I,JMNNI DSYEI,OPMENT A}'D KEY DECISTON POINTS AT 2,I FEBRUARY 1995 CN,JTICAL PATH ACTTVITY BEGIN. Irt ol END brt dry ol NEMAN,XS Amca cst rl RTC DEC 94 ,AN 9J Rcport FEB 95 Anelyrb of Amcr ttrt rclult. Dirusslon of m:mm:lun muugenicitY ctc rEB 9' r:EB 95 FEB 95 FEB 95 Apprrcntly clcrn. ASrccd lg rcquircd + Rrl tor rtudy (rt RTC. sith bid dor3c) APR 95 MAY 9' Nccds formuletcd drug Lnjectbn sia irriuncY (lt RTC) MAY 95 ,UN 9' Necds formulead drug. Allows prchminery dcc ision on orrl drug v irn Eflicecy of erundonrn: dccision on rrhich to go vilh tv{AR 9J ,UL 95 For discussion rt SEP SC PK rrulysis end dccirion on onl v irn MAR 95 APR,95 Flcckenstcin rcpon (- Dcsign, contncl out r.dblrbclhd rtudy MAY 95 AUG 95 Rcport OCT 95 Fineliz! crclc sody &sign rnd cerry il oul MAY 95 ocT 95 Rcport duc DEC 95 Design of protocol for 2t daY GLP chronr tor srudics in nt rnd dog NOV 95 DEC 95 28 dey GLP chronic tor sNdics in r.t rnd dog. Anrlysis of 2t deY tor srudy rcsuls ,AN 96 MAY 96 : + Dcsign of Phrsc l. hcPrrltion of dossrcr for CTX FEB 96 MAY 96 Submission of CTX MAY 96 CTX not wi0hcld ,UN 96 (. Phrsc I volunccr sMY for srfetY' rolcrrncc rnd PK SEP 96 FEB 97 Anelysis of Phrsc I result. DcriSn of protocol for Phrsc 2 MAR,97 MAR 97 C Phrsc 2 for refcry. tolcrrncc. cfficlcy end PK in prticns MAY 97 SEP 97 Anrlysis of Phrsc 2. DcsiSn of Phrse 3 ocT 97 ocT 97 a. Phesc 3 ,AN 9t DEC 9E Rcport MAR 99 Anelysis of Phrsc 3 APR 99 APR 99 C Dossicr rsscmblY ed cditing ,UL 98 ,UL 99 Dossier submissron AUG 99 Errliest rpprovll FEB M Coukl he up to 6 months latcr (:. lnl(. po oa G H'^ 0n N N NsN (a H ul4Hil 3Hh UH F{ fiAT >{ € qt H ut4HUil HUo EtU zo &oE @ Fo hTD o :!!I NI 1. .I3rET - qItJ' ;i- !r ${ E t :x o a at -J,,. .q: -...r {,tr..i.J.r:i::1... . : -- -:i.i.-idi.L:?--. a;'_l,it!. " E o6 t o e{ E a E 8 d E orN E fi E a E E ,\N sN g F6a t\N a F- E o ^lal r(, 6d E 3 EI E e 8 F. E g E E o6(a d E[E E c .E E T dtF E et = B(J EIF $E g Q E E 8 E g g 8 g I& ad,8p E E E R E 8 E 8 E p &oF o.I t\ a tI F\o r €d, EI g o E R E 8 E E E tn F a E 8 rh F\o o 6l r-\o- o t\ &ol- r 8 E E g Y16t CN !t 6 E rr1 FT E g E E B E g r! t g EI FIo\It- raFI6 86l FI & ot- 0.I tat e g E E @ EIt\ E o E g t R E g E oF I I 8lal oN al .iii (J :E o r, u c o a) A T .Ect,U a tr .9 €s;g or>EZ .2 so A)q, Io rt ts l5lF o\?ra o\o\ F( (9 zlita2 E " U rd1., oil 9r :fcE(AF. F\o-dZQ: <'! F =EFOz3 Fl inE; a5 EEa a .2 HtUI rdtt) fr1 * E)ao&0r oAI(, F{