Expert Advisory Committee: fifteenth session: Ouagadougou, 6-10 June 1994: progress report of the macrofil chemotherapy project for 1993-94

I{ORLD HEALTH ORCANIZATTON ORGANISATION MONDIALE DE I"A SANTE ONCHOCERCIASIS CONTROL PROGRAUUE IN I{EST AFRICA PROGRAITUE DE LUTTE CONTRE L',ONCHOCERCOSE EN AFRTQUE DE L'OUEST EXPERT ADVISORY COIO{ITTEE Flfteenth sesslon \ Ouas.adougou. 6-10 June 1994 ocPlEAC15.4 ORIGINAL: ENGLISH PROGRESS REPORT OF THE I{ACROFIL CHEUOTHERAPY PROJECT FOR 1993.94 1. COMPOUNDS IN CLINICAL TRIAL 1.1 Amocarzlne (CGP 5140) i On 27 January 1994, Ciba Geigy offlclally lnformed WHO that followlng an int,ernal exaninatlon of all drugs ln development, lt had decided not to conEinue with Amocarzlne for onchocerciasls. However, the company would be pleased to Eransfer all lnformatlon relating to this drug to WHO, to allow development by anoEher collaborator. It ls hoped to errange for transfer of lnformation on clinical trials resulcs in Latln America, methods for drug manufacture and analysls, etc Eo WHO in the neer future. Some 60 000 tablets of Amocarzine are currenEly available, buc are only valldated until June 1994, and Ehus reanalysls wlll be required if these cablets ere to be used for any clinlcal trials after Ehat daEe. Companies have been identifled ln India who are willlng Eo synEhesize Amocarzine for furEher cllnlcal trlals, and If efficacy were to be shown agalnst lymphatlc fllariasls as weII as onchocerclasis, then such companles would also consider manufacture and sale of the drug. Hopefully, AmocarzLne wllL be relntroduced to Africa for cllnlca1 crials, using the optlmlzed doses reported by Clba Geigy clintcians ln Lattn America sEudles, before the end of 1994. High-dose ivermectin studles Single, oral doses of lvermectln, up to 8OO 1tg/Kg, t"r" recently been used in OCRC Hohoe, Ghana on llghtly lnfected onchocerclasis patients. No severe or unususl adverse effects nere noted wlth any of these doses. Full cllnlcal data from Chle trlal wtll be dlscussed wlth l,tSD before proposlng multlple dosing wlth these higher drug levels. Any macrofllarlcldal actlon of these lvermecEln doses w111 be'ciamlned by nodulectomy six months post- treaEment. 1.2 wP/EACLS.4 Page 2 This successful safety study should allow hlgher doses of lvermectln to be used to glve posslble nacrofllarlcidal acElvlEy, or overcome any lvermectln resistance if Ehls were to appear aE any tlne ln the future. 2. COMPOUNDS IN PRECLINICAL DSVEI,oPI.TENT UMF 078 has now entered lnto che preclinical phase, and mutagcnlcity and acute toxicological studies are currently in progress. As the coupound exists as Erro enantiomers, Ehe efficacy and posslble Eoxicity of each of these cwo molecules needs to be examined, in addltion to Ehe racemic rnlxture used to the present tine. A labbratory ln the IJK has separated the two enantlomers using a chlral colurnn technique, tnd ls now scaling up chls nethod to produce the larger am\unts requlred (500 ng). Radiolabelled LIMF 078 is being prepared for metabolie studies and rhese will be initiated in June 1994. 3. COMPOI'NDS IN TERTIARY DEVELOPMENT Three compounds (IJR 251993, WR L29577, PD 10556) showing good accivlty against Onchocerca or Brugia in secondary screening have been synthesized in kilogram quantities, to allow Eesting againsE B. pahangi in dogs and O. e.ibsoni or O. ochengi in cattle. Preliminary pharmacokinetic studies of such compounds in calves are now rouEinely carried out before planning the fuI1 study in infected adult cattle. These studies should be completed in L994, and che potenEial of the three drugs for development as maerofilarlcides can be evaluated. 4. SCREENING OF POTENTIAL DRUGS Compounds for screening are being received in increasing quantiries, and there is now a backlog of compounds awaiting Eest. A two-year comparison of compounds entering both the O. eutturosa and O. volwulus in vicro assays, indicated that generally results were very sinilar using either species of adult worm. Thus, future screening will utilize mainly Ehe O. gutEurosa system (worms available from cattle) rather than the O. volvulus worms obtainable only from human patienEs. 5. POTENTIAL RESISTANCE TO IVERIECTIN Work has continued on Ehe developmenE of "molecular probes" able to identify individual worms which show resistance to ivermectin. Two "mode1" nematodes, resistanE to ivermectin are available, namely the ffee-living nemacode Caenorhabditis elegans, and Haemonchus contortus, the nematodeparasitic in Ehe gastroint.esEinal cract of sheep and other ruminants. CollaboraEors funded by MACROFIL have patented a simple technlque based on Ehe finding that nenatodes resistant to avermectins no longer take up a dyeinco their amphids (the sensory organs of nematodes). The appltcabiliry of this method to filariae will be srudied in coming months. It is already known Ehat there are several mechanisms by which a nemacode can become resisCant co ivermecEin. It is of interest thac ingenetic cerms the most common form of ivermectin resistance in C. qleeans is ocPlEAC15 .4 Pag,e 3 a double recessive mechanism, usually glving only a low level of resistance, whereas in Che parasltlc nematode Haemonchus contortus, the gene resPonsible for ivermectln reslstance is a single domlnant gene ' AIEhough the danger from a single dominant reslstance gene 1" gr""C"r, ivermectin resisEant strains of H. contortus isolat.ed from the fle1d have Eo date shown relaClvely low t""i"c""." levels (e.g. 7-fold lncrease in ECro doses)' As tt Is not known whLch nechanlsm(s) of resisEance may occur ingggbsslsg,ittsnecessaryEolnvestlgateallcommonformsofresistance i.d""tlff"d in che model nematodes, Eo develop potentlally useful Eechniques for the detection of lvermecEin reslstance if 1C occurs ln treaEed onchocerciasls paElents. Current work ls concenEraEing on Ehe cloning of ivernectln-resistance genes, and seeklng homologous gene sequences in Onchocerca. Aooendix: Lisc of research proJects currently funded by the MACROrIL proJect IoSP/EACL1.4 Page 4 RESEARCH PROJECTS CI'RRENTLY TUNDED BY UACROFIL A8 at 27 AgrLL 1994 Cloning of genes encoding hypodermal proteins from 08/LgL/255 Onchocerciasis Cheurotherapy Research Centre (OCRC) - Dr K. Awadzi., Hohoe Hospital Hohoe, Ghana Ucilisacion du modEIe A microfilaires dermlques 11. martini pour 1'6tude des pathologies oculaires et lymphatiques de 1'onchocercose hunaine eE pour les essais th6rapeutiques - Dr O. Bain, MNHR, Parls, France O. volwulus - Fr-r?-J.Gnett, Michigan State University, Michigan, USA Resynthesis of poEenEial antifilarial compounds - Dr P. Blumbergs, Ash Stevens Detroit, USA In vicro and in vivo drug tests of adult and larval O. volvulus and elect.ron rnicroscopic scudy of drug effects - Professor D.W. Brittner, Bernhard-Nocht InstituEe, Hamburg, Germany Bovine screen for O. gibsoni - Professor D.B. Copeman, James Cook University, Towrrsville, AusEralia BIind histopathological evaluation of Onchocerca nodules following drug therapy - Dr B.O.L. Duke, River Blindness Foundation, Lancaster, lJK 08/LgL/22e RP: 910558 us$143 434 o8o/tBL/L3 RP: TDR 910337 us$34 953 RP: OCP 93001 us$31 000 o8/L8L/245 RP: ocP 92005 us$254 380 08/L9L/224(c) RP: OCP 88005 us$100 000 08/L8L/22L(c) RP: OCP 89003 us$78 000 08/r8l/244 RP: OCP 92003 us$3 930 Curative treatment of chimps with onchocerciasis 08/l8L/25L - Dr M.L. Eberhard, Centers for Disease Control, RP: 93010 Arlanra, usA us$21 000 Development of drug assays for pouential O8/l8L/242 anrifilarial agenrs RP: ocP 89010 - Dr G. Edwards, Universiry of Us$24 743 Liverpool, Liverpool, UK Formulation of U!{F 078 and UHF 289 O8O/L8L/17 - Professor D.R. Flanagan, University RP: TDR 920791 of lowa, Iowa City, USA US$22 500 Phosphorvlcholine-glycan structures of O8/LBI/243 filarial parasites as a carget for chemocherapy RP: OCP 92001 - Dr W. Harnett, University of US$47 366 Strathctyde, Glasgow, UK Assay of circulacing anEigens from Onchocerca spp. to detect macrofllaricldal activlty - Dr tI. HarneEt, Universlty of Scrathclyde, Glasgow, lJK Performance of prellminary toxlcology of UtlF078 - Dr G. Haynes, Research Toxlcology Centre S.p.A., Rome, Italy Filarlal Trichinella chemotherapy screen - Prof E.R. James, Medical Universlty of South Carolina, Charleston, USA Ancicipating iverrnectin reslstance ln O. volvulus - Dr C.D. Johnson, NemaPharm, Inc., Cambridge, USA Hodelling ivermectin resistance ln O. volvulus - Dr C.D. Johnson, NemaPharm, Inc., Cambridge, USA - Dr A.P. Plaisier, Erasmus Unlverslty) Rotterdam, Netherlands ) lvermectin resisEance detection, and mode of action in H. concortus and C. elegans a model for O. volvulus - Dr L. Le Jambre, CSIRO Dlvlslon of Anlmal Health, Armldale, Australla Analysis of UI1F 078 and UMF 289 - Dr P. Lim, SRI Internaclonal t{enlo Pack, USA Training award: tlr A.S. t'lahmood, ICRC - Dr K. Awadzl, Onchocerclasls Chemotherapy Research CenEre, Hohoe Hosplcal, Hohoe, Ghana Screening potentlal fllarlcldes agalnst B. malayi - Dr J.W. Mak, InstltuEe for Medlcal . Research, Kuala Lr.rmpur, Malaysla Resolution of Ut[F078 enantlomers - Prof S.r Maclln, Universlty of Warwick, Warwick, UK Antifllarlal drug evaluat,lon ln dogs Professor J.W. McCal1, Unlverslty ' of Georgla, Athens, USA a.. Experlmental chemotherapy of filarlasis and screenlng of fllarlcldes .'Professor J.W. }tcCall, Unlverslcy of Georgia, Athens, USA ) ) ) ocPlEACl5.4 Page 5 08/Lgr/248 RP: OCP 92007 us$5 224 o8o/t9L/2L RP: TDR 931103 us$29 256 [502 from OCP] o8/t$L/256 RP: 93002 us$r5 000 o8o/L8L/2 RP: TDR 910625 us$84 000 o80/L8L/16 RP: TDR 920549 us$r.2 000 o8o/L8L/Le RP: TDR 920811 08/t$r/258 RP: OCP 93004 us$66 000 o8o/L8L/L8 RP: TDR 920790 us$19 000 t18/LlL/4/t4,.372 RP: OGPADR 910418 us$2 802 080/181/10 :r' rDR e1"0334 t o8o/L$L/22 RP: TDR 940085 us$10 750 08/L$L/23e RP: ocP 88013 us$144 078 o8o/L$t/8 RP: TDR 910332 us$88 298 ocP/EACL'.4 Page 5 Cysteine proteases of Brugia and Onchocerca as targets for chemoiherapy - Dr J.H. McKerrow, Anatsomlc Pathology Service, San Franclsco, USA Inhibitlon of Eransglucaninases ln fllariae - Professor K. Mehta, Universicy of Texas Houston, USA Pharmacokinecics of anEifilarlal drugs - Professor V. Navaratnam, Unlversiti Sains tlalaysia, Penang, Malaysia Suramin study on onchocerciasis - Prof P. Okonkwo, University of Nigeria, Enugu, Nigeria Chemical s)rnEhesis of carbon-14 labe1led uMF078 - Ms C.S. Parker, Research Triangle Inscitute, North Carolina, USA Tescing of poEential filaricides against W . kalimantani in leaf monkeys, with ancillary pharmacological and immunological studies - Professor B. Rukmono, University of Indonesia, Jakarta, Indonesia Dececcion of candidates for macrofilaricidal drugs using nuclear hormone receptors of C. elegans - Prof G.B. Ruvkun, Massachusetts General Hospital, Boston, USA Cloning and characterization of the ivermectin receptor b - Dr J. Schaeffer, Merck Research Laboratories, Rahway, USA Cuci.cular glutathione peroxidase in filariae - Dr M.E. Selkirk, Imperial College of Science, Technology and Medicine London, UK Synthesis of antifilarial compounds - Professor R.J. Sundberg, University of Virginia, Charlottesville, USA Experimental chemotherapy and screening of drugs against Onchocerca in vicro - Dr S. Townson, CABI Instituce of Parasicology, Sc A1bans, UK Discovery and developmenc of new antifilarial drugs ( in vivo) - Dr S. Townson, CABI Insticute of Parasitology, St Albans, UK 08/L$L/25L RP: OCP 91009 us970 554 o80/L$L/L5 R?: TDn 920607 us967 8rL o8/L&L/252 RP: ocP 92002 us$90 000 08/L&L/260 RP: OCT 93009 us$48 000 o8/L9t/26s RP: OCP 93014 us$53 338 o8o/L$L/9 RP: TDn 910333 08/L$L/257 RP: 93005 us$5s 716 08/L$L/264 RP: OCP 93013 us$43 000 o8o/L&L/L4 RP: TDR 920580 us$65 592 08/t$L/247 RP: OCP 92006 us$47 525 o8l181_/218 (B) RP: OCP 89001 us$136 882 o8l181/218 (D) RP: OCP 89012 us$138 193 O. ochengi infections in cactle as a cerciary screen for anti-onchocercal chemoEherapeutic studies - Dr A.J. Trees, LiverPool School of Tropical Medicine, LiverPool, UK - Dr R. Lucius, Inscicute for Parasitology, Hohenheim, Germany l.lacrofll lmmunology reference laboratory - Dr G. I{elI, The Jewish Hospltal of St Louis' Mlssouri, USA CharacterlzaEion of filari-al cyclooxygenase - Prof P.F. t{eller, Beth Israel Hospital, Boston, USA The role of lnflammaEory cytsoklnes ln adverse reactions to DEC Ereatmenc - Dr t{. Yazdanbakhsh, Universlty of Leiden, The Netherlands o(;t,/t,:AcI5 .4 Page 7 08 / L8r /2h9RP: OCP 91010 ussTl 000 08/L&r/263 RP: OcP 93012 us$92 8LI 08/Lgr/259 RP: OcP 93007 us$85 000 08/L&L/266 RP: OCT 93008 us$54 125