Progress report of the onchocerciasis chemotherapy project: OCT/macrofil for 1991

Onchocerciasis Control Programme in West Africa Programme de Lutte contre I'Onchocercose en Afrique de I'Ouest JOINT PROGRAMME COMMITTEE Office of the Chairman JOINT PROGRAMME COMMITTEE Twelfth session Rivadh. l-4 December l99l COMITE CONJOINT DU PROGRAMME Bureau du President JPCr2.5 ORIGINAL: ENGLISH September l99l JPC - CCP t Provisional asenda item g PROGRESS REPORT OF THE ONCHOCERCTASIS CHEMOTHERAPY PROJECT(oCT/MACROFTL) FOR t99l 1. EXECUTIVE SUM},IARY 1'1 Progress in the development of macrofilaricides is surmnrized. The compoundclosest to use in the field is CGp 6140 (amocarzine, from Ciba_Geigy). The companyanticipates that sufficient preclinicar and crinicar information is now avaiLable onthe compound to a]low submission of materiar- to the swiss Regrulatory Authority in1992. ocT will reintrod.uce amocarzine to the ocp area of west Africa when theciba-Geigy report becomes avaiLabl-e and satisfies the wHo secretariat corrnitt,ee onResearch Involving Human Subjects. ccr 18041 from ciba-Geigy hEentered precrinical toxicology stud.ies within thecomPany, whire the Macrofil Project is continuing efficacy tri;ls in animal rnodersof firariasis, using the 10 kg batch of compound. synthesized by the company. Thedecision to continue develoPment is dependent upon an acceptable toxicorogicalreport, which will become available at the end of 1991. phase r clinicaL trialscould therefore begin earry in 1992 if there are no toxicologicar problems. Good intramuscular activity is shown against Bruqia pahanqi in dogs by uMF 07g,a comPound coming from a programme of synthetic chemistry in an academiclaboratory. WHo will patent the synthesis and activity of IJMF 07g and its salts andPursue preclinical development by means of contract research companies.collaboration with a pharmaceutical company will be sought as soon as possibre. rtis not possibre to predict a d,ate for first clinical trial-s at this time. l'2 As an interim measure crinicar studies, using combination therapy of ivermectinplus albendazole, with possible macrofilaricidal activity, continue in Ghanarandfurther high multiple-dose therapy with ivermectin is under discussion for bothlymphatic filariasis and onchocerciasis. 1'3 Routine drug screening of compound,s from antifilarial activity continues with compounds coming from collaborative agreements with other screening groups and thepharmaceutical industry. This activity continues to be monitored by the preclinicalDrug Devel-opment Team. t JPC12 .5 Page 2 1.4 A Scientific Group meeting was held in Geneva in May 1991 with the theme xTargets for development of drugs against filariae", to enable more rational selection of drugs from the pharmaceutical industry and el-sewhere for antifilarial testing by the Macrofil Project. 1.5 The scientific meeting noted above included discussion on the mode of action and possibility of nematode resistance to avermectins, including ivermectin. Progress in this research area, mainly using the model free-Living nematode Caenorhabditis eleqans, will be monitored and, if appropriate, further work could be funded by OCT in areas relevant to detection of ivermectin resistance in Onchocerca. 1.6 There is an urgent need to find an inununological technigue able to complement or replace routine histopathological examination of Onchocerca noduJes to determine damage or death of worms caused by chemotherapy. In lymphatic fiLariasis there is no direct way to study adult worrns in the lymphatic system and currently all eval-uation of macrofiLaricidal activity is of necessit.y indirect. Known antifilarial agents have been used against onchocerca in man and cattle, and longitudinal sera and urine samples coLlected. These wiLl be made available to the scientific conrnunity with the expectation that a suitabLe analytical method can be developed. 2. CURRENT STATUS OF MACROFILARICIDE DE\IELOPMENT A sununary of current plans for macrofilaricide development in the period 1991-93 is shown in Pig. 1. 2.1 Comoounds from Ciba-Geiqv 2.1.1 CGP 6140 (amocarzine). A further publication suunarizing the macrofi.Iaricidal efficacy and clinical acceptability of amocarzine has been published by Ciba-Geigy (PoLtera, A.A. et aI. (1991) Lancet, 13J-, 583-4). In 1989 over 300 onchocerciasis patients in Ecuador and GuatemaLa were treated with the drug 3 mglkg twice daily after food for three consecutive days. At nodulectomy four months after treatment 73t of the adult female worms were dead, 19t necrobiotic and only 8t alive. Control noduLectomies in Ecuador showed a mean of 18.5t dead worms in nodules from an untreated population. The authors' surrtnary of clinical resuLts is as f oll.ows: "The 3-day postprandial regimen of 1989 in 200 Guatemafan men produced microfilarial counts of 11t of day 0 value within 1 week,' counts were still at 23* of day 0 values on day 364. The clinical tol.erability was goodl with no central nervous system abnormalities observed. The main complaints were mild dizziness (5t on day 0, 45t day 3, 53t day 4, 13t day 6) and mild pruritus with or without rash. No positive Romberg sigms were observed. The ocul-ar tolerance was good and the microfilariae Load in the anterior chamber of 55 eyes was reduced by 69t within a year.' while this dosing schedule, coupled with the low therapeutic ratio of the drug, make it unacceptable for routine conununity therapy where there is minimaL medical supervision, there is a possible role for the drug in control of disease recrudescence in isolated foci within oCP. 'r JPC12 .5 page 3 All results from oCT-sponsored cl-inical trials with amocarzine in Ghana and MaLi have been provided to Ciba-Geigy for combination with the results of companytrials in Latin America. Although the final report is stil-I awaited, at the presenttime the company anticipates that sufficient information is already availabte to allow a registration submission to the Swiss Regulatory Authority, IKS(Intelkantonale Kontrolstel_Le fur Heil_mittel) for use of amocarzine against onchocerciasis. rn view of the adverse effects seen in cLinical t.riaLs in Ghanaduring early dose-ranging studies, the wHO Secretariat Comnittee for ResearchInvolving Human Subjects has confirmed the decision of the Macrofil Steering Corwrit,tee that further trial-s of the compound in west Africa should not be initiated until the clinical data from the Latin American trials are made avail-able to wHo for review. ocT will therefore encourage Ciba-Geigy to proceed to registration with amocarzine and will undertake further studies in the treatment of onchocerciasispatients in foci of recrudescence within the oCP area, inunediately fuIl cl-inicaLdata become available. 2-l-2 CGI 18041. Although related chemically to both the earlier compounds, CGP 6140 and CGP 20316, ccl 18041 is a more lipophilic compound tilith very differentpharmacological Properties to these latter compounds, and also does not give the same high levels of the potentially toxic isothiocyanate metabolite. The company is currently carrying out the preclinicaL development work whj.ch will a1low the compound to enter Phase r trials in man, and has synthesized 10 kg of compound to aLlow toxicologicaL testing and the planned cl.inical- trials. Reports ofpreclinical testing should be available by the second half of 1991. rf results arefavourable, the compound wil] then be tested first in uninfected voLunteers and thenin lightly-infected onchocerciasis or lymphatic filariasis patients in 1992.Further efficacy testing in secondary and tertiary screening modefs, including onchocerca qibsoni in cattLe, has been initiated using the pure CGf 1g041 nowavailable and these resuLts shoul-d be available by the time the preclinicaltoxicology is completed. AnaJ.]rt,ica1 methodology for assay of CGr 1g041 and itsmetabolites is being developed by ocr in fuLl collaboration with Ciba-Geigy. The important decision point comes when the reports on preclinical toxicity arecompleted. rf no toxicity has been reported at doses known to give good macrofilaricidal activity in animal model.s, then ctinical trials will be initiated.If there would be unreasonable risk to man based on the observed toxicity, then thedevelopment of CGI 18041 will cease. 2.1.3 'Back-up" compounds CGP 20309 and 21833. Two other compounds from thebenzothiazole and benzoxazole series have previously shown good activity againsto. qibsoni in cattle using a multiple-dose oral regimen. The company therefore undertook preliminary toxicological studies on these compounds and the full reportsprovided to OCT state it has to be concluded that CGP 20309 and CGp 21833 within the present evaluation in mice and/or rats displayed pronounced central nervous system effects. These became aPParent at oral doses above 30 mg/kg and 100 mg/kg, respectivel.y. with view to such findings and in the light of a proposed effective antifilariaL dose (50 mg/kg), the safety margin might be rather smaII. The company therefore considers that these two compound,s offer no advantage over the analogues currently under development, and they will not be deveLoped further. JPC12 .5 Page 4 Ciba-Geigy continues to carry out aJ.L development work on antifilarial compounds within the company at no cost to OCP, funding coming from an internalCiba-Geigy "Risk Fund". 2.2 UMF 078 and UMF 289 (Universitv of Michiqan, USA). In 1990 OCT reported on thepromising macrofilaricidal activity of UMF 0?8 when used intramuscularly againstBruqia oahanoi in dogs. This work has been confirmed and extended during the yea!.ALl of the adult rf,orms of B. pahanoi were kilLed when UMF o?g (in a peanut oil vehicle) was given by intramuscu.Lar injection at 50 mg/kg for three consecutive days. The soluble hydrochloride saft of IJMF 078 has been made (UMF 289) and this compound shows activity by oral administration, but greater amounts of drug are regr.rired. For 99.71 efficacy against E -pEh.e.0g.i in the dog a dose of 100 mg/kggiven twice a day for five consecutive days was required. These dosing schedutesfor UMF 078 and lrl'lF 289 were egually microfilaricidal- causing microfilarial numbersto decline by seven days post-treatment, with compLete clearance by day 14. It is hoped that dose confirmation and titration studies in the dog wiII be completedduring 1991. A development plan for UMF 078 has been prepared by oCT in collaboration r{iththe Product DeveloPment Unit of the Special Progranune for Research and. Training inTropical Diseases (TDR). wHo is proceeding with patents on the slmthesis and antifilarial activity of the compound, which searches have shown to be novel. Forintramuscular injection in man, detaifed formulation and toxicological_ stud,ies needto be carried out at an early stage, and the first of these will be irritation studies of the drug and chosen formulation vehicle in rabbit muscle. A mutagenicity study will also be initiat,ed in the near future. Once a patent is obtained, wHo will seek an industrial partner for collaborative devel.opment of the compound. 2.3 Combination theraov - ivermectin olus albendazole Following a preliminary clinical study in OCRC, Ghana in which increasing oraldoses of albendazoLe al-one were given to onchocerciasis patients, including effects of food on drug absorption, analysis of onchocercomata removed from patientsindicated that the Lowest dose regimen usedl i.e. 800 mg x 3 days, lras as efficient as higher doses (i.e. 800 mg x ? days or 1200 mg x 3 days) in terms of damage todeveloping embryos within the uterus of adult femare o. vo]vulus. No macrofiLaricidal. effect was seen at any dose but microfiLariaL nurnbers at 12 months Post-treatment (using 800 ng x 3) were only 35t of pretreatment levels. Therefore 800 mg Pel Patient was used in the final combination study in which the albendazole treatment was preceded by a single standard dose of ivermectin (150 pslks) given one week earli.er. The hospital studies are now completed and the resultb of nodule analysis are awaited to see if the drug combinationr €ach with differing modes of action, has any macrofilaricidal or sterilizing activity. 2.4 Hiqh-dose ivermectin Two recent rePorts have again raised the guestion whether certain dose regimens of ivermectin treatment might have some degree of macrofilaricidal activity. Duke, B.O.l. et af . (am. .r. Trop. Med. Hyg., L:L(6), 651 (1990)), noting that there ras a sigmificant increase in the nr:mbers of moribund and dead mal-e and female worms in post-treatment nodules, concluded that the standard dose of ivermectin (150- 200 yS/kS) given monthly for one year 'may have a slow action of attrition only on a certain group of worms which are potentially susceptible, perhaps because of increased age'. However nivermectin did not show a clear-cut, universal macrofilaricidal, effectr such as seen after adequate dosage with surarnin'. JPC12 .5 Page 5 In Haiti, patients suffering from Bancroftian filariasis grere given a higher than usual dose of ivermectin (400 pglkg) and to avoid a severe Mazzotti reaction a single low dose of ivermectin l2O fS/Xg) was given five days beforehand(Richards, F.o. et al. (1991) Am. J. Trop. Med. Hyg., !3.(t1,3). patients receiving this high and divided dose of ivermectin, when examined one year post-treatment, showed only 1.3t of the microfilarial load present before treatment. This compared weLl with a standard multiple-dose DEC treatment (6 mg/kg/day for 12 days) where mf counts were 0.5t of Pretreatment levels, and the authors speculate that'complete clearance fox L2 months may be interpreted as evidence of death or steriLization of adult worms". It has now been proposed that for lyrnphatic fil.ariasis this divided and high dose of ivermectin should be extended such that five additional 400 pS/kS doses begiven at monthl-y intervals to patients with Bancroftian filariasis. ' In view of these results OCT reguested Professor D.B. Copeman to test high and repeated doses of ivermectin against Q.-g.ib.tgEi in cattle. Such trials have been completed, cattle slaughtered and the macrofiLaricidaL effects wilL be evaluated by histopathology. If macrofilaricidal effects occur with Q.-g.ibgg[i it will encourage further tria].s of high-dose (and repeated dose?) ivermectin studies in man. 3. DRUG SCREENING ACTTVITIES Primary in vivo screening of novel compounds is carried out in three Macrofil- sponsored l-aboratories using three filariaL species - B. malavi, E -Beb.a.Dg,i and Acanthoeheil.onema viteae - in gerbils. If only smal} guantities of drug are avairabl-e, material is sent directly for i.uilIg screening against adurt o- qutturosa (obtained from cattle) . Secondary testing of active compounds is carried out against B. oahanoi in the dog and Monanema martini in the rodent Lemniscomvs striatus. Tertiary screening utilizes o. qibsoni/o. qutturosa in cattfe and B- malavi or Wuchereria kaLimantani in the leaf monkey. The rol.e of the primate models of lYmphatic filariasis is currently under review by the project. New corrPounds have been obtained from the walter Reed Army Institute ofResearch, the National Cancer rnstitute and from the industrial companies Ciba-Geigy and Parke-Davis. Following the activity of a series of parke-Davis compound,s against o. outturosa and O. volvulus a legal agreement has been signed between the comPany (warner-Lambert/Parke-Davis) and WHO to a]Low further screening ofParke-Davis compounds, and resynthesis of active compounds has been undertaken byMacrofil. Progress of active compound,s is monitored by the precLinical Drug Development Team and reconunendations made to the Steering Conunittee on how toproceed with their development. 4. ST]MI.I.ARY: PROSPECTS FOR A USABLE MACROFILARICIDE IN THE FUTURE Ciba-Geigy is reviewing preclinical and clinical data on ccp 6140 (amocarzine) and anticipates that available information will be adequate for a submission to theSwiss Regulatory Authority in 1992. This is encouraged by oCT as registration woul.d al.Low more widespread trials of the drug in onchocerciasis and would also make it easier to initiate trials against llmphatic filariasis. N.-8. The compound has alsobeen shorn to have antischistosome activity (Poltera, A.A. et al. Activity of thiocarbamazine in patients duarry infected with schistosoma and glg.hgggrca' voIvulus, The Lancetr p. 726t 1 April 1989). As amocarzine seems unsuitable for widescale treatment in a rural environment it will be used mainly by oCp in foci of recrudesc€DC€2 and the search for a safer, more efficient and easily administered macrofiLaricide will continue. e. .rPc12 .5 page 6 It is hoped that Ciba-Geigy compound CGI 18041 may prove to be such a drug but first clinical trial-s against infected patients will only begin in 1992. If successfuL this would aflow the drug to become more widely available towards the end of the fourth Financial. Phase of OCP. Although UMF 0?8 shows some promise in secondary screening at present, a single oral or parenteral dose has not. been shown to give complete macrofilaricidal activity, and preclinical formulation work for an intramuscular injection may prove complex. It is therefore impossible to forecast the time of first clinical trial-s of this compound, or any others behind it in the deveLopment progranune. 5. TARGET IDENTIFICATTON. SCIENTIFIC GROUP MEETING As discussed in the previous OCT report to JPC, to alfow Macrofil to approach the pharmaceutical industry for test compounds, it is necessary to have as much specific knowledge as possible about the chemotherapeutic targets in the target parasite, or in nematode worns related to it. In llay 1991 a Scientific Group meeting was held in Geneva, funded jointly by OCP and TDR, with the theme 'Targets for develoDment of drugs against filariaL rrormst. Following the technical presentations it was clear that insufficient information was available for filariae, or even nematodes in general, to a1low any listed target to be excLuded from consideration, or alternatively to be allocated priority funding for accelerated development of inhibitors. While more basic research is essential to be more conclusive about efficacy and selectivity of inhibitors of the chosen targets, it was cfear that suitable assays exist for many of the targets, and lead compounds of known rnode of action are avail.able from industry and elsewhere. The meeting, with a wide spectrum of academic and industrial participants, both from tropical medicine and other disciplines, confirmed that the current approach of the Macrofil Project is generally the correct one, i.e.: (a) to maintain awareness of what is going on in rel-ated scientific areas, particularly with nematodes of veterinary importance, and the model nematode @; (b) to bring potential therapeutic targets in fifariae to the notice of the pharmaceutical industry and request compounds for testing; and (c) if a specific scientific advance makes any one target area a more likely site of drug action in filariae, specific work can then be funded in that area. The l,lacrofil Chemotherapy Project wilL therefore continue its antifilarial screening progranme, utifizing specific inhibitors where possible, and where appropriate, stimulate research on target characterization in filariae to affow more specific development of inhibitors and potential macrofil-aricides. Having defined the target areas it is now necessary to seek out suitable eompounds for testing, and to stimul.ate interest in the scientific cornrnunity in these targets. ra 66 .rPc12 .5 page 7 RESEARCH AREAS REQUIRING DEVELOPMENT 1 Inrnunoloaical techniques of nonitorinq death or damaqe of adul-t filarial woms Alternative methods are needed to compLement or replace the time-consuming histoPathological technigues currently used to evaLuate chemotherapeutic effects ofpotential drugs against adult fiLariae in man and experimental animals. To allow development of such techniques the Macrofil Project has sponsored two laboratories to treat patients and cattle, infected with onchocerciasis, with known macrofilaricidal agents, and to transfer serial bl.ood and urine samples to the TDR/ Filariasis serum bank in Basle, Switzerland. The availability of these longitudinally-collected samples will be advertised internationally and made available to workers who have suitable antigen or antibody assay techniques available, Potentially capable of detecting drug damage to fiLariaL rrorms. Suramin has been used in both man and cattle, and additionally in cattle the arsenical MeI Cy and ivermectin have been used as standard drugs, with known anti-glg.hgggEge activity. 6.2 Technioues for detection of ivermectin resistance in Onchocerca Recent work with the free-living nematode C. eleoans has generated information on the possible mechanism of action of the avermect,ins on parasitic nematodes, and on the Potential- ability of nematodes to become resistant to ivermectin or other avermectins. It has been possible to clone and express the ivermectin receptor from c. eleqans in amphibian oocytes and to demonstrate that ivermectin may interact with a gLut,amate-controLled chloride channel in the membrane. Between 30 and 70 genes are abfe to mutate and give rise to different 1evels of avermectin resistance in C. eleoans. Genera}ly, the level of resistance is low(5-20x) but an occasional mutation can bring together two recessive genes to give ahigh leve1 of resistance (100x), but occurring at very low frequency. The objective of these studies is to characterize the gene mutations which create avennectin resistance and hopefully provide diagnostic tests of resistance at a molecul-arI'eveL. This work wilL be closel-y monitored by the Macrofil project and funding maybe given to any work which rnay be relevant to onchocerciasis. ADMTNISTRATION AND FINAI{CE 1 . ADMINISTRATION OF THE T.IACROFIL CHEMOTHERAPY PROJECT Since EAc.10 of oCP reconunended in 1989 that oCT be more closeLy integratedinto the structure of TDR, the concept of a jointly funded and administ,ered project to deveLop macrofilaricides for onchocerciasis and llmphatic filariasis has beendiscussed and approved by the governing conurdttees of both OCp and TDR. The report of the Standing Comnittee of TDR to the recent meeting of the Joint Coordinating Board (JCB), held in June 1991, recotnmended that JCB.1{ endorse the administrative and financiar arrangements made for the Macrofil chemotherapy project, and this was done. 8. BUDGET OF OCT FOR THE FOURTH FTNNICIA! PHASE Eollowing discussions over the past year by EAC and CSA of OCp, the plan of OPerations for OCP in the fourth FinanciaL Phase reconrmends that a total budget of USS14 million be allocated to oCT as oCP's contribution to the running of the llacrofil Project. ft has been suggested that the peak expenditure should occur in 1994, when new drugs such as IrMF 078 and CGf 18041 should be at the preclinicaL and expanded clinical stages (Phases II and III). ffg.2 gbolrs graphically the past and I JPC12 .5 Page I anticiPated annual exPenditure of OCT on drug discovery and deveLopment. These annual estimates represent the minimum funding reguired if current compounds continue in deve.lopmentl and some year-to-year flexibility in funding is necessary due to the uncertain nature of drug development. fn Fig. 2 tbe hatcned areas of the histograms for 1991-93 represent the financial contribution from TDR to the Macrofil Project. For 1991 TDR has made a contribution of USS430 000 and will provide a further USS900 000 for the 1992-93 biennium. This has been provisionally allocated as $400 000 in 1992 and $500 000 in 1993. These contributions will help to maintain the momentum of increasing l'lacrofiI activities, as shown in the figure. It should be noted by JPC that many of TDR's research objectives are now directed to OCP operational reguirements, and this represents a non-cash contribution to OCP activities, e.g. inununodiagnosis of early (re)infections, DNA probes to identify strains of O.-yg.lgg.Ilig in blackflies and man, optimal methods of ivermectin distribution and inununological assays of chemotherapeutic efficiency. T .1 Fig.], DEVELOPMENT OF Na. 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