Report on the onchocerciasis chemotherapy project

Onchocerciasis Control Programme in the Volta River Basin arca Programme de Lutte contre I'Onchocercose dans la R6gion du Bassin de la Volta JOINT PROGRAMME COMMITTEE Office of the Chairman JOINT PROGRA},IME COMMITTEE Fifth session Ni 3-6 December 1984 Provisional Agenda item 7 JPC.CCP COMITE CONJOINT DU PROGRAMMEBureau du Pr6sident JPC5 .9 ORIGINAL : ENGLISH October 1984 1 REPORT ON THE ONCHOCERCIASIS CHEMOTHERAPY PROJECT Administration and Budget , The Steering Conunittee has met twice during the past year. The Secretary to the Steering ConnriEtee has been appointed and will take up his duties early in January 1985. In the meantime the funcEions of the Secretary continue to be carried out by the Chief, Filarial Infections unit, Parasitic Diseases Progranune. The secretarial post for Ehe Steering Cormnittee Secretary has been filled since February 1984. The OCT has now assumed responsibility for the Onchocerciasis Chemotherapy Research Centre at Tamale in Ghana. The budget approved for 1984 is $2.5 million. That proposed for 1985 is $3.45 mil1ion. 2. Scientific ress 2.L Clinical trials In view of the increasing number of clinical trials envisaged of new drugs for onchocerciasis, a E-am free to move from place Eo Place as required and consisting of an ophthalmologist and a clinician/epidemiologist has been established, based on the Center for Epidemiologic and Preventive Ophthalmology in BalEimore and on the Department of Medicine, Case Western Universit.y, Cleveland, Ohio. l JPC5.9 page 2 2.L.1 Ivermect in Cooperation between WHO and Merck. Sharp and Dohme The drug ivermectin (Merck, Sharp and Dohme) continues to show promise in the treatmenE of onchocerciasis and iEs further development towards registration is being pushed by the comPany. WHO/OCT is cooperating closely with Merck in clinical and other E.rials of ivermectin. A legal agreement is being drawn up between the two parties and this programme has been accorded top priority by the SEeering Conrnittee' Clinical trials in pro ress t- An open trial on 17 patients aE the onchocerciasis chemotherapy Research CenEre (ObnC) aE Tamale, Ghana has now reached the l2rnonth follow-up stage' Four double-blind trials to comPare the effects of ivermectin versus DEC versus placebo at Bamako, Dakar, Liberia and Tamale have reached the 6-nonth i;ii;;{;,-rt rti.t, p"i"i the codes were broken. The first and the last two ofEhesetrials.'...,ppo'tedbyoCT,theothersbyMerck.Thetrialsall followed the same protocol which was developed with-ocT inpuq. A.total of 67 patients in these crials have received a single dose of 12 mg ivermectin(i.L. in the range of 160-240 micrograms/kg)' From these trials it appears that in adult males ivermectin is well toleratedinitselfaEasingledoseof12mg;andatrhisdosageitisan effective microfilariciae ca[able of reducing skin concentrations as effectivelyasDEC'over1-2weeks,whileexcitingverylirtleorno|4azzotti reaction. rn the open study at ramaie counts of microfilariae in the skin have remained at ,"ry 1o, llve1s for L2 months afE.er Ereatment. These ;;;i.;;;-hrJ ,g.i.g-irri""rior," and came from well-conrrolled areas of the ocp. In che 4 0thIr studies counts at 6 months after treatment with ivermectin were 10wer than DEC in each insEance. These four trials were all done in areas where Eransmission continues' Ef fec E on skin microfilariae Ef fecEs on microfilariae in the Ef fec t s on adult t^rorms e Ivermectin has very little direct action on microfilariae in the cornea oranteriorchamberandcauseslessadverseeffectsontheposteriorSegment oftheeyethanDEC.Howevernumbersofmicrofilariaeinthecorneaand anterior chamber fa11 gradually over the weeks afEet EreaEment' possibly by a f.o"."" of emigration without replacemenE' Examination of nodules excised uP to 6 monf'hs after dosage with ivermectinindicatethatthedrugdoesnotkilltheadultwormsoraffect theirembryogenesis.tloweveritappearsthatintrauter:inemicrofilariaein wormsfromtreatedpatientsareunabletomaketheirusualactiveescapefron the vulva of the female and, after about 2 monEhs retenEion in utero' they begin ro degeneraEe. This proce", Ixrv acco,rnE f9T ih. aelayil;E[5fiuIaEion of skin microfilariae after ivermectin treatment, which compares favourably with DEC. JPC5 .9 page 3 Effects on Ehe transmission of O. volvulus by Simulium damnosum ocT-sponsored trials are currently being carried out in both the forest and savanna zones of West Africa to assess the effecEs of ivermectin on Ehe intake and developmenE of microfitariae of O. volvulus- by Simulium damnosum s.1. Preliminary resultsEffifhat the inEake of microfilariae by fee, ivermectin, the effe microfilariae thaE a development to infec ding flies is very greacly reduced after a single dose of ct being more marked than after DEC. However, those re ingesEed appear to be fuLly capable of completing their tive (L3) larvae in che fly. Effects on the earl develo nEal st s( and L ) in the verEebrate os c axls An OCT-supported invesEigation into the chemoprophylacEic action of ivermectin on the L3 and L4 stages of O. volvulus in chimpanzees has recenEly been sEarted in Liberia. This will take about 2 years to complete. FurEher investigations planned Plans are nor^, being made for Phase IIIIII trials of ivermecEin to sEart early in 1985 at 5 centres in Africa and one in America. These will involve both dose-finding studies and safety studies. Over 1000 subjects will be treated at single doses of 50-200 micrograms/kg, excluding for Ehe time being chiLdren under 12 years and women of child-bearing age. Groups infected wich the i'lest African foresE and savanna strains of O. volvulus wilI be investigated separately. In the savanna zone patienEs from ins the area under oCP conErol will be investigated. ide and outside PotenE.ial toxic effects Ivermectin does noE normally pass the blood-brain barrier but in veterinary rnedicine this passage has been recorded only in one breed of dog(the co1lie, which has a congenital weakness of the blood-brain barrier) resulEing in ascending and sometimes fatal paralysis. No similar accident has been seen it 26 million cows and horses which have been t.reated with ivermectin. Meningo-encephalitic conditions (such as might occur in sleeping sickness or in cerebrospinal meningitis) are Eo be investigated in monkey and dog modeLs for these two conditions to determine whether there is any possible danger of ivermectin crossing the blood-brain barrier in people so afflicted. Conc lusions ObeervaEions Eo date indicaEe that ivermecEin holds promise of being a useful 6top-gap drug for the control of onchocerciasis which could reach registraEion within 3 years. IE is an effecE.ive, non-toxic, single-dose microfilaricide, which does not produce a significarLt YlazzotEi reaction or damage the eye. As such, it has potenEial for use on a large scale as a long-acting microfilarial suppressanE, which might need Eo be given only once a year and which could serve to reduce microfilarial concentrations, (a) in the eye, thereby preventing the onset of eye lesions and blindness, and (b) in the skin, thereby reducing che reservoir available for transmission. I JPC5 .9 page 4 Limitations and cautions IE must be remembered that ivermectin is not a macrofilaricide and the search for a non-toxic drug with this action must stil1 be vigorously pursuedif ever a definitive treatment for onchocerciasis is to be found. Furthermore, only about 150 adult male patients have been treated with ivermectin to date. The possibility of toxic manifestations revealing themselves as larger numbers of patients (including women and children) are involved must be borne in mind. 2.1.2 Flubendazole Cooperation continues with Janssen Pharmaceutica for the development of a more acceptable formulation of flubendazole, a drug which has shown promising action againsE O. volvulus in a s ingle smalI trial in Mexico. The formulation used in this trial caused Eoo much local pain and inflanrnation at the injection site for ic to be furEher used in man. T\ro other formulations have since been tested in animals without success, but a third now under trial appears to cause less pain and inflanrnation. Its bioavailability and antifilarial activity are now being investigated. 2.L.3 Ciba-Ge und 6140 This compound, GCP 6140, which iras shown a macrofil-aricidal action against O. gibsoni in cattle, has now been put th rough its preclinical toxicology preparatory to a Phase I/IIA clinical trial being undertaken ar the OCRC, Tamale. The Ames' tesE and the V79 hamster lung ce11 muEagenicity test have been compleEed with satisfactory negative results. The preclinical dossier and protocols for the trial have been prepared and approved by Ehe Ghanaian Ethical Conrmittee, and a1l equipment needed for the Erial has reached Tamale. Capsules of Ehe drug have been sent to Ghana ready for a sEep-by-step trial up to a dose of 100 mg in uninfected and lightly :'.nfected volunteers, at which leveI pharmacokinetic studies wiII begin in man. Initiarion of this trial was held up for a number of monEhs awaiEing ethical approval of the WHO Secretariat CommitEee on Research Involving Hrrman Subjects. This approval has norv been given and the trial is due to sEart early in December, the first date that it can be included in the programme there. 2.L.4 oqlq _4:cc_9 Arsenicals It has been deL !;;.-4 l-.r stop furtnei 'n,ori< on nrelarninylthroarsenites, ,r series of m.rcrofilar-rcides prepared by Dr E.A.11. Friedheim, since there now appears to be no likelihood that new drugs in this series will be Eaken through to man for sleeping sickness treatment. In view of the risk of arsenical encephalopathy, it is not considered ethical to take these compounds initially to man for E.reatment of a non-fatal disease such as onchocerciasis. t JPC5.9 Page 5 Lodoxamide ProEocols have been developed for a trial of lodoxamide in the conErol of Ehe Mazzotti reaction to DEC; and a supply of the drug has been donated by the Upjohn Company. However, in view of Ehe recent promise shown by ivermectin, Ehe need to control reactions to DEC has become less pressing and, since lodoxamide has shown no act.ion in controlling the reacEion to DEC in the guinea-pig eye model (developed recently with OCT supporE), it has been decided for the time being not to block up our relarively limited clinical trial facilities with investigation of Ehis drug. 2.2 Basic Research on Filaricides Work conEinues at the large basic filaricide group set up in the Wellcome FoundaEion Research Laboratories in Che UK. A number of promising chemical lines are being followed in the search for new filaricides but so far no compound has emerged EhaE is sufficienEly promising to pass to the Eertiary cattle screen. Five proposals E,o form a second large basic group on filaricide research have been reviewed by the Steering Conrnit.tee. None was found inmrediately suitable, but a consortium of the Upjohn Company and I"lichigan State University has since been recommended for funding following a site visit and further negotiation. Action is being E,aken for a legal contract to be established in Eime to starE work on 1 January 1985. The Upjohn Company has a number of groups of novel compounds with anthelminthic activity and rhe Michigan University team has an onchocerciasis projecE in the Sudan. As a result of the guidelines laid down by an OCT-sponsored Working Group on Biochemistry of Filarial Parasites held in 1983 a considerable number ofprojects on verious aspect6 of filarial biochemistry and meEabolism (including one on chitin meEabolism) have been funded. These projects aim at finding metabolic pat,hways in the parasite which differ from those of man and which can thus be exploited for novel drug action. A supply of frozen nodules, both of Onchocerca volvulus and of O. gibsoni I 81so neccs$ary in support of the biochemical progranune. ContracEs have been enEered into with the onchocerciasis control authorities in Mexico and in Guatemala in an attempt to provide adequate quantit:.es of O. volvulus to the I biochernists. It ie hoped that the first nodules will 1984. Other potential sources of supply in Africa are come on 1 also bei late in exp lored ; 1ne n8 end arr 0. gibe 'angements have been made to ship regular and large oni from Australia to biochemical laboratories in quantities of Europe. The importance of in vitro culEure and maintenance of Onchocerca worms is also recognized as a baffiiE biochemical work. work on ffifficrtr subject is being supported, and a small working group meeting on the subject was held in september 1984. The report of this meeting will doubtless stimulaEc innovaEive approaches Eo E.he problem. I