Briefing Paper: The Importance of New Drug Discovery to Control


Lymphatic Filariasis (Elephantiasis) and Onchocerciasis (River Blindness)

"We need … above all, to find a macrofilaricide suitable for large-scale field use. If resumption of the research effort is not financed now, it may be too late to remedy a future ivermectin-resistance situation." Brian Duke, Emeritus Medical Director, River Blindness Program, A plea to continue the search for an Onchocerca volvulus macrofilaricide, 2002.

Summary
Lymphatic filariasis and river blindness, two diseases caused by filarial nematode worms, are the most important human tropical diseases after malaria. Nearly 140 million cases exist and over 1 billion people are at risk for infection. Despite admirable global efforts underway to control these devastating diseases, eradication will be extremely challenging with current technology. No vaccines are available, vector control programs have ended or are facing insect resistance, and drugs are largely ineffective against the worm's adult stage. Current drugs can effectively eliminate the worm's larval stages, but their broad use also increases the likelihood of accelerated drug resistance. To build on the current treatment regimen successes and to ensure that the path towards reduction and elimination of these diseases continues, new classes of chemistry with novel modes of action are urgently needed. The most critical of these are new macrofilaricides (drugs which kill or permanently sterilize the adult nematodes). Such drugs could:

• accelerate programs to eradicate lymphatic filariasis
• make elimination of onchocerciasis possible
• increase patient benefit and compliance
• decrease the likelihood of drug resistance and program failure.

Lymphatic Filariasis (Elephantiasis)


What is it? - A parasitic disease caused by the microscopic filarial nematode worms Wuchereria bancrofti and Brugia malayi that colonize the human lymphatic system. Worms have a life span of up to 8 years and release millions of microfilariae into the blood.

What are the symptoms? - Symptoms include blockage of lymph ducts by adult worms leading to dramatic swelling of appendages (lymphedema, elephantiasis), or genitals (hydrocele). Once elephantiasis has occurred, it is extremely difficult to reverse and secondary infections are common. Kidney and lung damage can also occur. Disease causes disability, loss of work and marriage opportunity, and social stigmatization.

How is it spread? - Nematodes are transmitted between humans by blood-feeding mosquitoes of the genera Anopheles, Aedes, Culex and others.

What is the magnitude of the problem? - 120 million people are infected in 80 tropical and subtropical countries, according to World Health Organization (WHO) estimates, with the largest numbers in India, Nigeria, Bangladesh, and Indonesia. 15 million people have clinically significant lymphedema or elephantiasis and 25 million men have genital hydrocele. Morbidity is estimated at 5.5M disability adjusted life-years (DALYs), the highest of all tropical diseases after malaria. Lymphatic filariasis is the world's second leading cause of long-term disability. In most endemic regions, efforts to control the disease have yet to make an impact on incidence and increases have been seen in conjunction with urbanization and population growth. Also, due to altered immune cell characteristics, infection with filarial worms could enhance the replicative capacity of HIV.

What are current treatment options? - Drug treatments attempt to reduce the incidence of circulating microfilariae in the human population, thereby disrupting disease transmission. Options include annual doses of albendazole (400 mg) plus diethylcarbamazine (DEC) (6 mg/kg), albendazole plus ivermectin (200 µg/kg), or use of DEC fortified salt. These treatments are fairly ineffective at killing adult worms and provide only partial benefit to infected patients. Efforts to alleviate suffering and disability for infected patients focus on hygiene aimed at decreasing secondary bacterial and fungal infection. There are no vaccines or potent macrofilaricidal drugs.

What are the current global strategies for combating the disease? - Since 1998, albendazole has been donated for world-wide lymphatic filariasis control by GlaxoSmithKline (formerly SmithKline Beecham). Merck donates ivermectin in areas where filariasis is coincident with onchocerciasis (see below) since DEC cannot be used in these areas due to side-effects. In 2000, control efforts were formalized as the Global Alliance to Eliminate Lymphatic Filariasis, a coalition including WHO, endemic country control programs, drug companies, academics, and non-profits with the goal of eliminating the disease by 2020. The alliance is funded by a $20 million grant from the Bill and Melinda Gates Foundation among other sources. Control efforts work to interrupt disease transmission through annual drug treatments of entire at risk populations with the goal of ensuring low levels of microfilariae in the blood of most individuals. These efforts are rapidly scaling up with 54 million people in 32 countries treated in 2002, an increase from just 3 million in 2000. Since available drugs do not kill adult worms, repeated annual treatments for up to 8 years will be required to prevent the reemergence of microfilariae in an infected population.

Onchocerciasis (River Blindness)


What is it? - A parasitic disease caused by the microscopic filarial nematode worm Onchocerca volvulus. Adult worms live up to 14 years in nodules under the skin and release millions of microfilariae.

What are the symptoms? - Circulating microfilariae cause persistent, debilitating itching, severe dermatitis, and ocular lesions resulting in blindness. Adult worms form skin nodules.

How is it spread? - Nematodes are transmitted by Simulium blackflies that breed along rivers. Fear of the disease has led to abandonment of fertile riverside farm land.

What is the magnitude of the problem? - 17.7 million people are infected in 37 tropical countries of Africa and Latin America, according to WHO estimates. 500,000 individuals are visually impaired and an additional 270,000 are blind, making onchocerciasis the second leading cause of infectious blindness worldwide after trachoma. Morbidity is estimated at 951,000 DALYs.

What are current treatment options? - Ivermectin (1 dose at 150 µg/kg) is used to treat infected individuals, curing skin itching and preventing further damage to the eyes and skin. Annual treatments of entire populations can reduce circulating microfilariae thereby disrupting disease transmission. These treatments do not kill adult worms. There are no vaccines or macrofilaricidal drugs available.

What are the current global strategies for combating the disease? - Since 1987, Merck has provided annual doses of ivermectin in Africa and Latin America as part of the Mectizan Donation Program, the largest medicine donation program in history. Other partners include WHO, endemic countries, and the Carter Center. Ongoing annual treatments are required as the drug does not kill the adult worm. From 1974 - 2002, WHO and the World Bank also worked to control onchocerciasis in West Africa by aerial spraying of insecticides to kill blackfly larvae. While this effort succeeded in opening 25 million hectares of arable river valley farmland to settlement and cultivation, closure of the program places the entire burden of disease control on ivermectin treatment. A 2002 conference considered whether the aim of onchocerciasis programs could be changed from control to elimination. The conference concluded that onchocerciasis cannot be eliminated from Africa with current technology, but may be eradicable in the Americas and Yemen.

Weaknesses of Current Control Strategies

• Global elimination of a disease, as is being attempted for lymphatic filariasis, is an extremely ambitious and long-term undertaking. Only one human disease (smallpox) has ever been eradicated, and in that case a vaccine was available. Historically, during the 1960's and 1970's a global program to eradicate malaria with drugs and vector control was a failure with incidence of the disease and drug resistance rising dramatically.
• The lack of current drug efficacy against adult filarial nematodes necessitates multi-year treatment regimens to maintain disruption of the nematode lifecycle in infected individuals. Long-term preventive treatments and multi-year disease treatments are vulnerable to failure due to supply-chain disruptions (wars, political turmoil, natural disasters, emigration) and variable patient compliance.
• Discontinuation of vector control efforts, due to insecticide resistance and environmental concerns, places increased pressure on drug treatment as the one point of worm lifecycle disruption.
• Broad spectrum chronic use of a limited number of drugs increases the likelihood of resistance development. This is especially a concern for onchocerciasis where only one drug is in use, non-responders to treatment have been observed, and widespread resistance monitoring is not yet in place. In veterinary applications, resistance to albendazole and ivermectin is widespread for some worm species. The spread of drug resistant filarial worms would put programs to control river blindness and eliminate lymphatic filariasis in great jeopardy.

The current drugs of choice, donated by Merck and GlaxoSmithKline, were developed for profitable indications in veterinary medicine. Since most clinical cases of human nematode diseases occur in developing countries, there is no pharmaceutical industry research infrastructure to discover new compounds for human nematode infections.

The Need for a Macrofilaricide

Development of new classes of anti-nematode chemistry effective in killing or permanently sterilizing adult filarial worms (i.e. macrofilaricides) is considered a top research priority by WHO's Program for Research and Training in Tropical Disease and the Programme to Eliminate Lymphatic Filariasis. Such compounds could:

• Accelerate the eradication of lymphatic filariasis and onchocerciasis from entire populations by eliminating the reservoir of worms without the need for repeat treatments.
• Provide health benefits to patients with lymphatic filariasis by removing adult worms from the lymphatics thereby decreasing lymphedema and hydrocele. Increased health benefits from such a drug would likely result in increased patient compliance with treatment and further raise public support for drug therapy.
• Ease reliance on current classes of chemistry and decrease the likelihood of drug resistance and program failure since worms resistant to one chemistry would still be susceptible to a drug with a new mechanism of action.

New Research and Development to Find a Macrofilaricide

Efforts to develop a macrofilaricide have been largely unsuccessful, but have yet to take advantage of modern advances in molecular biology, genomics, and chemistry. Work on WHO-sponsored compounds PD105666, amocarzine, UMF078, WR129577, and 3WR25199 were discontinued due to toxicity to mammals or lack of efficacy. Tetracycline and doxycycline, which acts on the filarial endosymbiont Wolbachia, have macrofilaricidal properties but require too many doses to be practical. Moxidectin, a veterinary drug developed by Fort Dodge, works by the same mechanism of action as ivermectin, making resistance to both drugs possible.

Investment in basic research fortunately presents current researchers with a potent new array of tools for macrofilaricide development. Genomics is generating an increasingly comprehensive list of potential nematode drug targets; the genome of the model nematode C. elegans is complete, along with hundreds of thousands of expressed sequence tags from parasitic nematodes, and sequencing of a filarial nematode genome (Brugia malayi) is in progress. Rapid gene knockout by RNA interference to functionally validate genome-identified targets was pioneered in C. elegans and has recently been extended to B. malayi. Funding for this work has been provided by the U.S.'s National Institutes of Health and the British Wellcome Trust. Techniques in chemical library development and molecular modeling likewise have advanced to take advantage of genome information. Companies like Divergence Inc. have succeeded in developing anti-nematode chemistries by mining nematode genome targets.

Conclusions

Now is the time for investment in new drug discovery for nematode control with a focus on macrofilaricides for lymphatic filariasis and onchocerciasis. In both cases, worldwide efforts underway have the potential to control or even eliminate these dreadful diseases, yet new approaches are needed to ensure success. Recent breakthroughs in genomics and chemistry now make macrofilaricide development feasible. A directed program to discover and develop new macrofilaricides could bring compounds into clinical trials within a handful of years. Since clinical development, even in the best cases, takes time, the need to get substantial research efforts underway soon is urgent.

Background Information

Quotes from the Literature

"With the OCP (Onchocerciasis Control Programme in West Africa) closing down, future control relies almost entirely on the continuing success of the macrofilaricidal / embryostatic actions of ivermectin… Since 1976, the search for an O. volvulus macrofilaricide, suitable for large-scale use in rural populations, has continued, but without practical success and now, sadly, with fast-diminishing enthusiasm. Unfortunately, there is now a considerable risk of ivermectin resistance developing in O. volvulus. Indeed, the present CDTI programmes may well already be slowly selecting for the spread of resistance genes. Before this potential disaster develops and spreads on any large scale, undoing previous achievements, we need to develop a diagnostic tool for ivermectin resistance in O. volvulus and, above all, to find a macrofilaricide suitable for large-scale field use. If resumption of the latter research effort is not adequately staffed and financed now, it may be too late to remedy a future ivermectin-resistance situation." Brian O. L. Duke. "A plea to continue the search for an Onchocerca volvulus macrofilaricide," Transactions of the Royal Society for Tropical Medicine and Hygiene, 96:575-576, 2002.

"In Africa, after the cessation of larviciding (in 2002), control of infection will rely on decentralized annual ivermectin distribution, which has been made available by Merck and Co. for as long as it will be needed. This has several disadvantages. First, in view of imperfect geographical and therapeutic coverage, and density dependence in the microfilarial uptake by flies, low level transmission may continue. Second, resistance to ivermectin might develop and spread, as it already has in some nematode parasites of veterinary importance. Third, in man, the average life-span of adult worms is approximately 10 years, and while repeated treatments of ivermectin seem to have some permanent effects on the fertility of adult worms, this effect manifests itself only after years of treatment. Unfortunately, the number of safe and effective alternative treatments is limited. Diethylcarbamazine, also a microfilaricide, causes severe side effects in onchocerciasis. Suramin, the only currently available highly effective macrofilaricide has even more serious side effects. The advantages of macrofilaricidal drugs are obvious. With a 100% effective macrofilaricide and 100% coverage, elimination could be achieved almost instantaneously. By contrast, with ivermectin, even with 100% coverage - impossible under current exclusion criteria - elimination of the infection from the community would take over a decade." William S. Alley et al, BMC Public Health, 1:12, 2001.

"The specter of the emergence of resistance to ivermectin in O. volvulus was considered a future potential threat to the great progress and considerable investment made so far in research and control against this disease. In particular, there is need for additional research in developing macrofilaricides (drugs which could kill or permanently sterilize the adult O. volvulus parasite), tools for ivermectin resistance monitoring, and improved diagnostics." Final Report of the Conference on the Eradicability of Onchocerciasis, The Carter Center, Atlanta, Georgia, January, 2002.

"Enormous strides have been made over 25 years of concerted onchocerciasis control activities through dedicated regional programs, which together have reported a total of 27,326,349 ivermectin treatments for the year 2000. However, O. volvulus is still with us… With the closure of OCP vector control activities, onchocerciasis control will be completely dependent on the success or failure of mass ivermectin treatment programs. Some authorities have expressed concern about the potential emergence of ivermectin resistance following broad use of a single drug, particularly in the setting of ongoing parasite transmission. Should the ivermectin window of opportunity close, continued research is required to develop new therapeutics, macrofilaricides, or vaccines." Frank O. Richards et al. "Control of onchocerciasis today: status and challenges," Trends in Parasitology, 17:558-563, 2001.

Ascaris, Hookworm, Whipworm, and Other Parasitic Nematodes

Parasitic nematodes besides the filarial worms include the three major geohelminths, Ascaris, hookworm, and whipworm, all of which infect over 1 billion people, and dozens of other worms. Totally morbidity attributable to nematodes is a substantial 11,311,000 DALYs, a number that rivals diabetes or lung cancer. Symptoms include abdominal discomfort, diarrhea, malnutrition, bleeding, and rectal prolapse. Blood loss due to hookworm is also thought to be a major contributor to the 26,650,000 DALYs attributed to iron-deficiency anemia. While mortality is low in proportion to the huge number of infections, deaths are still estimated to total to 100,000 annually. Ascaris, for instance, can block the bile duct. In individuals with weakened immune systems, Strongyloides can proliferate and spread throughout the body. There are no vaccines available. New classes of chemistry with efficacy against filarial nematodes would likely also be effective against geohelminths. (Current compounds are particularly poor at treating whipworm.)

Profile of Current Treatments

Albendazole:

strengths - excellent microfilaricide for lymphatic filariasis, given annually with DEC or ivermectin can greatly reduce microfilarial levels in an at risk population, inexpensive, donated by GlaxoSmithKline, good safety profile

weaknesses - does not kill adult worms; does not greatly improve symptoms of patient with elephantiasis, lymphedema, or hydrocele; requires repeated annual treatments to prevent reemergence of microfilaria; susceptible to resistance; resistance monitoring has not been done

Diethylcarbamazine (DEC):

strengths - effective microfilaricide for lymphatic filariasis; given annually with albendazole can greatly reduce microfilarial levels in an at risk population; inexpensive; partial macrofilarial activity with repeat doses and some patient improvement in lymphedema; can be delivered through salt

weaknesses - safety challenges; can precipitate acute inflammatory reactions when treating Brugia malayi; cannot be used in Africa or Latin America where river blindness (Onchocerca volvulus) or Loa loa filarial worms are co-endemic because of potentially severe side-effects (Mazzotti reaction); not an effective macrofilaricide; requires repeated annual treatments to prevent reemergence of microfilaria

Ivermectin:

strengths - excellent microfilaricide for lymphatic filariasis and onchocerciasis; given annually alone for onchocerciasis or with albendazole for filariasis can greatly reduce microfilarial levels in an at risk population; temporarily sterilizes the adult worm (6-12 months of dead microfilaria in the uterus); can halt skin itching and further eye damage in onchocerciasis; inexpensive; donated by Merck

weaknesses - does not kill adult worms; requires repeated annual treatments to prevent reemergence of microfilaria; susceptible to resistance - non-responders to treatment have been observed in onchocerciasis which could indicate resistance; for filariasis, does not improve symptoms of patient with elephantiasis, lymphedema, or hydrocele; 30% adverse reactions on first dose; dangerous reactions in presence of Loa loa.

Web Accessible Resources:

The Global Alliance to Eliminate Lymphatic Filariasis,

www.filariasis.org

The African Programme for Onchocerciasis Control,

www.who.int/ocp/apoc/

WHO's Program for Research and Training in Tropical Disease,

www.who.int/tdr/index.html

(The opinions expressed are those of the author alone. Please send suggestions or corrections to J. McCarter, mccarter@divergence.com)