One of the major reasons why some of the major healthcare problems related to neglected diseases are not addressed by large pharma companies is the lack of large markets which are enablers for ensuring adequate returns on the investments made. For example with rising costs of drug discovery reaching over $ 1.5 billion for every new drug reaching the market, there are not many drugs for neglected diseases which could attract adequate markets in value terms. Recent new drugs particularly those based on biotechnology processes are sold at very high prices unaffordable to the patients in poor countries. On the other hand if costs can be brought down and appropriate distribution systems can be put in place, a portfolio of drugs for neglected diseases could be very attractive targets for investments in R&D. Based on current costs of manpower, infrastructure and other overheads, it is fair to assume that the costs of new drug discovery for some of the neglected diseases could be as low as $ 100 million if carried out in low cost economies such as India, which would be 10% of the costs of discovery and development of a new drug based on the Western and currently followed  model. Even at these costs to develop the presently available pipeline candidate drugs and leads for neglected diseases which number over 50, the amount required would be around $ 5 billion, an amount which is outside the scope of available resources from all the funding agencies, governmental and non-governmental organisations, philanthropists and other donors. Globally it should be possible to mobilise resources of this order provided there is a strategic approach to use such funds effectively.

What is required is to have an integrated approach which will define a roadmap, based on priorities, medical needs, resources requirement and innovative potential to realise the objectives of discovering and developing new drugs for the neglected diseases. Incentives similar to those offered for orphan drugs through appropriate legislations would encourage investments in this area. India certainly as a leader among the developing countries should take the lead and set up strong public-private partnerships at the global level to coordinate net work programmes in the area of neglected diseases on a priority basis.

Indian scene
Except for Schistosomiasis and Trypanosomiasis, all the other diseases, the so-called neglected diseases are problem areas for India. India is in the forefront of R&D for drug discovery research among the developing countries. Indian capabilities in terms of scientific and technical strength is unparalleled among the developing countries. Over a dozen of the leading pharma companies have active programmes in drug discovery. Their areas of interest are diabetes, cardiovascular and central nervous system diseases, infections, respiratory disorders and cancer. It is notable that none of them have programmes of drug discovery for neglected diseases. The only exceptions are TB and malaria, the former a collaborative project with GSK, UK and the latter sponsored and financed by the Govt of India in various govt labs and under the NMITLI programme. The public sector Central Drug Research Institute has a variety of programmes which include most of the neglected diseases including TB, malaria, visceral leishmaniasis, parasitic infections etc. Some of the other national labs also do have programmes in neglected diseases areas. However, these labs have no facility or even mandate to develop the candidates to reach the patients. Once again you would need the collaboration of R&D based domestic or international companies to take the candidates forward and make them available in the market. Such collaborations and investments in time and resources will depend upon their own priorities which at present are not in these areas.

Case of leishmaniasis
For developing countries, apart from Malaria and TB which are no longer neglected from the point of interests, efforts and investments, the major problems other than emerging viral infections such as SARS, Swine, Avian and H1N1 flu infections are visceral leishmaniasis and parasitic infections of diverse types, aetiology and intensity. There has been a reduction in  intestinal helminthic infections due to better public health measures and effective drugs belonging to the bendazole class.

Visceral leishmaniasis is characterised by high fever, weight loss, swelling of the spleen and liver and anemia. Over 200 million people across the world are at risk of getting the disease. Even though around 88 countries are vulnerable, over 90% of the disease is confined to a few countries. Of this 67% are from India, Nepal, Bangla Desh and bulk of the rest from Brazil and Sudan. The problems are related to lack of adequate knowledge about the disease even though the deciphering of the genome of the organism will be very helpful for discovering better diagnostic, curative and prophylactic agents. Currently some reliable, easy to use diagnostic tools are available. No effective vaccines have been developed and as such control is based on chemotherapy. All the drugs available such as antimonials, liposomal amphotericin B, paramomycin and miltefosine have unacceptable toxicity levels apart from the fact that there is evidence of resistant strains evolving making chemotherapy ineffective.  A survey conducted in Bihar where the disease is endemic showed that not adhering to treatment or non-compliance to the prescribed drug usage was a major factor in unsuccessful outcomes of intervention. Non-compliance has led to wide spread problems of drug resistance. Analysis of genome data of resistant clinical strains and comparing them with those of the normal strain may provide answers for the raison d’etre of resistance. Yet another problem is that except for miltefosine, all the others are injectables, making them inaccessible and expensive for poor populations which form the majority of the patients. Improving public health measures to control the vectors through use of insecticide treated nets even through public-private partnerships have been hardly successful due to logistic problems.

Global efforts
Like most other neglected diseases, there has been very little efforts at discovery of new drugs for Leishmaniasis by MNCs in developed world. Due to international travel and the deployment of US forces in disease prone areas, there have been sporadic reports of infection even in the US. Marginal US efforts have come from the Centre For Disease Control (CDC), Dept of Defence, US AID and the National Institute of Health (NIH) all from public funding. In 2007, R&D spend on Leishmaniasis in the US mostly on basic research and clinical trials amounted to around $ 25 million, clearly much below the minimum critical funding required for tackling a disease of this magnitude.

In 2003, a global organisation termed Drugs for Neglected Diseases initiative (DNDi) was set up jointly by Medicines sans Frontieres, Kenya Medical Research Institute, ICMR, Malaysian Ministry of Health, Oswaldo Cruz Foundation of Brazil and Pasteur Institute in Paris. The WHO has a permanent position as an observer. The objectives are to develop field relevant treatments for patients with neglected diseases such as malaria, Trypanosomiasis and Leishmaniasis (both visceral and cutaneous), create awareness among the public and develop R&D capabilities in countries where these diseases are endemic. DNDi has initiated several projects in these areas.

Indian efforts on all aspects of the disease including basic research has been substantial. The two major institutes which have deployed massive efforts on visceral leishmaniasis are the  Indian Institute of Chemical Biology (IICB) in Kolkata and the Central Drug Research Institute  (CDRI) in Lucknow. Both the Institutes have been carrying out elaborate studies in understanding the disease, host-parasite interactions, the role of protein kinases and protein phosphatases and identification of targets which are useful for drug discovery and development. CDRI in addition has been working on development and screening of both  synthetic and natural products as well as combination products with miltefosine as the prime drug. Several new  drug targets have been developed and are being used for the discovery of new candidate drugs.

The stated objective of the joint programme between the affected countries, the WHO and other agencies was to ensure eradication by 2012. Notwithstanding substantial efforts by many groups, appropriate modalities for the control of L. donovani infections are still a fair way off and are clearly outside the scope of realisation in the immediate future. It is obvious that leishmaniasis is yet another example of our inability to ensure control of diseases affecting large populations in nations suffering from the ravages of poverty and underdevelopment in the public health space.