Research and development of affordable AIDS medicines for the developing countries
“With scientific rigour and respect for cultural boundaries”
Von Rainer von Mielecki, Marcel Tanner & Alex Matter / Esperanza Medicines Foundation / Schweizerisches Tropen- und Public-Health Institut (Swiss TPH)
The goal of Esperanza Medicines Foundation is to discover and develop novel, efficacious and safe treatment and prevention modalities that can be produced locally, with the technologies that are already available, at little or even negligible cost.
The global AIDS epidemics continues its terrifying spread throughout the developing world; currently it is estimated that 40 million people are infected world-wide and 5.8 million people are considered in immediate need of treatment with antiretroviral (ARV) therapy. Sub-Saharan Africa is by far the most affected region with 26 million infected and 4 million AIDS patients, followed by East, South and South-East Asia with 1.2 million patients. In both regions the number of people getting access to ARV therapy is still only about 8%, despite a vigorous and very commendable effort through the so called “3x5” initiative of the WHO and UNAIDS.
Thus, it is apparent that, while AIDS has become a chronic disease, with much improved chances of survival in industrialized countries, the needs of HIV-1 positive people and AIDS patients in the developing world are still neglected to an alarming degree, at all levels. Use of diagnostics, prevention methods and therapies based on well-established drug regimens of the West have only reached a limited number of patients; chances of infection remain very high, and AIDS patients rapidly succumb to one or several opportunistic infections, to a major extent caused by M. tuberculosis. The epidemics shows no signs of reaching a plateau; HIV-1 is worldwide the most deadly virus with which the human race has ever been confronted.
This has been of considerable concern to us and led us to formulate proposals which were discussed in several workshops and meetings during 2003. A consensus emerged that new, complementary and alternative approaches should be examined. These approaches should, whenever possible, deal with the almost insurmountable problems of cost, storage, distribution, and should ideally not encounter issues linked to intellectual property in order to reduce the complexity of project management.
Based on locally available resources
The strategies of the Esperanza Medicines Foundation are based on locally available know how, technologies and raw materials.
Locally available technologies include grinding, cooking, drying and fermentation in cheese manufacture and breweries.
Locally available raw materials include plants, fruits, fungi, yeast and microbacteria. It is then obvious that Natural Products will need to be reexamined for their potential as powerful medicines. Natural Products appeared to us insufficiently explored despite the fact that several or even hundreds of compounds had been shown in earlier studies to exert potent anti-HIV-1 effects.
Oral route: any anti-HIV medication that fulfills the above requirements will have to be given orally, thus eliminating any peptide- or protein-based drug.
Topical application: prevention modalities that can protect women against HIV-1 transmission can be used topically (i.e. vaginally), and there the possible use of peptides and proteins can be envisaged.
If Natural Products with proven anti-HIV-1 activity could be produced in plants, fruits, seeds, fungi, yeast, bacteria or other host expression systems the way was in principle open for direct consumption of fermented products (yoghurts, curds, tofus, beers) and for relatively simple extraction procedures such as watery extracts of dried or ground material (teas). The workshops in 2003 led us to believe that such an approach would in principle be technically feasible. We also took note of the many practical and political difficulties that such approaches would necessarily encounter at the level of regulatory authorities, political opinion leaders, NGOs, granting agencies and others.
Based on the above rationale, a first step was to scout for libraries of Natural Products that could serve as raw materials. Generously, Novartis permitted access to its pure Natural Products collection of more than 10’000 compounds. Dr. Frank Petersen, Dr. Esther Schmitt and Dr. Hans-Ulrich Nägeli form the Natural Products Unit in Novartis Basel have been exceptionally helpful in getting the studies of these Natural Products underway.
The Foundation was registered on July 6, 2004 with the Commerce Registry of the Kanton Basel-Stadt and a Board of Trustees was assembled with leading personalities representing scientific disciplines, clinical aspects and the social/political context.
Several generous donations have allowed the Foundation to develop a panel of projects that are meeting the above objectives. The Foundation made its public debut on October 6, 2005 when it discussed its projects with a selected panel of around 50 leading experts in the field generating broader and public interest. At the same time, a website was created that contains the proceedings of this major Workshop.
Portfolio of Projects
Anti-HIV-1 activity of pure Natural Products (work performed at InPheno, in Basel, Dr. Thomas Klimkait and Dr. François Hamy):
Based on the available pure Natural Products library of Novartis a collaboration was started at InPheno. This company (a spin off of the University of Basel) has the technologies to determine precisely the antiviral activity of chemical and biological compounds in cell culture systems. In their labs, a variety of cells can be studied including human lymphocytes and macrophages from the blood of healthy donors.
The assays are fairly complex but reliable and can work with a variety of HIV-1 subtypes (A, B, C, etc.), and clinical variants thereof. InPheno possesses to date a data bank of more than 1,000 distinct, infectious clones issued from a comprehensive series of documented clinical contexts (treatment failure, resistance to existing drug, etc.).
At present, about 50 substances have been identified with potent anti-HIV-1 activity that do not exert any non-specific cytotoxic activity on cells. These are the prime candidates for further profiling (see below). We are currently studying whether these compounds fall into classes of widely known antiretroviral drugs, such as reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors or entry inhibitors.
Topical microbicide based on Cyanovirin-N (work performed at the Institute of Plant Sciences, ETH, Zurich, Prof. W. Gruissem, Carmen Faso):
HIV-1 infections occur primarily via unprotected intercourse; heterosexual intercourse is the source of the majority of new infections worldwide. Young women (15 – 24 years old) in the hardest hit countries are now three times more likely to be infected than males of the same age group and additional preventive strategies (besides condoms) are urgently needed. An effective vaginal microbicide could significantly reduce the spread of HIV-1 infections.
One recently discovered compound that irreversibly inhibits HIV-1 entry into host cells is cyanovirin-N (CV-N). The potent virucidal activity of CN-V occurs through a novel molecular mechanism and has shown to be protective in a monkey vaginal SIV/HIV transmission model. It is therefore of prime interest to be developed as a topical microbicide.
The aim is to develop a low-cost, large-scale production system for cyanovirin-N by using plants or microorganisms as natural bioreactors. One of these could be cassava (M. esculenta), which is widely grown in Sub-Saharan Africa, southern China, South America, and several other tropical countries. However, the use of a food crop plant such as cassava also must address the problem that the plant-produced CV-N may accidentally enter the food chain. One possibility would be to insert a specific genetic marker in CV-N transgenic plants to distinguish them clearly and obviously from the non-transgenic plants. In any case, extensive analysis of the digestibility, allergenicity and general safety features of CV-N must be performed before plants producing CV-N can be deployed. Another host could be tobacco, which is not used for nutritional purposes but is still convenient for growth in developing countries. This work should demonstrate feasibility, laying the groundwork for future work that is truly directed at a satisfactory galenical formulation of a topical (vaginal/rectal) microbicide with the required safety and efficacy profile.
Project of Prof Robin Offord and Prof. William Hartley, Mintaka Foundation at the CHUV, Université de Genève in the area of RANTES analogs for possible use as topical microbicides :
These researchers have shown that a chemically modified analog of RANTES, a major ligand of the CCR5 chemokine receptor, was able to prevent vaginal transmission of SIV in monkeys, in a dose-dependent manner. This inhibition of viral transmission is thought to occur through blockade of the co-receptor of M-tropic simian (and most likely human) immunodeficiency viruses. As such, this analog appears to be safe, is devoid of any agonist activity on the CCR5 receptor, and could be produced by means of a relatively simple chemical process. Other analogs, composed of natural amino acids, are in the testing phase; these latter can be produced by recombinant expression vectors in suitable plant or other vectors.
A long way towards clinical trials
Not surprisingly, it would take until about 2010 until the start of any clinical trials. This would require sustained funding. The steps that would allow us starting clinical trials are the following:
Antiviral drug candidates for possible use as AIDS treatments: Clear cut demonstration of potent and selective anti-HIV activity for NP; up scaling to gram quantities that allow to perform pharmacology (safety, pharmacokinetics, formulation); search for one or several suitable expression systems (bacteria, yeast or plants); peparation of GMP material, comprehensive toxicity studies, preliminary environmental acceptability studies.
Microbicidal drug candidates for possible preventative use against HIV-1 transmission: Demonstration of potent and selective activity in cellular models of HIV-1 infection; protective effects in SHIV monkey model; further steps as above.
Quite obviously, this kind of planning is subject to the progress achieved and the uncertainty of sustainable funding. Increasingly robust data will allow to address major funding sources.
Esperanza Medicines Foundation has ventured into a new area of AIDS research & development with projects that are uniquely defined to serve the needs of poor people in developing countries. It has defined one avenue in the area of AIDS treatment, already showing promising results, and two approaches targeted at topical microbicides. This is motivated by the severe lack of access by more AIDS patients to antiretroviral therapies, and by the fact that no effective prevention strategies yet exist that give women some control over the risk encountered with sexual partners that very often reject the use of condoms.
Clearly, these difficulties present high technical, societal and political hurdles and risks and there are no shortcuts. We need to approach this with scientific rigour and respect for ethical, cultural and political boundaries, while at the same time realizing the magnitude of the problem and shift in the risk-benefit ratios for patient populations in developing countries.
Esperanza Medicines Foundation is confident that the basic rationale for setting up this work is of value, as underpinned through many discussions with leading scientists around the world. The Foundation is also acutely aware of the many technical, medical and socio-political issues that still need to be addressed. However, the Foundation is convinced that these can be overcome and that eventually, we shall be able to create entirely novel AIDS medicines and prevention modalities, for the poor of the developing world.
*Alex Matter, the CEO/Chairman and Cofounder of Esperanza Medicines Foundation,
is Director of the Novartis Institute of Tropical Diseases in Singapore. Rainer
von Mielecki, Head of External Relations and Cofounder of Esperanza Medicines
Foundation, is Head of Corporate Communication at Syngenta AG, Basel. Marcel
Tanner is Director of the Swiss Tropical Institute, Basel. Contact: