Malaria Drug Development

Rob Ridley

Introduction

It's a pleasure to be here, and Bob has set the scene extremely well, both to the disease itself and the basic science underlying the disease. He mentioned that vaccines and the perfect mosquito are a long ways off into the future, and in the short term we're really dealing with insecticides, vector control, and drugs. The drug efforts that I'm going to talk about are really intermediate efforts while we're waiting for the vaccine and the ideal mosquito to appear.

I've worked for an organization called the Medicines for Malaria Venture (MMV). It's a public-private partnership to discover and develop anti-malarial drugs, and what I'm going to do in the talk is divide it into several sections. I'll talk a little bit more about the disease burden, I'll then talk about some perspectives on controlling the disease in Africa, and moving on from that the role for chemo therapy and the continuous need for new drug R&D to counter the ever-present threat of resistance development to existing drugs, then go into some detail about MMV, and finish up with some perspectives of how things might go into the future.

Disease Burden

There are 3 to 5 million clinical cases of malaria per year, well over a million deaths, and over 95 percent of those deaths are in Africa, mainly children under 5. You have disability due to the severe form of the disease. The burden isn't just on individuals and the health sector, it's on the entire infrastructure and systems of the country that has to deal with the disease. The health sectors, given their limited resources, are essentially swamped by the disease. And it's been calculated that malaria reduces Africa's GDP by about 1.3 percent per year. If you think of that over 50 years, and imagine the United States developing 1.3 percent less over 50 years, that would mean you'd be half as wealthy today as you are.

We can talk about disease burden in terms of morbidity and mortality. Health economists have described disease burden in another term called "disability-adjusted life years." It's interesting to look at some comparative diseases. Leukemia, about which there is lots of interest in the West, has a disease burden of five and a half million, and some of those leukemia victims are of course in the developing countries. War and global conflict account for eight and a half million disability-adjusted life years. It doesn't take a rocket scientist to see the discrepancy between the disease burden of the major diseases and war and global conflict and the amount of effort, resources, and finances that go into those different aspects.

As Bob mentioned, malaria is confined to the tropics. The main disease burden is in Africa. There is a link to poverty. If you do a map of the world according to poverty, it almost exactly overlaps the map of the malaria index. Where you have poverty you have malaria. It's not just that poverty causes malaria. Malaria also feeds back into poverty. If you have malaria, you are less productive, and the economy suffers, your wealth suffers, so health and wealth are inextricably linked. You can talk a lot about statistics, but at the end of the day, the issue is about people in Africa, mainly children, suffering from the disease.

Disease Control

Now, to consider how you go about controlling the disease it's important to understand the evolution of the disease. Once you are infected, if you have a degree of resistance or immunity to the disease, which does build up in people who are continuously exposed, then the disease may resolve, or you may progress to obtain the disease. Coming from the West with no immunity you will almost 100 percent be certain that if you are infected you will get the disease. If you get the disease and are fortunate enough to get treatment early enough and the drug is effective, then you can be cured. If not then you progress to the severe form of the disease. Again, there is a chance there that you may still be treated and cured, if not, then the outcome is death. And the sting on the tail is of course that the mosquito will again take the disease from infected people to infect uninfected people.

So there are several points on this process where you can target interventions. One, prophylactically, to try to prevent people getting the disease at all, involves issues of vector control, use of bed nets, and a lot of work going on in the area of insecticide-treated nets, people moving from disease areas to non-disease areas, and intermittent treatment for women during their first pregnancy, and so on. However, if those preventive methods don't work, then you're left with curing the disease. That requires early diagnosis. It requires appropriate and very rapid treatment. It's an acute infection, it's not a chronic infection like HIV, so you have to respond very quickly. Children getting the disease may be dead within 24 hours. In the health systems in Africa, responding very quickly is a huge challenge.

If the disease is severe, you need treatment and referral to more detailed medical care, and ultimately if you have severe disease you need hospital-based management. Now, there are lots of constraints to those ideal control measures. Many health services are underdeveloped. There are severe shortages of trained staff to administer treatments. There is also a lack of research capacities in many African countries, and I think it's often underestimated, the value of having a strong research base, feeding into control systems. We take it for granted in the North, and it is a severe constraint in Africa. And again we have the issue of poverty, since many of the interventions we need to use are just unaffordable. The unaffordability leads to limited access to drugs, and a very small percentage of children who need treatment actually get it. You have the problem of a dis-regulated system, you have counterfeit drugs on offer, so the regulatory environment is very poor and very often the drug you are taking is not the drug that you think it is. You have a rise in insecticide resistance. And also globally there's a lack of research and development on new tools compared to work done on the diseases of the North. It's been calculated for example, that if you look at medical research globally, about 90 percent of the expenditures are on diseases affecting about 10 percent of the people, and 10 percent of R&D expenditure on diseases affecting 90 percent of the people.

So that's by way of background. USAID, WHO, and many development agencies throughout the world have long been involved in the control of malaria, but it's been given a huge boost over the last few years with the arrival of the new director general of WHO, who initiated a serious program designed to make a serious impression on this disease, to halve the disease burden due to malaria over the next decade. The plan to do that is through strengthening health systems, by building capacities in countries where it's needed, very importantly -- and this is the crux of the whole issue -- to gain appropriate levels of finance, and to feed that finance into appropriate policies. Technically, there's a requirement for country-level ownership of the programs, community involvement, strategies that are developed locally, rather than pushed down from above, a recognition that private sector involvement is going to be important, and the need for further research efforts. And within that research effort context there's a need for new tools and technology development. If we're talking about preventing the disease, we need improved ways of presenting insecticide-treated bed nets, we need better, safe, effective insecticides, and insecticides that are effective given current resistance, we need drugs that can be used during pregnancy -- many of the current drugs are contraindicated for pregnancy, which is difficult in situations when you may not know whether the lady in question is pregnant or not -- and of course, the holy grail of vaccines, which Bob talked about.

Malaria Drugs

On the cure side, there's a need for drugs, improved diagnosis, and better uses of drugs we now have. There's a large effort going on at the moment, taking existing anti-malarials and trying to combine them so that they're more effective, and can delay the onset of resistance. There's a need for better drug formulations, so that they can be used more easily, and of course there's a need for new drugs. In the Medicines for Malaria Venture, the focus is on drugs, not vaccines or insecticides. Its focus is on new drugs, but it's also interested in helping any way it can to advance combination therapy and improved formulations of existing drugs.

You need to think about drugs as a continuous process. You're not going to have a magic bullet of a drug to cure malaria. You're going to have something that can be used as a tool in certain situations for a certain period of time. If you're lucky, like with chloroquine, it might last for 50 years, if you're unlucky, like with SP, it might last for 10 years. Drug resistance and development is a process that takes 10, 12, 15 years, so if we want to avoid a disaster in 20 years' time, we have to begin the research and development for that now.

New drugs have come out at the rate of about two per decade. However, the level of investment that has produced that rate has now dropped off, due to the competitive nature of the pharmaceutical industry, and you essentially have the situation that malaria is a neglected disease. The industry is not competitively engaged, you have a disease for which there is a medical need but there is no competitive industrial R&D. The reasons for that are quite obvious. You look at the anti-bacterials market, that's about a 16 billion dollar market, and you get 3 new products a year, and in 1996 there were 92 antibacterials listed in the American Drug Index. Now, even with that level of activity, people are still worried about antibacterial drug resistance. With malaria, the market is a couple of hundred million, you're getting one to two products per decade, and many of those drugs are not affordable to Africans and are limited to travelers. From the industry perspective, R&D costs are very high, and the malaria market won't support the level of revenues needed to recapture expenses before patent expiry.

Now, the funny thing is that although the industrial R&D is being withdrawn, the scientific opportunities for drug discovery and development have never been better. We understand the life cycle, this year we'll have the complete genome of the malaria parasite, there's improved technologies within the industry for drug discovery, high-throughput screening, and obviously there's a need for improved R&D activity. It is recognized within the public sector that the expertise needed is largely within the private sector, and we need to find ways to combine the public sector expertise and the private sector expertise to meet this public health need.

Several years ago a number of organizations had discussions with industry to search for an appropriate mechanism. The public sector's main requirement was that private industry would really engage in projects rather than give lip service, and that there was compatibility with other efforts. The private sector were concerned that if they were engaged that there wouldn't be any risk to other areas in which they were engaged and had commercial interest, there had to be strong competition, no anti-trust concerns. If they engaged we're talking about a 10 to 15 year commitment in that drug development process, and the commercial environment could very well change during that time, so there were exit mechanisms included in any agreements entered into. It was recognized on both sides that we're talking about a public health need, so the main burden should be on the public sector. Health is a public sector responsibility. So the public sector agreed to take the lead. That led to the establishment of MMV. Basically, MMV recognized the high cost of risk associated with R&D, it combines expertise and resources from both sectors, it aims to deliver products at prices that are accessible to poor people, and underlying it all is a recognition that it has to be organized in a business-like fashion rather than as a huge public sector enterprise.

The strategy is to create what we call a public venture capital fund, which we will use to invest in drug discovery and development projects. This isn't investment for a commercial return, it's investment for a public health return. But the concept of investment and risk is still similar to the concept of venture capital. Most projects that you fund, at millions of dollars per project, will not succeed. You have to define and monitor the goals, you have to access knowledge and experience from the private sector. The projects that we have in hand at the moment, the companies are allowing us access to their private libraries, their high-throughput screening technology, and access to discovery technologies and development expertise that they normally would not be making available to any of their competitors, for example. And again, the majority of the resources so far are from the public and philanthropic sector.

What I've said so far is fine words, and you have to convert fine words into action. So MMV, if you like, is putting itself on the line. It's aiming to develop one new antimalarial every 5 years. We feel that that's a minimum level at which you can make an impact on public health. We estimate that that will cost about 30 million dollars a year plus the support we're getting in kind from industry. It will operate like a small nonprofit business, it will have a small management team, it will not have any laboratories of its own, it will utilize a virtual R&D process, and it will manage the portfolio in much the same way the pharmaceutical industry would manage its portfolio. There will be out-licensing for commercialization. Critical for all of this is that the products and drugs at the end are affordable. It's no good having an anti-malarial that costs the same as anti-retroviral therapy, for example. It won't be used. So we have to have projects where the manufacturing costs would be minimal. Because MMV is paying for the R&D, the R&D costs needn't be included in the pricing calculation. The end price is low, and that has to be managed through appropriate intellectual property rights arrangements and negotiations. The net effect is essentially to lower the cost and the risk to the company that finally takes on the commercial production and manufacture of the good, so we can ask of that manufacturer to accept a lower price and profit margin.

The idea is to scale up to that 30 million dollar a year level by 2004. We've started to fund some projects. The first round of projects there were 104 applications. We selected three, and we'd like to increase that number to about 14 or 15 by 2003, 2004, to deliver one new drug every 5 years. Our experience with the pharmaceutical industry so far in this process has been positive. Our experience in the first year with regard to providing affordable products has also been positive. We find that both industry and academic partners have recognized that affordability is a main goal of the whole process. In each of the cases we have so far, we have agreements where the intellectual property rights of anything coming out of the process is being given to MMV, so we can be in control of the development process, and through that have a degree of control over the end price of the product. But within all of that we have to recognize that we cannot set very hard and fast rules about intellectual property. We have to have a flexible negotiating stance. Anything that will result in a product and a product that is affordable, is something that we will support.

We've initiated a second round of funding. We have 85 applications this time. We've got 12 short-listed and we'll make the final selection next month. Our goal this time round is to have 1 or 2 projects that are close to or already in clinical development. So the idea there is that within a shorter space of time we can begin to have an impact on the control of the disease and start to deliver products where they are needed.

Within all of that background it's important to see MMV in context. We're not saying that the Medicines for Malaria Venture is the answer to malaria. It's a component. It's a small, technical component of all the issues involved in malaria control. It's only through global partnerships involving governments, international organizations, NGOs, and industry, that malaria can be handled or tackled. It requires many approaches and MMV is just a part of that process.

I've also mentioned that the issue of drugs in developing countries is more than just an issue of R&D. We do need R&D for new drugs, but those new drugs are not worth anything if they are not used rationally, if there is no access to those drugs, or if they are manufactured in a way that does not provide quality assurance and follow appropriate regulatory procedures. So you have to have the professionalism through your R&D, associated with quality assurance, and policies and funds in place that can assure rational use, and policies in place that can assure access.

MMV is essentially investing in R&D and operating through a so-called "push" mechanism. It is producing the drugs and then asking groups or making arrangements for those drugs to be utilized. Another mechanism that's being discussed by many is to try to develop "pull" incentives, to bring industry into R&D and facilitate commercialization. If you had some funds that would ensure that drugs can be sold or purchased at a dollar a treatment, as opposed to ten cents per treatment, that would go a long way to induce companies to produce drugs and maybe even do some R&D, if the market was big enough, and MMV would not need to exist.

Finally, what is unique about this operation is the focus of R&D on malaria in disease-endemic countries. Probably for the first time we're getting large-scale industrial involvement on development of drugs that we're intending to use in Africa, as opposed to on the military or for travelers. You have to remember where these drugs are going to be used. There are drugs that are going to be used in the hospital, peripheral health systems, in the community, and the home. Now, home use in Africa, or in the village setting, is very different from what you envisage with home use in the United States. Here, home use often requires going to a doctor, getting a prescription, you go to a pharmacy, you get the drug, you take it home. In Africa, pharmacies are not very abundant, and if the mother has a sick child she has 24 to 48 hours to find appropriate treatment. This is a very different environment in which the drugs are being used, and that has to be taken into account during the R&D.

You should also remember that malaria, although current a disease of the South, has a history of disease in the North. If the disease is not kept in check it could spread northward. So even if you're not interested in controlling malaria from a purely philanthropic interest, from the perspective of enlightened self-interest it is also worth considering.

In the future, the scientific opportunity for malaria research is extremely strong, it's never been better. The political will at the moment is there, we have to ensure that it remains that way. We have to see that political will expressed in terms of funds, not just for R&D but also fro control measures, purchase of drugs and improvement of health care infrastructure. We have to be inventive with appropriate mechanisms particularly for the development of new tools and find ways to involve industry. And what I've been describing is essentially quite a new way of working. It's been in operation for a couple of years. It's in itself a large experiment. We're still learning how to proceed. So probably it'll be five years before I can really tell you whether anything I've told you today is at all worthwhile. We're talking about something in its infancy.

Q&A

Q: What is the feasibility of getting the industrial sector to take primary responsibility for drug development in the "pull" strategy you described, and how important is it to develop R&D capacity in the African countries?

A: Push and pull can go together, and from a public sector perspective that is the most efficient way to proceed. If you have a fund or a market of 2 billion dollars a year and you just left it as a free-for-all, I don't think you'd necessarily get the drugs out that are the most effective at treating the disease. But I think some mechanism for putting money in the hands of the people who need to buy the drugs -- whether it's the countries or agencies like UNICEF or some other mechanism -- has to be found. There's a lot of discussion at the G8 level about making funds available to people to buy drugs for HIV and TB, and something like this needs to be done for malaria. With respect to research capability in developing countries, MMV primarily selects projects based on what we see as the quality of that project, and our belief is that developing country scientists and groups will be able to make an impact on that, and that's been borne out by some of the projects that we are considering. Some of the benefits of R&D will not be seen right away but will be seen downstream, because not all of these drugs are going to be taken on and marketed by big pharmaceutical companies. Probably many of them might be taken on by smaller pharmaceutical companies operating in Africa, India, and Southeast Asia. And through that process I think we can start developing industrial R&D capacity in developing countries. That's the hope.

Q: Are border areas or refugee and migratory populations more likely to suffer from malaria than other areas or populations?

A: I'm not an expert on that, I'm more of a lab person, but I think where you have movements and migration and breakdowns in unified control strategy, you will get enhanced malaria. The issue isn't just the level of malaria, but because of inappropriate control you have a rapid rise of drug resistance. In Africa now and in many parts of the world you're also getting huge population migrations and epidemics of malaria. So epidemic malaria and controlling malaria in complex emergency situations where control has broken down, there's also going to be an increasing problem. And the types of drugs you need for that type of situation are different from the ones you need in a village setting. In complex emergencies you basically need something you can give to someone once, and that's quite a tall order.

Q: Are other warm-blooded animals affected by malaria as well?

A: There are four mosquito species that infect man, and they tend just to infect man. There are other mosquito species that infect rodents, birds, monkeys, but they tend to be different species.

Dr. Robert Ridley is Chief Scientific Officer of the Medicines for Malaria Venture (MMV), a public-private partnership under the auspices of the World Health Organization. Dr. Ridley is a malaria research specialist with research management experience in both the public and the private sectors.

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