Simple ACTs for malaria for 50 US cents

Treating malaria with ACTs was getting expensive - and complicated. Now the problems may be solved, with a new, cheap co-formulation, and a version for children. And the development model that DNDi has adopted could be used for other diseases - like TB.

SUMMARY: With chloroquine no longer recommended, Africa desperately needed cheap, simple artemisinin combination therapies. The Drugs for Neglected Diseases Initiative, DNDi, provided them as its first product. They will suit most - but not all - African countries. Director Bernard Pécoul tells RealHealthNews the story, and describes DNDi's style and approach to cooperation with other public and private bodies.

The Drugs for Neglected Diseases Initiative, a global health partnership created in 2003 by Médecins sans Frontières - with six major public research organizations - to develop useful drugs for the diseases of the poorest, has scored its first hit with a treatment for malaria.

In Africa hundreds of thousands of children die of malaria each year for lack of effective and practical treatment. DNDi’s artemisinin drug combination, announced in March, isn’t new, but DNDi’s unusual approach to drug development – starting first with real human need, based on the real experience of health care in the poorest communities - will make it a much more practical treatment, reducing loose jumbles of 24 different tablets to just three packaged doses. And it will be cheap.

(May 07)

Bernard Pécoul, Director, DNDi: We have just launched the first product to be developed by DNDi - and many partners - to try to improve the management uncomplicated malaria cases. The drugs are useful anywhere, but I would say the first target of this product is Africa.

The development has taken the last five years. It’s a co-formulation of artesunate with amodiaquine, so it’s one of the few artemisinin combination therapies recommended by WHO. It’s already used, in a loose combination, in many countries. Some 20 countries in Africa have selected this combination as a first line treatment. But for the time being they use loose combination, so a tablet of artesunate on one side, and tablet of amodiaquine on the other side.

RHN: So, what made you decide to develop this, since it was already on the market? Is it a new formulation, a new package?

BP: It’s more than packaging. Because of rising malaria drug resistance, in 2001 WHO recommended countries to switch to the use of artemisinin combination therapies (ACTs), from the classical, cheap chloroquine.

But the selected combinations for Africa were very few. One was artesunate with sulfadoxine-pyrimethamine [SP], but this is impossible to co-formulate because it’s three days artesunate, followed by one day of SP. The older combination was Coartem - artemether and lumefantrine, the product developed by Novartis. And the third combination in Africa was a combination of artesunate with amodiaquine.

However this last combination was not co-formulated, so it was large number of tablets. For an adult, for example, it was four tablets a day of artesunate and four tablets a day of amodiaquine, twice a day for three days. So 20-24 different tablets to treat a crisis of malaria. So a lot of different tablets, with a risk of patients taking one tablet and not the other.

So the recommendation from WHO was to try to develop a co-formulation. We were also pressed to do it by Médecins Sans Frontières (MSF) [the founder of DNDi], because MSF was one of the main users of the combination.

So we entered into this project in 2002. We started with pharmaceutical development. It was not easy to co-formulate, for a very simple reasons: when you put artesunate with amodiaquine, one of the products produces water. That dilutes the other one, so you cannot maintain a good level of both drugs in the combination.

So we were obliged to look for a special technology, what’s called a ‘bi-layer technology’, to separate the two products.

The second objective was to reduce the number of tablets, and ideally to have only one tablet a day for three days.

And the third objective was to have a formulation for children, for different ages.

RHN: That was a lot of objectives! Did you also have to do clinical trials?

BP: The first challenge was the pharmaceutical part, because of the water problem, because of the reduction of the number of tablets. So we worked with several groups, one the University of Bordeaux, one the biotech company Ellipse, and later on, one pharma partner to test the capacity to scale up production.

So the first step was to have tablets. And then, yes, you need to do some clinical studies. So we developed a large clinical study in Burkina Faso, involving 750 children. And, and we collected some other data on bioavailabilities. So we did a series of studies to have a package ready for registration.

In parallel, we looked for industrial partners to be in charge of the completion of the dossier, to be in charge of registration, to be in charge of distribution, and in charge of the promotion of the product.

So we signed the first agreement with sanofi-aventis at the end of 2004, as the first industrial partner to complete the registration file and the distribution of this product.

When I say sanofi-aventis is first, it’s because they’ve accepted the non-exclusivity on this contract. So they will be the first to register and produce, but the dossier will be in the public domain.

RHN: You started this when?

BP: We started 2002 with many partners. TDR was one of the key partners. It’s taken five years.

RHN: Let me ask you just briefly, a personal question - what is your background?

BP: I’m a medical doctor, and spent 20 years with MSF in many different places. During the 1980s and 1990s I was in management in MSF. I was the Executive Director in Paris. And then I moved to Geneva to set up our international campaign on access to essential medicines.

RHN: I ask because what you’ve described for your new product is a massive management problem, isn’t it? Apart from the technical problem, there are so many components to it.

BP: Yes. But we were really lucky to attract, right at the beginning of the exercise, a very competent project manager - someone coming with 30 years experience of management in industry: Jean-René Kiechel. He’s still the project manager today. But I have to say it’s a pro bono contribution - because he was recently retired from industry, and he spent the last five years co-ordinating this project between its some 15 or so different partners.

RHN: So he made a big contribution to getting this done.

BP: Yes, in managing the project steps and coordinating the different the different steps.

RHN: But tell us more about the technical solution. What was the technical trick that finally made it possible to combine the two components?

BP: The first was the bi-layer technology, just to separate the two. But the second technique was to, to reduce the number of tablets, as well as the size of the tablet to facilitate doses for children. So it was a kind of compression system. This is where the biotech company played a very, very important role.

And the last technique, also important, is the packaging, because another challenge was to be sure that the product would be stable in tropical conditions.

So of course, the nature of the product was important but also the packaging was important, so we end up with, what we call a ‘double alu’, a double aluminium packaging to, to get a reasonable shelf life in tropical conditions.

RHN: And, of course, the bottom line is the price. What’s the price?

BP: Of course the price was another big issue, so yes it was another objective of this project was to try to reduce the price for the number of patients. So we wanted to have a partner accepting to work at cost. It could be at cost with a small margin - we were open to that - but we felt that the price should very close to the real cost of the product. So sanofi-aventis accepted this condition.

So the target price per treatment is less than one US dollar for adults, under 50 US cents for children under five years old.

RHN: That is amazing, compared to the existing ACTs.

BP: Yes, it’s a reduction. But one reason for that, of course, is that while artesunate is the same price as in other ACTs, our companion drug, amodiaquine, is much cheaper than the companion drug used in the Coartem, lumefantrine.

RHN: What exactly did the clinical trials test?

BP: The pivotal study was a Phase Three study of the co-formulated product versus the loose combination, in 750 cases of clinical malaria in children from six months to five years old in Burkina Faso.

RHN: So what were the numbers?

BP: The level of efficacy is over 95%, which is quite good for malaria products. That was the objective. And in terms of tolerance, the side effects are comparable to the side effects observed in all malaria studies. You cannot have zero side effects with malaria, because after treatment you have a mix of symptoms linked to the disease, with symptoms that could be the consequence of the treatment. It’s the same for all malaria treatments.

RHN: Directly or because of the killed parasites?

BP: Both. Typically you have fever at the beginning, after that you have vomiting - the classical symptoms that you find with the disease. The fever disappears rapidly with artesunate and amodiaquine. But some vomiting was observed in some of the cases.

RHN: What about adults?

BP: The non-co-formulated combination of artesunate and amodiaquine, the loose combination, has provided a lot of data [for adults], in terms of tolerance and toxicity. We collected this data to bring into the registration pack.

RHN: And what’s the position of WHO on this drug?

 BP: In January 2006, WHO produced formal malaria treatment guidelines, four years after the official recommendation for ACTs, which already recommends the use of this drug. It was considering the existing loose combination, but it also mentioned that as soon as the co-formulation would be available, then countries should make a complete switch to the co-formulation.

However we have to be clear. Some countries in Africa are not candidates for this drug. Because you need an assessment of the efficacy of the amodiaquine [on the malaria parasites in that country] in order to recommend a combination of effective drugs. In some countries, amodiaquine is not sufficiently, effective.

So, particularly in some countries in the eastern part of Africa, today I would not recommend the use of this, drug. The situation could change later, but today, with the data that is available, I think it’s better to use another regimen. But in other parts of Africa, a large part of Africa, it will work, and 20 countries have decided to go with this combination as the first line treatment. The issue for them will be to switch from the loose combination to the co-formulation.

RHN: What will the co-formulation mean, then, to, to a minister of health in one of these countries?

BP: I hope that for them the main advantage will be that it will make it easier to implement a malaria strategy at national level. You need to involve thousands and thousands of people, because you need to treat - depending on the size of the country - one million, two million, three million cases, even five million cases in some countries.

So I think they will find that they have a product that is extremely easy to manage, because you have just three different dosages, for each category of age. And a regimen of one tablet a day for three days, I think it’s much easier to promote, to explain, to use, and to distribute.

RHN: To store, as well?

BP: To store, because, we’ve been working a lot with sanofi-aventis to try to improve the packaging, so they are preparing a blister pack for different categories. And packaging of 25 treatments in order to facilitate the logistics for the clinics, and so on. We have tried to think about this kind of issue, to facilitate the distribution.

RHN: You don’t make a profit out of selling this?

BP: DNDi is not for profit, so I think it’s clear for DNDi. Also in this case sanofi-aventis has accepted for all the public sector, international organisations, NGOs, and the not-for-profit sector within the private sector, because they try to promote, what they call the “Impact Malaria” project. So they are trying to give access to this low cost product also to some private companies and pharmacies.

RHN: But still at the same price.

BP: Still at the same price. So they’ve already started Impact Malaria in three countries, but they have the ambition to extend to other countries, to bring this, at cost, to private pharmacies.

RHN: So the marketing will be done by sanofi-aventis, will it?

BP: Yes.

RHN: What results do you hope from this, if we think of the numbers of malaria cases, and numbers of malaria deaths – which is an extraordinary high figure in Africa.

BP: Yes.

RHN: What impact could this have?

BP: Well, it’s difficult, but when we started talking with WHO, the target population for this product was somewhere between 50 million cases to 100 million cases a year, maybe more.

RHN: As for deaths, they are mostly in young children, aren’t they?

BP: Yes. So the advantage of creating something for children is that you will address this issue. Because today, the use of artemisinin combinations for children today is quite complicated. You have to cut the tablet, so it’s not easy to use.

RHN: What proportion of malaria deaths occurs in that first six months, where this combination is not indicated?

BP: Few, because in the first six months most of the children are protected by the antibodies from the mother. So I think the most affected population is six months to five years.

RHN: So you have a formulation for that period now.

BP: Yes. It’s not a syrup, so it’s not exactly a paediatric formulation - because a paediatric formulation is something that can be absorb directly. But it’s a small sized tablet that small children could take if the mother just squashed the tablet into water or some liquid food – a soup, or something like that.

RHN: Now you’ve done an enormous amount already, but what about getting the drug to the end of the track? How do we make sure that once we’ve got we’ve got a good product, and it’s accepted by the government, that there are implementation processes that get it to the people who need it?

BP: It’s still a big, big challenge, I think we’ve taken some steps in the right direction, to reduce the price, to make the product much easier to use, and to make something adapted to children. That facilitates a process.

But after, of course, you need to implement the strategy at a village level. But, but these things are connected because if you have something very easy to use, you can much more easily think about using community health workers to implement the strategies.

RHN: Sure.

BP: Also training the mothers at this community level becomes much simpler when you have an easy strategy. When you have a very complex strategy, it’s difficult to explain.

RHN: Yes, the home management of malaria, for example, was tested in Ethiopia, in fact, by, by TDR, and proved to be extremely successful. But, unfortunately, that was the pre-artemisinin days…

BP: Yes, and they, and they tested mainly with SP, which is only one dose to treat. But, unfortunately today, SP is not effective in many cases. So you cannot comment.

RHN: How many doses of the co-formulation do you need for the children?

BP: It’s one tablet once for three days.

RHN: That’s still quite straightforward.

BP: Still quite simple.

So it will be very interesting to have implementation at this level. I think it’s the next challenge. So one of our challenges is to involve more partners in implementation. But we also must to document a little bit.

We have to be very careful that the product is being used properly, that we continue to monitor the efficacy, the toxicity, and the tolerance. So we plan and sanofi-aventis have some plans to do pharmacovigilance studies, and we have now decided that we will also support some groups to do pharmacovigilance in some places.

RHN: So you don’t wash your hands of the product now. You take a downstream interest.

BP: We try to. But, of course, with, with the resources, the limited resources of DNDi, and our limited, capacities, so I think it’s why partnership is the way to do it. I don’t think that the DNDi will play a major role, but will try to facilitate partnership.

RHN: Taking a more abstract, strategic view of your product, what do you think it demonstrates about DNDi’s capability and future contribution to drug development? Is there, would you say, something very individual about this project? Or does it illustrate something that DNDi will be able to bring to other diseases?

BP: I hope we’ll use this model for the rest of our portfolio. We’ve brought in partners from academia, from the disease endemic countries, and we’ve attracted private partners – from very big partners like sanofi-aventis, to small but very high-technology ones like the biotech company Ellipse.

RHN: But involving all these partners, as we discussed earlier, is a very complicated management problem. How much does success depend on the management skills of that one individual, Jean-René Kiechel?

BP: An organisation such as DNDi depends on its human resources. Our main objective is to have a small team, but of very competent people, each prepared to bring their experience to this field. But I think it’s a challenge facing any business activity today. The management of projects is key.

RHN: And are you finding the people you need?

BP: Yes. Of course, in terms of salary we are not very attractive. But in terms of the vision, and the mission of DNDi, the chance to work in a very interesting environment with many nationalities, I think we are attractive. So now we have more and more candidates for this kind of position.

RHN: So what’s the next product in the pipeline?

BP: Well, we have a similar project with another combination: artesunate and mefloquine, which has been developed in parallel, with a key industrial partner in Brazil. This product is recommended today in five or six countries in Latin America, and in South East Asia.

So the target population is different, but we went through exactly the same process, with the objective of combining the components in a single tablet, of reducing the number of tablets, and of having something for children.

In this case it has been possible to combine the two compounds, so we have not been obliged to use the same technology. The tablets are very small. It’s one tablet a day for two days. And it’s coming very soon.

RHN: Mefloquine is counter-indicated in some situations, isn’t it? It is somewhat psychoactive.

BP: Mefloquine has been found, of course, to have some very rare side effects. But now there is a lot of information on mefloquine, and even in combination with artesunate. It has been extensively used in Thailand, Burma, Cambodia, and Vietnam, so there is plenty of data.

RHN: So you’ve covered malaria in South East Asia, Latin America, West Africa, and South Africa - but what about East Africa?

BP: East Africa is a potential candidate for artesunate mefloquine. WHO is pressing us to develop a study in East Africa, because again this combination will be extremely easy to use, and it could be an alternative for other treatments. But I don’t think that today, either the countries or WHO intend to have only one treatment to recommend. So it may be a first line, or probably a second line or third line treatment.

RHN: When will this be ready?

BP: Well, if we, well, this artesunate mefloquine is, more or less, on the same timing so the dossier has been submitted for registration in, in Brazil. We are expecting information in the next few months… during the course of 2007, probably first in Latin America, and then in Africa.

RHN: What about artemisinin supply? Is that a problem these days?

BP: Not these days. The situation has improved, and in this case, sanofi-aventis have secured the sources of artesunate for the next few years.

RHN: Where is it coming from?

BP: China first, Vietnam second. But the next source could be Africa – from Tanzania and Kenya.

RHN: Well, this is a brilliant step for DNDi.

BP: DNDi and many parties. TDR was a key partner, and many others were involved in this project at different stages.

RHN: So your contribution was to conceive of it and to manage it?

BP: To conceive, coordinate, manage and fully negotiate contracts, bearing in mind that our objective is the interest of the, of the most neglected; and then the public approach. But the contract with sanofi-aventis is a kind of model contract because the company accepted non-exclusivity. I think it was quite exceptional, accepting to make the product at cost for most of the production; they will have a small private market but they consider that it will represent only 10-20% of the global market.

RHN: Is there anything to be done for HIV along these lines?

BP: This could be a model for HIV or TB, tuberculosis.

RHN: To simplify DOTS?

BP: Yes, to simplify DOTS, and to include some new antibiotics, because you know today DOTS has some problems. It has a lot of problems with resistance, and it’s still six to eight months’ treatment. With new antibiotics, it’s probably possible to reduce that to three or four months - a relatively short period. But everything takes time - to develop this co-formulation, we would have to spend almost five years.

RHN: So are you going to be working on TB?

BP: In fact no, considering what all of the partners in this field are now doing. In fact, even malaria will not be the top priority for DNDi. We have a very good relationship with the Medicines for Malaria Venture (MMV), and they have an interesting portfolio of new work. In2002 MMV decided to develop new drugs, totally new drugs.

RHN: What you say is fascinating because this is not a competitive world of pharmaceutical development. You’ve got potentially competitive organizations, but you’re working with each other, to make use of each other’s capacities.

BP: Yes. I think so. That’s one of the major advantages of this approach.

RHN: How do you do this coordination? Do you do it at director level? Or at all sorts of levels?

BP: It’s a combination of continuing, very informal communication. And when we have something to do in common, we just formalise.

So, just to give you an example, MMV developed a new product for malaria, and this product was provoking some interest for leishmaniasis, one of the key diseases for DNDi; so we signed an agreement to share all information on this product with DNDi, and we have continued the development together.

RHN: Let me just back up one step, and go back to the ministerial perspective. Suppose you’re a malaria manager in a ministry of health in Africa, and what do you hear about this new product of yours? You may get a message of recommendation from WHO, you get a press release from DNDi, but how does it move from there, to purchase and use?

BP: I think for some of them it will be extremely simple because for those who have decided to go with the loose combination of artesunate plus and amodiaquine, they will be very happy to switch to the co-formulation. It will be cheaper and [easier].

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