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Insider Interview: The battle to defeat antimalarial drug resistance

Published on 11/05/17 at 11:35am
David Reddy (left), Dr Harald Nusser (right)

Pharmafocus spoke to Dr Harald Nusser, Head of Novartis Social Business, and David Reddy, CEO of Medicines for Malaria Venture (MMV), to discuss their efforts to fight antimalarial drug resistance across the world and the challenges they have met along the way.

What is thought to be causing the rise of malaria drug resistance?

DR: It is believed, at least partly, that there has been use of drugs for a very long time as monotherapies – using one agent at a time. The agent is then not protected; it isn’t protected by anything else and it does give the opportunity for resistance to arise. Ideally, we use drugs in combination so that they can protect each other and deliver a harder punch against the particular parasite.

How did the MMV come about, and what has it achieved so far in the fight against malaria?

DR: The MMV was founded in 1999 and it was really trying to reenergise the drug development engine because, at that time, we were beginning to see resistance to the old-classes of drugs. We worked very strongly with our partners to bring forward a newer class of drug and in 2009 the first of those products, from MMV’s point of view, was the line extension for Novartis’ drug Coartem. This was a paediatric drug that was really important because, at the time, 95% of people dying were children of less than five years of age, so we urgently needed a state-of-the-art therapy for them. Now, we’re seeing resistance to the current classes of drugs arising in Southeast Asia. We’re also seeing some anecdotal reports of resistance from Africa now, which is really concerning; we need to watch that and there is a case for the intensification of surveillance. The development of drugs that can detect the parasite in totally different ways and can be active against these resistant forms – that’s what we’re aiming for.

HN: The paediatric formulation Coartem is close to my heart because we have been jointly, alongside donors – getting important medicines in the hands of patients – so now there is not a child under five dying of malaria every 30 seconds, but every two minutes.

It’s incredible but it’s still happening, particularly in Nigeria and the Democratic Republic of Congo, that adult formulations are being taken, crushed and then the child somehow needs to swallow or intake the drug simply because it’s a couple of cents cheaper. You can never be sure whether the dosage of the drug is correct and, if this is not the case, then there is higher chance of children developing resistance. It’s highly critical that we make stronger efforts, particularly on the side of Novartis as well, to make the paediatric formulations actually available in the communities where they are needed. It’s not easy and many partners need to pull in the same direction.

What are the biggest challenges we face in responding to antimalarial drug resistance?

DR: I think that, in the work we’re doing, the importance of partnerships, such as with Novartis, centres around the quality of medicines. A lot of the problem is to do with developing resistance to current drugs but there is also the problem of people receiving inadequate treatment with substandard medicines that are either not the standard of care, and shouldn’t be used, or drugs that are just sub-quality; you’re not giving people the substance you think you are or not giving the right amount or right quality, and these things breed resistance and endanger people’s lives – if somebody is suffering from malaria, they need to be treated properly. By making quality medicines available and affordable, you can begin to push these other treatments out of the market and that’s one of our strongest hopes.

Is affordability a key concern when bringing new treatments to market in developing countries?

HN: Affordability criteria, apart from the clinical profile, is one of the most important when researching and developing the best formulations. You may have a good substance but, in the development process, you need to optimise it in a way so that it can be affordably produced on a timescale. This is important when speaking about social business and public sector collaborations, as this is a crucial factor, particularly in lower-middle income countries. It’s not enough to have a next-generation, powerful drug – it also needs to be affordable. It’s an additional development challenge.

DR: The biggest mistake that’s made in these types of endeavours is not having the conversation upfront about access and affordability, and then having surprises down the road. With partners like Novartis, we have those discussions; we start off with an understanding of what we’re both trying to achieve so the rest of the road is that much easier. I think we’ve all seen examples where it has gone wrong, and these are the things that are often spoken about in the media, where public money is used to fund a drug that comes out with an unexpectedly high price. In this case, we can start off with a common understanding of where we’re shooting towards on the efficacy of the drug and then, at the other end, the price – I think that’s hugely comforting, as well as to our donors.

What barriers could stop new treatments reaching the patients who need them?

HN: When the programme for Coartam was launched initially, it took some time until it really became recognised as the gold-standard therapy by the WHO. It was not only about making it an affordable medicine, at pricing and cost – not even considering the development costs that came into this that were never recouped. A fascinating thing happened once it became the recognised gold-standard therapy – the demand went up dramatically. From hindsight we had underestimated the pick-up of this drug by a factor of 15, which means that if demand suddenly jumps up, you need to scale up in production so quickly it is hardly possible. You are placed in a critical situation where you need to deal with this increase in expectation – an expectation that you have co-created, of course – and then how you cater to it. All of those investments: to produce the medicine, how to further improve the cost structure of the medicine in this different production size – this is never being taken into considerations nor communicated. This is huge money.

Although it was very difficult times ten years ago, we have gotten so much out of it and learned so much about those interactions with partners like MMV, and have understood the public health landscape so much better. In this, we feel much more confident and more competent to risk launching new access programmes in malaria.

Affordability is central to the debate, but is communication of the issue a major concern? Are people as aware of antimalarial drug resistance as they are of antibiotic resistance, for example?

DR: I think you can look at the issues from a number of directions, one of which is the issue of resistance and the need for new drugs. There is also the issue around communicating to the public and the Western world, particularly where governments are funding these kinds of activities. Malaria is having a dramatic impact but it’s something that people in this part of the world simply haven’t experienced, so the full magnitude of the impact isn’t really felt. I think it’s getting an understanding of how communities and individuals are suffering, but beyond that, also the cycle of poverty created.

People also need to know what the impact of initiatives that they have effectively supported has been. Since 2000, when the Millennium Development Goals were brought into place, 6.2 billion lives have been saved, and that it is largely with the support of the developed world and the public. I think that’s important to understand, especially when there’s often a discussion of development aid – this is an area where they have had unprecedented impact. I think the other challenge is just to identify and overcome some of the barriers to access in the countries that need the drug. That in itself is an infrastructure problem as well as a communication problem.

How do you address issues with infrastructure to ensure effective treatment?

HN: You need to invest into health literacy and awareness so that people are aware to seek consultation with a physician or a nurse. It’s difficult because, in certain communities, a physician is not necessarily an accepted profession or person. Beyond this, you need people to properly follow up on the treatment; you need to consult with the community health worker and the patient that a full regimen of the treatment must be taken – not only one and half days of the treatment, but the full three day course. Trying to find new medicines which are more convenient, where they don’t have to take the full course for three days, for example, would help a lot.

Where in the world do you believe is under the greatest threat of antimalarial resistance, and what needs to be done to help?

DR: In Southeast Asia we have seen the emergence of resistance with multidrug-resistant parasites. The controls that were put in place seem to be working, but if you were to see that spring up in Africa, it would be a totally different situation – it would be horrifying. This is why we need new drugs and to better use the drugs we have today to try to push malaria down and lessen the chance of resistance emerging. The signs are already there, and they’re not good.

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