Q&A: Malaria research efforts open a 'window of opportunity'

Dr. David Hughes, senior global program head anti-infectives at Novartis.

A raft of new financing, research, and development efforts in the past week represents a significant statement of intent in the fight against malaria and a boon to the global health community.

At the Commonwealth Heads of Government Meeting — or CHOGM — in London, politicians, donors, and private sector representatives announced $4.1 billion in new commitments in the fight against malaria — a disease that still claims the life of one child every two minutes, despite tremendous progress in recent decades.

In addition to significant United Kingdom government support for the Global Fund to Fight AIDS, Tuberculosis and Malaria and pledges by the Bill & Melinda Gates Foundation and GlaxoSmithKline, fellow pharmaceutical giant Novartis confirmed it will invest more than $100 million through 2023 to advance research and development of next generation treatments to combat emerging antimalarial drug resistance, including global clinical trials for two new malaria drugs. The commitment also includes expanding access to pediatric antimalarials and implementing capacity building programs to contribute to the World Health Organization's target of reducing malaria-related child mortality by at least 90 percent by 2030.

Opinion: African experts warn big changes needed to eliminate malaria
A new independent policy study, commissioned by Novartis, reveals what African experts think is the best way to push forward progress on malaria elimination. This guest column details the biggest findings of the Malaria Futures for Africa, or MalaFA study, and explains why we need to take advantage of these African insights and learnings.

In conjunction with CHOGM and the 7th Multilateral Initiative on Malaria Conference — or MIM — in Dakar, Senegal, Novartis announced a five-year commitment to the fight against malaria and launched a major new study titled "Malaria Futures for Africa" — or MalaFA — that reveals what malaria experts in Africa think about progress and challenges toward malaria elimination.

Among other key findings, respondents expressed widespread support for making better use of the currently available tools, while stressing that more emphasis should be placed on improving the delivery of existing and new interventions to fight malaria.

To find out more about the next frontier for malaria research and development, Devex sat down with Dr. David Hughes, senior global program head anti-infectives at Novartis. Excerpts of the conversation have been edited for length and clarity.

There has been a raft of funding announcements this week, not least from Novartis that announced a $100 million commitment to the fight against malaria. How will this funding be used and how does it tie in with the company's new malaria commitment?

The general trend over 20 years has been very positive, but recently people have become increasingly concerned. Data from WHO’s 2017 World Malaria Report showed that progress is beginning to plateau and some countries are really struggling to maintain the gains that have been made. We've seen the number of cases and the number of deaths rise with the possibility that resistance to current effective treatments is beginning to emerge, particularly in the greater Mekong sub-region in Asia, which is where previous resistance to antimalarial treatments has often started to appear.

In this context, Novartis — which has a leadership role in malaria, having registered the first fixed-dose ACT [artemisinin-based combination therapy] some 20 years ago — has chosen to continue investing in research, development, and planning for new treatments against this scourge. We've recognized the potential future impact of resistance, so all of our research efforts in combination with multiple partners have been aimed at discovering new mechanisms, and new compounds specifically designed to treat the malaria parasite that may be resistant to ACTs.

Looking ahead, particularly in the area of R&D for new antimalarials, could you tell us how the compounds you're working on differ from existing treatments and from each other?

We have two drugs currently in phase II trials: KAF156 and KAE609. Both came through high-throughput screening that specifically identified compounds against falciparum malaria, but also activity against resistant strains. In other words, we've screened more than 2 million compounds and selected two drugs that are new in class, have novel mechanisms of action, and work against the strains of malaria that are resistant to current treatments. And that gives us a window of opportunity for drug discovery: We're not modifying previous classes of drugs, we're really trying to find new categories.

The drugs are different chemical compounds, different chemical classes and they work in different ways against the parasite. KAE609 has actually shown the fastest parasite clearance time of any that have been tested in humans so far, but we still have to figure out the right dosing to be sure that we have the safety and efficacy parameters. That's ongoing in a study currently underway in Ghana, Uganda, and Mali, which we hope to complete next year.

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And in terms of those and other clinical trial programs, which countries are being targeted for inclusion and why?

Our largest trial is assessing KAF156 with a new formulation of lumefantrine and it’s running at 15 sites in nine countries, seven in Africa and two in Asia — Vietnam and Thailand. One of the reasons we include the Asian sites is that they have a higher chance of having parasites with markers of resistance to the current drugs. Most of the burden of malaria, however, is in Africa: More than 90 percent of the mortality, and about 90 percent of the cases worldwide. So that's where we have the bulk of the patients in our studies and we want to be sure that we have the benefit-risk profile of our compounds characterized among the population that needs it the most.

What is the development timeline once you've gone through this trial stage  can you give an estimate on when this treatment might reach the market?

The pathway to registration and approval by a stringent health authority is determined by phase I, II, and III studies. We're currently in phase II and plan to complete that by the end of next year.

It's a very complicated study, one of the most complex that we're doing at Novartis this year. We're trying to determine a combination of drugs — the most effective antimalarials are done in combination — and we try to increase efficacy and stave off the possibility of resistance while ensuring the safety of the treatment.

We're testing two different doses of drugs and three different durations — for three days, which is the current standard of care, for two days, and a single dose treatment. The latter is quite a high bar and we need to make sure that we're not undertreating it, which could lead to resistance. The malaria parasite hides in the liver and other places, and it comes back out after a period of time, so even if you take one dose today you need to have the medicine around at least for another week to 10 days to make sure there is no recrudescence. It's a tall order, but our chemists have done an amazing job of reformulating one of the partner compounds to enable it to stay in the system through seven days.

How will you ensure accessibility and affordability to those most impacted by malaria, including avoiding excessive out-of-pocket expenses at the point of sale?

As we announced in our commitment last week, not only will we invest $100 million into R&D for next generation antimalarials, we’ll also implement an equitable pricing strategy to enable patients in malaria endemic countries to afford these new treatments once they become available. We plan to do so in consultation with our development and funding partners and other stakeholders.

We also applaud the efforts made on the funding side, where global organizations and the public sector are investing in public health interventions effective in preventing the disease and providing high-quality, effective treatments that are affordable. Similarly, other partners in the supply chain need to ensure that the drugs are there when patients need them.

And how can governments and other sectors ensure a joined-up approach to programming and collaborating on malaria without duplicating or detracting from each other's efforts?

There's no doubt that partnership is key here across all sectors — especially the R&D community and pharmaceutical-based industries — both to bring new products to market and then to make them available at a reasonable end-cost to the patient. For example, our Coartem program has so far delivered over 850 million treatments without profit and we've also developed a paediatric version with dispersible tablets specifically designed for children that we've also delivered more than 350 million treatments. That effort will have to continue in terms of affordability and we'll continue to work with our partners and co-funders in terms of our drug discovery and development efforts. All of us want to ensure that the drugs get to the patients who need them.

We also have early discussions with funders and there's been some very impressive efforts made with the Global Fund and the [United States] President's Malaria Initiative in terms of making these quality-assured, currently approved products available at an affordable price for both ministries of health in endemic countries and the end patient.

“Malaria disproportionately impacts developing economies and so smart investments and judicious spending on public health interventions that deliver results can make a huge difference.”

— Dr. David Hughes, senior global program head anti-infectives, Novartis

I do think there's a need for the public sector — in particular the African and Asian countries most impacted — to step up their game a little bit. There have been some very strong contributions though, and countries like Senegal have gotten over the hump on the path to malaria elimination and are making good progress toward its goals. This is where it shows how important strong public health systems are — without strong primary health care you can very quickly run into challenges.

Aside from operating in fragile settings, for example, what is the biggest emerging threat to a successful intervention against malaria  I'm thinking here about threats such as insecticide resistance, ACT resistance, counterfeit drugs, and substandard treatment?

I think they are all important and we could debate at length which is more important than the other. At this time I don't think it's worth the debate — I think we need to address all of them.

On insecticide resistance, there's a need for next-generation treated nets for indoor use and indoor residual spraying, but I think we now have a much better understanding that vector control is very effective — if we lose that as one of the tools, we're in for trouble.

Similarly, with ACTs — I worked as a government medical officer in Zimbabwe in the 1990s when we had a lot of malaria and when chloroquine resistance became a real problem. I saw personally the impact, particularly among patients who were HIV co-infected, that the drugs didn't work, and many patients died, particularly children. So the possibility that ACTs will also fail in that way is something I'm very concerned about and something that drives me personally — and others at Novartis as a company — to make sure we do whatever we can to get new drugs to market as quickly as possible.

And is ACT resistance inevitable?

That's an interesting debate. If you look at the biology and genetics and the evolutionary pressures that you have for various anti-infective medicines then yes, it's likely the case. However, you look at a drug like quinine that's been around for something like 500 years and it's still efficacious. So hopefully the new drugs will also continue to maintain their efficacy. Simply by extending the dose, you may be able to overcome resistance, but the general evolutionary force is so powerful that yes, I do believe that resistance will come at some stage.

Finally, what's your key message to global development and health professionals?

There are few things that can make such an impact on lifelong contribution to society than to cure a child of a curable disease. For the broader development community to recognize the importance of health as a contribution to human development is important, and clearly malaria plays such an important part within that. We need to continue to make the case for spending in that area, and, at the same time, work with people who are responsible for delivering results: We need to be much smarter about how we use funding and then measure the results, manage and tailor the impact of different interventions.

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