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August 7, 2018

The next generation of antimalarials

Novartis has launched a programme to add novel treatments to its malaria pipeline and to complete clinical trials for two new candidates. So why are new antimalarials needed? Abi Millar finds out.

By Abi Millar

Over the last two decades, the fight against malaria has been overwhelmingly successful. Between 2000 and 2015, global malaria deaths fell by more than 60%, largely thanks to better vector control, for example via insecticides, and advances in treatment.

Unfortunately, the disease remains an enormous healthcare burden, with nearly half the world’s population at risk of infection. In 2016, there were 216 million reported cases of malaria, claiming the lives of 445,000 people. More than two thirds of these malaria deaths (285,000) occurred in children under five.

On top of this, a number of African nations lack the capacity to develop healthcare systems that can deliver appropriate treatment and care.

“A recent study, which pooled data from 33 African countries, estimated that only about a fifth of children with a malaria-induced fever currently receive the right diagnosis and appropriate treatment,” says Dr Harald Nusser, head of Novartis Social Business. “A child dies every two minutes from malaria.”

He points out that, despite the fall in mortality rates, now is not the time for the medical community to lose momentum.

“If we continue to be successful in the fight against malaria, complacency will set in as the number of cases and deaths continues to decrease,” he says. “Global attention will be diverted onto other illnesses, not least noncommunicable diseases, which are rapidly increasing in many African countries.”

Novartis’ investment: a $100m commitment to fighting malaria with new treatments

Attuned to this threat, Novartis recently announced a renewed commitment to combating the disease. Speaking at the London-based Malaria Summit in April, the company said it plans to invest more than $100m in R&D over the next five years. Ultimately, it hopes to develop next-generation antimalarials that could treat the condition in a completely different way.

“So far, more than 850,000 treatments have been distributed without profit.”

“The company will also implement an equitable pricing strategy adapted to maximise patient access in malaria-endemic countries when these new treatments become available,” adds Nusser. “It will further help expand access to paediatric antimalarials and implement healthcare system strengthening programs in four sub-Saharan countries heavily affected by malaria, including Nigeria and the Democratic Republic of the Congo.”

Novartis already has a strong track record in antimalarials. In the early 1990s, the company began to look at underserved areas in global health, giving rise to the Novartis Malaria Initiative.

“In 1994, a joint venture between Novartis and Chinese partners was agreed to develop, test and manufacture an antimalarial treatment – the first collaboration of its kind in Chinese history. This led to the development of the world’s first fixed-dose artemisinin-based combination therapy (ACT),” says Nusser.

Following a landmark agreement with the World Health Organization (WHO) in 2001, Novartis committed to making this ACT available without profit to the public sector of malaria-endemic countries. Although this agreement expired in 2011, the company continues to provide treatments on the same terms.

“So far, more than 850,000 treatments have been distributed without profit,” Nusser explains.

ACTs of resistance: continued pathogen mutation threatens global malaria treatment

As recommended by WHO, ACTs remain the first line of treatment for uncomplicated malaria. Since they combine two active ingredients with different mechanisms of action, they approach the disease from a dual angle, representing a key step up in malaria treatment.

“ACTs remain the first line of treatment for uncomplicated malaria.”

To give some context of their development, the 1980s and 1990s saw the emergence of resistance to earlier therapies (chloroquine and then sulphadoxine-pyrimethamine). This is thought to have contributed to rising malaria mortality throughout the 90s.

“The Institute of Health Metrics and Evaluation at the University of Washington, which provides estimates of malaria deaths, shows mortality increasing from around 746,000 in 1990 to reach a peak of over 990,000 in 2003,” says Nusser. “Many experts believe that this increase in mortality was due to the emergence of treatment resistance, with insecticide resistance also being a strong contributor.”

Since the introduction of ACTs and widespread bed net use, great progress has been made. Unfortunately, history could be set to repeat itself as the pathogens continue to mutate. Cases of ACT-resistant malaria have been seen in the Greater Mekong Region, prompting concerns that it could spread further around Asia and on to Africa.

“In addition, some experts believe that de novo ACT resistance in Africa is also possible. Widespread ACT resistance would have a devastating impact on the global capacity to treat malaria,” says Nusser. “That is why Novartis is working with partners to develop successor treatments so that we will be ready when that day comes.”

New drug candidates: upcoming solutions primed to help reduce malaria death rates

Novartis’ R&D investment, then, is intended to advance its malaria pipeline through 2023, developing new lines of defence against the disease. The company will complete clinical trial programmes for two drugs: KAF156 and KAE609 (currently in Phase IIb and Phase IIa respectively).

“The current antimalarial pipeline is stronger than it has been for many years.”

“Phase IIa studies have demonstrated that KAF156 rapidly kills both Plasmodium vivax and P. falciparum malaria parasites, including strains seen in the Greater Mekong Region that are showing markers of resistance to ACTs,” says Nusser. “It has the potential to be an important new antimalarial drug, because it may not only clear malaria infections but also block transmission of the malaria parasite.”

Launched in 2017, the phase IIb trial is being run across 17 centres across nine countries in Africa, and expects to yield interim results are in 2019.

KAE609, meanwhile, is currently being evaluated in a phase II safety study in seven centres, across Ghana, Mali and Uganda. In a proof-of-concept clinical trial, it was able to clear the blood stages of malaria for all 21 patients enrolled, including those with markers of ACT-resistant infections.

“In addition, our scientists are working on other projects, with a new compound targeting other novel mechanisms against malaria scheduled to enter testing in humans within the next couple of years,” adds Nusser.

These plans mesh nicely with WHO’s goal, which is to reduce malaria deaths by at least 90% by 2030. As stated in the ‘Global Technical Strategy for Malaria 2016-2030’, the WHO also wants to eliminate the disease in at least 35 countries and prevent resurgence in countries where it has already been vanquished.

Nusser believes that, if such a thing is possible, it will only be through a sustained effort and investment.

“I think that the current antimalarial pipeline is stronger than it has been for many years, so in that sense I am optimistic,” he says. “Our aim is to ensure our new medicines are designed to benefit the populations with the greatest disease burden and needs: women who are pregnant or with child-bearing potential, and children. But if funding and political will drop, the malaria parasite will fight back as it has done throughout human history.”

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