This technique – of throwing hundreds of thousands of drugs through a variety of high-throughput tests and hoping to find the ones that perform well – is common practice in the drug discovery world, Hughes told Drug Delivery Business News. Consequentially, researchers sometimes know that a drug works, but don’t quite understand why.
“Anti-infectives are examples of drugs that have been approved and used widely for many, many years before people understand the mechanism of how they work,” Hughes told us.
Novartis is developing one of those drugs: KAF156, a compound it discovered in a class of antimalarials called imidazolopiperazines.
“As far as we’re aware, it’s an entirely novel class,” Hughes said, explaining that Novartis researchers have a hunch that the drug works using a mechanism related to the plasmodium flaciparum cyclic amine locus – or the PfCARL.
“And why we know that is there are couple of types of parasites we’ve been able to generate in the lab that don’t seem to respond as well and they have a mutation specifically at that locus,” he said. “But this sort of science that goes on in parallel with the work that we do in the clinic.”
Last month, Novartis announced a partnership with the nonprofit Medicines for Malaria Venture to launch a trial of KAF156 in Africa and Asia. The first trial center is already operational in Mali, the company said. The trial is slated to test the efficacy of KAF156 in combination with an improved formulation of an existing antimalarial, lumefantrine.
By combining the two drugs, the Novartis team is hopeful that it can tackle the growing problem of drug-resistant parasites.
“The odds of two completely independent genetic mutations occurring at the same time are very low, so that’s essentially what we’re trying to do,” Hughes explained. “The way we believe resistance develops to antibacterial or antiparasitic agents is that you may have one resistance mechanism that generates from a genetic mutation and if that happens, those parasites that are able to overcome that drug will very quickly proliferate and they will take over and become the predominant clones in that infection.
“But by having two different mechanisms in parallel, what you essentially need to do is have two different mutations generate spontaneously at the same time. So we’re really playing a game against genetics,” he said.
In other areas of infectious disease, like hepatitis C, combination therapies have been more effective at treating infection and preventing resistance than a single drug.
“So we’re learning from other fields of infectious disease and trying to apply that in the field of malaria,” Hughes said.
The Phase IIb study is designed to study multiple dosing combinations and schedules of KAF156 and lumefantrine, including the feasibility of a single dose therapy in adults and kids.
The trial will begin with 12 patients, Hughes said, and will assess how the drugs work together. Then, the company plans to test seven different groups, all in parallel, in an attempt to optimize dose combinations, duration of treatment and other factors.
“We’re taking advantage of adaptive design where you start and modify and maybe drop certain doses or tweak the dose depending on the data as it comes in during the study,” Hughes said. “And it’s all in the hope of doing good scientific research, but also trying to do the study as quickly and efficiently as possible so you get to the patients that need the medicine as soon as we can.”
Novartis plans to eventually enroll patients as young as two years old. Kids are especially vulnerable to malaria, Hughes said, because their immune system hasn’t had the time to mount a response.
“That’s where the burden of mortality in particular is – 85% to 90% of the deaths in malaria are with children,” he said. “So the sooner we can get kids with a new drug, the better.”