Novartis drug clears malaria parasite in phase II study

Last Updated: 2014-07-30

By Gene Emery

NEW YORK (Reuters Health) - A phase II trial of an experimental malaria drug given once a day found that it rapidly cleared the parasite from the blood within 12 hours, with mild nausea being the most common side effect.

The test, reported in the New England Journal of Medicine, comes at a time when doctors are desperately searching for a new weapon in their fight against a disease that kills roughly 627,000 people worldwide each year and has been showing increasing resistance to established therapy.

The experimental drug, developed by Novartis, is designated KAE609 and was formerly known as NITD609. The company financed the study.

"This is rare good news in malaria treatment and prevention," said Dr. Christopher V. Plowe, leader of the Malaria Group at the Center for Vaccine Development at the University of Maryland School of Medicine in Baltimore. He was not involved in the study but has served as a paid consultant to Novartis on development of the drug.

Research published in 2013 showed that the drug kills the parasites by disabling their molecular pump for removing excess salt. The organism, which lives in red blood cells, dies from a salt overdose.

The open-label test in Thailand, conducted in the first half of 2012, involved 21 volunteers who received 30 mg of the drug each day for three days. The patients ranged in age from 21 to 46. Only one was female, because women with childbearing potential were not eligible.

The median clearance time was 12 hours. The interquartile range was 8 to 16 hours for the 10 people infected with Plasmodium vivax and 10 to 16 hours for the 11 with P. falciparum.

And while fewer than 1% of a group of 5,076 patients with P. falciparum who were treated with oral artesunate had a parasite clearance half-life of less than one hour, half the people receiving KAE609 had a comparable removal time.

"We were surprised how quickly the parasitemia was cleared," Dr. Nicholas White of Mahidol University, chief author of the team, told Reuters Health in a phone call from Bangkok.

Fourteen of the 21 volunteers reported some type of adverse event. Nausea was the most commonly reported adverse effect, but its severity was assessed as grade 2 in only one patient.

"This study was too small for us to derive valid conclusions regarding safety and efficacy," the White team concluded.

"One patient withdrew but nobody was unable to take it," said Dr. White. Three patients vomited, but "vomiting is quite common if you have malaria."

Three patients had elevated liver enzymes, the authors said. They wrote, "Elevated aminotransferase levels may also occur in patients with acute malaria, so much larger studies will be necessary to assess fully the safety and adverse-event profile of this new antimalarial agent."

Studies underway now are designed to find the correct dose, Dr. White reported.

"The way we hope we will develop antimalaria drugs in the future will be to spend some time getting the dose right, because in the past we tended to introduce the drug at a dose that was too low, so that tended to induce resistance," Dr. White said. "Once we get the dose right, we will partner it with one or more other antimalarial drugs in the hopes that it will eventually be used as a fixed-dose combination drug, like we treat tuberculosis, HIV and malaria now."

A companion study in the Journal, in which Dr. Plowe is a coauthor, illustrates how artemisinin-resistant malaria has spread to eastern Myanmar, western Cambodia, western Thailand and southern Vietnam. Such resistance is also appearing in northeastern Cambodia and southern Laos.

The researchers found that standard three-day treatments were failing but longer, six-day treatments with a combination regimen that included artemisinin is continuing to work, with a cure rate of 97.7%.

"We have a finger in the dike at this point against drug-resistant malaria in Southeast Asia," Dr. Plowe told Reuters Health by phone. "But I don't think we have very much time and don't have good options in hand."

"We can extend the course of treatment as we've done with this study. That may provide answers to what we can do to treat malaria until these new drugs come online," he said.

SOURCES: http://bit.ly/WIUC7j and http://bit.ly/1zoCuxp

N Engl J Med 2014.