October 6, 2021

UPDATE: Therapeutic malaria treatment shown to be 100% effective in Phase 2 trial

WEST LAFAYETTE, Ind. - The fight against one of the world's deadliest infectious diseases — malaria — may soon have two new weapons.

The World Health Organization this week endorsed a vaccine, Mosquirix, made by British pharmaceutical company GlaxoSmithKline, that prevents malaria and, according to The New York Times, “could save the lives of tens of thousands of children in Africa each year.”

Meanwhile, a second approach is still in clinical trials. A cancer drug repurposed to treat malaria has been shown to be nearly 100% effective in helping to defeat the disease in just three days. This is according to the results of a Phase 2 clinical trial, the results of which were published recently in the Journal of Experimental Medicine.

The trial of the therapeutic drug shows that addition of the drug Imatinib to the customary malaria therapy enables clearance of all malaria parasites from 90% of patients within 48 hours and from 100% of patients within three days, says Philip Low (rhymes with "now"), Purdue University’s Presidential Scholar for Drug Discovery and the Ralph C. Corley Distinguished Professor of Chemistry in the College of Science, who co-directed the international research team. The patients receiving Imatinib were also relieved of their fevers in less than half of the time experienced by similar patients treated with the standard therapy.

“In our trial, 33% of the patients treated with the standard therapy (but without the Imatinib supplement) still suffered from significant parasitemia after three days,” Low said. “Delayed clearance rates are a precursor to and an indicator of potential drug resistance, which has been a problem with malaria for decades. So, this could be significant.”

Imatinib was originally produced by Novartis for the treatment of chronic myelogenous leukemia and other cancers. It works by blocking specific enzymes involved in the growth of cancers.

"When we discovered the ability of Imatinib to block parasite propagation in human blood cultures in petri dishes, we initiated a human clinical trial where we combined Imatinib with the standard treatment (piperaquine plus dihydroartemisinin) used to treat malaria in much of the world," Low said. "The phase 2 clinical trial that is described in the paper in Journal of Experimental Medicine compares the standard treatment with Imatinib plus the standard treatment. We did not test Imatinib alone because it would have been unethical to treat patients suffering from a potentially lethal disease with an untested therapy."

Malaria infects human red blood cells, where it reproduces and eventually activates a red blood cell enzyme that in turn triggers rupture of the cell and release of a form of the parasite called a merozoite into the bloodstream. Low and his colleagues theorized that by blocking the critical red blood cell enzyme, they could stop the infection. The data from the drug trial confirms that.

Low said that for the past 50 years, malaria treatments have used drugs that target the parasite itself, but the microorganism eventually developed resistance to the drugs.

“Because we’re targeting an enzyme that belongs to the red blood cell, the parasite can’t mutate to develop resistance — it simply can't mutate proteins in our blood cells,” Low said. “This is a novel approach that will hopefully become a therapy that can’t be evaded by the parasite in the future. This would constitute an important contribution to human health.”

Malaria is caused by a single-cell parasite, Plasmodium, which is carried by mosquitoes. The World Health Organization estimates that the disease caused 409,000 deaths in 2019 (the most recent year for which data is available). The WHO also notes that 67% of those deaths were in children under 5 years old.

The deadliest form of the parasite is P. falciparum, and although most malaria deaths occur in sub-Saharan Africa, a variant of P. falciparum that is developing drug resistance has become established in a corner of Southeast Asia, particularly in Cambodia, Myanmar, Thailand, Laos and Vietnam. In some regions of the area, up to 80% of malaria parasites are at least partially drug resistant.

In 2019, professor Olivo Miotto from the Wellcome Sanger Institute of the University of Oxford, told the BBC the rise of the drug-resistant variant in Southeast Asia raises the “terrifying prospect” of the drug-resistant variety traveling to Africa. A similar event occurred in the 1980s with malaria resistant to the then-standard treatment of chloroquine, which resulted in millions of deaths.

Low and his colleagues tested Imatinib in a hot zone of drug-resistant malaria on the border of Vietnam and Laos, in the Quang Tri Province of Vietnam.

“It’s such a remote region of the country that most of the clinics are one- or two-room cinder block buildings with just six or seven cots where people can come in and get treated,” Low said. “Not only was the drug 100% effective after three days, but the patients saw their fever disappear on the first day, and they felt much better sooner.”

Although malaria is not a significant disease in North America, Low is planning to apply for approval by the U.S. Food and Drug Administration.

“The FDA is so widely respected around the world that if they approve it, almost all other nations, especially developing countries that suffer from malaria, will rapidly adopt it,” he said. “The FDA requirements for Phase 3 approval are very rigorous. You have to demonstrate the drug combination’s efficacy and safety in a large patient population and then show that you can manufacture and store it safely and reproducibly. You also have to start from scratch and end up with a product that is more than 99% pure.”

An international priority patent application has been filed in Vietnam by Purdue Research Foundation, VinUniversity in Vietnam, University of Sassari in Italy, and Italian company NUREX SRL.

Low said he has been in discussions with drug manufacturers in India and Vietnam to produce the drug and estimates that they can produce the drug for roughly $1 per pill.

“We’ll turn over the technology to any company committed to distributing it to developing malaria-infested areas,” he said. “I’m not interested in making a penny off of this. I just think it’s important for humanity to have it.”

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Writer, Media contact: Steve Tally, steve@purdue.edu, @sciencewriter

Source: Phillip Low, plow@purdue.edu  


ABSTRACT

Imatinib Augments Standard Malaria Combination Therapy Without Added Toxicity

Huynh Dinh Chien, Ph.D.1, Antonella Pantaleo, Ph.D.2, Kristina R. Kesely, Ph.D.3, Panae Noomuna, MSc3, Karson S. Putt, Ph.D.4, Tran Anh Tuan, Ph.D.5, Philip S. Low, Ph.D.3-4,*, and Francesco M. Turrini, Ph.D.6.

1 College of Health Science, Vin University, Hanoi, Vietnam

2 Department of Biomedical Sciences, University of Sassari, Sassari, Italy

3 Department of Chemistry, Purdue University, West Lafayette IN 47907 USA

4 Institute for Drug Discovery, Purdue University, West Lafayette IN 47907 USA

5 Huong Hoa District Health Center, Quang Tri, Vietnam

6 Department of Oncology, University of Turin, Turin, Italy

DOI: 10.1084/jem.20210724

To egress from its erythrocyte host, the malaria parasite, Plasmodium falciparum, must destabilize the erythrocyte membrane by activating an erythrocyte tyrosine kinase.  Because imatinib inhibits erythrocyte tyrosine kinases and since imatinib has a good safety profile, we elected to determine whether co-administration of imatinib with standard-of-care (SOC) might be both well-tolerated and therapeutically efficacious in malaria patients.  Patients with uncomplicated P. falciparum malaria from a region in Vietnam where 1/3 of patients experience delayed parasite clearance (DPC; continued parasitemia following 3 days of therapy) were treated for 3 days with either the region’s SOC (40mg dihydroartemisinin+320mg piperaquine/day) or imatinib (400mg/day) + SOC.  Imatinib+SOC-treated participants exhibited no increase in number or severity of adverse events, a significantly accelerated decline in parasite density and pyrexia, and no DPC.  Surprisingly, these improvements were most pronounced in patients with the highest parasite density, where serious complications and death are most frequent. Imatinib therefore appears to improve SOC therapy with no obvious drug-related toxicities.


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