UPDATE: Antimalarial therapy shows 100% effectiveness in Phase 2 trial
WEST LAFAYETTE, Ind. – The battle against one of the world’s deadliest infectious diseases—malaria—may soon have two new weapons.
The World Health Organization this week confirmed a vaccine, Mosquirix, made by British pharmaceutical company GlaxoSmithKline, prevents malaria and, according to The New York Times, “can save lives. tens of thousands of children in Africa every year.”
Meanwhile, the second approach is still in clinical trials. A repurposed cancer drug to treat malaria has been shown to be almost 100% effective in helping to beat the disease in just three days. These are the results of the Phase 2 clinical trial, which was recently published in the Journal of Experimental Medicine.
Therapeutic trials showed that the addition of imatinib to conventional antimalarial therapy cleared all malaria parasites from 90% of patients within 48 hours and from 100% of patients within 48 hours. within three days, Philip Low said. “), Purdue University Presidential Scholar for Drug Discovery and Distinguished Professor of Chemistry Ralph C. Corley at the College of Science, who co-directed the international research team. Patients taking imatinib also decreased. fever in less than half of the time compared with similar patients treated with standard therapy.
“In our trial, 33% of patients treated with standard therapy (but not in addition to imatinib) still had significant parasitic infections after three days,” Low said. “Delayed cure rates are a precursor and marker of drug resistance, which has been a problem with malaria for decades. So this can be very important.”
Imatinib was originally manufactured by Novartis to treat chronic myeloid leukemia and other cancers. It works by blocking specific enzymes involved in cancer growth.
“When we discovered imatinib’s ability to stop the spread of parasites in human blood cultures in petri dishes, we started a human clinical trial where we concluded Imatinib combination with standard treatment (piperaquine plus dihydroartemisinin) is used to treat malaria in many parts of the world,” Low said. “Phase 2 clinical trial described in the article in Journal of Experimental Medicine comparison of standard treatment with imatinib plus standard treatment. We are not testing imatinib alone because it would be unethical to treat patients with a potentially deadly disease with an untested therapy.”
Malaria infects human red blood cells, where it reproduces and eventually activates a red blood cell enzyme, which in turn causes cell rupture and the release of a form of the parasite called merozoite into the bloodstream. . Low and his colleagues hypothesized that by blocking an important red blood cell enzyme, they might be able to stop infection. Data from the drug trial confirm that.
Over the past 50 years, malaria treatments have used drugs that target the parasites themselves, but the microorganism has eventually developed resistance to the drugs, Low said.
“Because we’re targeting an enzyme that belongs to red blood cells, the parasite can’t mutate to develop resistance — it simply can’t mutate the protein in the blood,” says Low. our blood cells. “This is a new method that will hopefully become a therapy that parasites cannot escape from in the future. This will constitute an important contribution to human health.”
Malaria is caused by a single-celled parasite, Plasmodium, which is transmitted by mosquitoes. The World Health Organization estimates that the disease caused 409,000 deaths in 2019 (the most recent year for which data are available). WHO also notes that 67% of those deaths are in children under 5 years of age.
The most dangerous 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 resistance has developed in parts of Southeast Asia, especially in Cambodia, Myanmar, Thailand, Laos and Vietnam. In some parts of the region, up to 80% of malaria parasites are at least partially resistant.
In 2019, Professor Olivo Miotto from Oxford University’s Wellcome Sanger Institute, told the BBC that the rise of the resistant variant in Southeast Asia raised the “scary prospect” of the resistant variant spreading to Africa. A similar event occurred in the 1980s with malaria that was resistant to the then standard treatment, chloroquine, resulting in millions of deaths.
Low and his colleagues tested imatinib in a hotbed of drug-resistant malaria on the border of Vietnam and Laos, in Vietnam’s Quang Tri province.
“It’s such a remote part of the country that most clinics are one- or two-room buildings with only six or seven cots so people can come and get treatment,” Low said. “Not only is the drug 100% effective after three days, but patients also see their fever disappear within the first day, and they feel much better right after.”
Although malaria is not a serious disease in North America, Low is planning to apply for approval from the US Food and Drug Administration.
“The FDA is so widely respected around the world that if they approved it, most other countries, especially developing countries with malaria, would quickly adopt it,” he said. “FDA requirements for Phase 3 approval are very strict. You must demonstrate the effectiveness and safety of the drug combination on a large number of patients and then demonstrate that you can safely manufacture and store it and reproducibly. You also have to start all over again and end up with a product that is more than 99% pure.
International priority patent applications have been filed in Vietnam by Purdue Research Foundation, VinUni University 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 make the drug, and estimates that they can produce the drug for about $1 a pill.
“We will transfer this technology to any company that commits to distributing it to malaria-infected developing areas,” he said. “I am not interested in making a dime out of this. I just think it’s important for humanity to have it.”
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Writers, Media Contact: Steve Tally, steve@purdue.edu, @sciencewriter
Source: Phillip Low, plow@purdue.edu
ABSTRACT
Imatinib enhances standard antimalarial combination therapy without additional toxicity
Huynh Dinh Chien, Ph.D.firstAntonella Pantaleo, Ph.D.2Kristina R. Kesely, Ph.D.3Panae Noomuna, MSc3Karson S. Putt, Ph.D.4Tran Anh Tuan, Ph.D.5Philip S. Low, Ph.D.3-4,*and Francesco M. Turrini, Ph.D.6.
first Faculty of Health Sciences, Vin University, Hanoi, Vietnam
2 Faculty 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 Medical Center, Quang Tri, Vietnam
6 Department of Oncology, University of Turin, Turin, Italy
DOI: 10.1084/jem.20210724
To escape its erythroid host, the malaria parasite, Plasmodium falciparum, must destabilize the erythrocyte membrane by activating erythrocyte tyrosine kinase. Because imatinib inhibits erythrocyte tyrosine kinases and because imatinib has a good safety profile, we decided to determine whether co-administration of imatinib with standard of care (SOC) could be well tolerated and beneficial. effective treatment in malaria patients or not. Uncomplicated patient P. falciparum malaria from an area in Vietnam where one-third of patients with delayed parasite clearance (DPC; continued parasitemia after 3 days of treatment) were treated for 3 days with a regional SOC (40 mg) dihydroartemisinin + 320mg piperaquine/day) or imatinib (400mg/day) + SOC. Participants treated with Imatinib+SOC did not exhibit an increase in the number or severity of adverse events, a significantly rapid decrease in parasite density and fever, and no DPC. Surprisingly, these improvements were most pronounced in patients with the highest parasite densities, where serious complications and death most commonly occurred. Therefore, Imatinib appears to improve SOC therapy without apparent drug-related toxicity.