UPDATE: Therapeutic Treatment of Malaria Proven 100% Effective in Phase 2 Trial

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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 approved a vaccine, Mosquirix, manufactured by British pharmaceutical company GlaxoSmithKline, which prevents malaria and, according to the New York Times, “could save the lives of tens of thousands of children in Africa. every year “.

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

The trial of the therapeutic drug shows that adding the drug Imatinib to the usual antimalarial treatment allows the elimination of all malaria parasites from 90% of patients within 48 hours and 100% of patients within three days, explains Philip Low (rhymes with “now”), the Purdue University Presidential Fellow in Drug Discovery and Distinguished Ralph C. Corley Professor of Chemistry at the College of Sciences, who co-led the international research team. Imatinib also got relief from their fevers in less than half the time experienced by similar patients treated with standard therapy.

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

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 the spread of the parasite in human blood cultures in petri dishes, we initiated a human clinical trial in which we combined Imatinib with the standard treatment ( piperaquine plus dihydroartemisinin) used to treat malaria in much of the world, ”says low. “The phase 2 clinical trial which is described in the article in Journal of Experimental Medicine compares standard therapy with Imatinib plus standard therapy. We have not tested Imatinib alone as it would have been unethical to treat patients with life-threatening disease with untested therapy. “

Malaria infects human red blood cells, where it reproduces and eventually activates an enzyme in red blood cells which in turn triggers the cell to break down and release a form of the parasite called merozoite into the bloodstream. Low and his colleagues hypothesized that by blocking the critical enzyme in red blood cells, they could stop the infection. Data from the drug’s trial confirm this.

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

“Because we are targeting an enzyme that belongs to the red blood cell, the parasite cannot mutate to develop resistance – it just cannot mutate the proteins in our blood cells,” Low said. “This is a new approach that will hopefully become a therapy that the parasite cannot escape in the future. This would constitute an important contribution to human health.

Malaria is caused by a single-celled 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). WHO also notes that 67% of these deaths concerned 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 develops drug resistance has established itself in one corner of Asia. Southeast, especially Cambodia, Myanmar, Thailand, Laos and Vietnam. In some parts of the area, up to 80% of malaria parasites are at least partially resistant to the drugs.

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

Low and his colleagues tested Imatinib in a hot area of ​​drug-resistant malaria on the Vietnam-Laos border in Vietnam’s Quang Tri province.

“It’s such a remote area of ​​the country that most of the clinics are one or two room block buildings with only six or seven beds where people can go in and get treatment,” Low said. “Not only was the drug 100% effective after three days, the patients saw their fever go away on day one, and they felt much better sooner. “

Although malaria is not a major disease in North America, Low is considering seeking approval from the United States Food and Drug Administration.

“The FDA is so widely respected around the world that if it approves it, almost every other country, especially developing countries that suffer from malaria, will adopt it quickly,” he said. “The FDA requirements for Phase 3 approval are very stringent. You must demonstrate the efficacy and safety of the drug combination to a large patient population, and then show that you can manufacture and store it in a safe and reproducible manner. We must also start from zero and end up with a product that is more than 99% pure.

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

Low said he is in talks with drug makers in India and Vietnam to produce the drug and estimates that they can produce the drug for around $ 1 per pill.

“We will hand over the technology to any company committed to distributing it to developing areas infested with malaria,” he said. “I’m not interested in making a dime with this. I just think it’s important for mankind to have it.

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Editor, Media Contact: Steve Tally, [email protected], @sciencewriter

Source: Phillip Low, [email protected]


ABSTRACT

Imatinib improves standard combination therapy with antimalarial drugs without additional toxicity

Huynh Dinh Chien, Ph.D.1, Antonella Pantaleo, Ph.D.2, Kristina R. Kesely, Ph.D.3, Panae Noomuna, M.Sc.3, 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 Sciences, Wine 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 get out of its erythrocyte host, the malaria parasite, Plasmodium falciparum, must destabilize the erythrocyte membrane by activating an erythrocyte tyrosine kinase. Since imatinib inhibits erythrocyte tyrosine kinases and imatinib has a good safety profile, we chose to determine whether co-administration of imatinib with standard care (SOC) could be both well tolerated and therapeutically effective in patients with malaria. Patients without complications P. falciparum malaria in a region of Vietnam where 1/3 of patients have delayed parasite clearance (DPC; parasitaemia continues after 3 days of treatment) were treated for 3 days with SOC of the region (40 mg of dihydroartemisinin + 320 mg of piperaquine / day) or imatinib (400 mg / day) + SOC. Participants treated with imatinib + SOC showed no increase in the number or severity of adverse events, a significantly accelerated decrease in parasite density and pyrexia, and no CPP. Surprisingly, these improvements were most pronounced in patients with the highest parasite density, where severe complications and death are most common. Imatinib therefore appears to improve SOC therapy without any obvious drug-related toxicity.


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