As malaria continues to pose a constant and often fatal threat to billions around the world, new treatments are urgently needed to combat the infection. This is made more difficult by the multiple stages of the parasite’s life cycle.
New exhibition at Scientific Advances reports of tafenoquine, a prodrug that could qualify for a mass eradication campaign.
Study: Subcutaneous liver-targeted polymeric prodrugs improve the therapeutic window of tafenoquine for the radical treatment of malaria. Image credit: nechaevkon/Shutterstock.com
The malaria situation
The world saw nearly 250 million malaria infections caused by the malaria parasite Plasmodiumwith over 600,000 deaths as a result in 2021. The biggest malaria-related public health emergency is likely to occur within 20 years, according to African leaders.
While P. falciparum is the deadliest pest, P. vivax causes the most cases because it has the largest habitat. Thus, approximately 3.3 billion people are at risk of P. vivax infection worldwide. They live in the American continents, India, Southeast Asia and the Western Pacific regions.
With habitat expected to expand, the situation will only worsen in the coming decades. P. vivax it goes through a hypnozoite stage, in which the parasite becomes dormant within the liver cells. At this stage, it is immune to standard malaria treatments.
Hypnozoites not only carry the risk of relapses, but are key to continuing the chain of transmission from such individuals even after they have been treated for malaria. The need for new drugs suitable for mass administration and eradication campaigns is obvious.
Only two 8-aminoquinoline (8-AQ) drugs, primaquine and tafenoquine (TQ), are approved for the radical treatment of malaria. This term refers to abstraction P. vivax hypnozoites from all liver cells.
The problem with tafenoquin
Tafenoquin is an oral medication that is taken as a single dose, unlike the 14-day regimen required for primaquine. However, it is not suitable for people with glucose-6-phosphate dehydrogenase (G6PD) deficiency, a common enzyme defect, or for people whose G6PD status is unknown.
This deficiency, which affects about 400 million people worldwide—nearly 17% in some areas—offers some protection against severe malaria, but also complicates treatment with tafenoquin.
In affected individuals, the drug can cause toxic oxidation of red blood cells, leading to severe hemolytic anemia, kidney failure, and possibly death in cases of severe failure. Ironically, the same oxidative metabolites that cause these effects are also what allow tafenoquin to kill malaria parasites.
Given unequal access to G6PD testing, particularly in low-resource areas that also suffer from high malaria prevalence, tafenoquine is inappropriate for many who need it. Additionally, those with the deficiency serve as a reservoir for the parasite, hindering efforts at mass eradication.
To address these challenges, prodrugs have been researched to potentially widen the therapeutic window, even slightly. Previous studies suggest that these modifications may make tafenoquine safe for use in people with G6PD deficiency.
“While the approved dose of 300 mg TQ was dose-limiting in the G6PD-deficient group, a dose of 100 mg did not cause hemotoxicity.” However, a dose of 300 mg of TQ may not be enough to create a radical cure.
A possible solution
Researchers developed a polymeric prodrug to enhance the therapeutic index of tafenoquine (TQ) administered subcutaneously (SC). This modification results in lower peak blood concentrations, reducing the risk of hemolytic anemia.
The prodrug has also been engineered to optimize transport through liver cells, aiming to achieve radical treatment with a single dose while minimizing the production of hemotoxic metabolites in the liver.
The prodrug is designed to remain stable in the bloodstream, but is broken down by cathepsin enzymes within the body. Given the absence of non-8-aminoquinoline (non-8-AQ) options for radical treatments and the practicality of SC administration in mass eradication efforts, this development could represent a significant advance.
In comparative studies, this prodrug was more effective against Plasmodium berghei sporozoites than oral TQ and showed reduced hemolysis in a humanized G6PD-deficient mouse model.
A major obstacle to drug development for radical therapies is the lack of animal models that accurately mimic the effect of anti-hypnozoan drugs on Plasmodium vivax. Currently, the only available primate model uses Plasmodium cynomolgi hypnozoites, and there are significant metabolic and pharmacological differences between human and primate responses to TQ.
Therefore, the study used primary non-human primate hepatocytes with P. cynomolgi hypnozoites to evaluate the prodrug. In addition, the research evaluated cost of goods sold (COGS) and manufacturability to determine the feasibility of producing the prodrug on a mass scale.
What did the study show?
By modifying the blood-stable ligand in the prodrug, the researchers increased the stability of the prodrug fourfold during SC administration.
The modified optimized pSVCTQ prodrug was readily cleaved within liver cells.
Surprisingly, it targeted the liver, with hepatocyte exposure significantly higher than oral TQ. At the same time, it showed selectivity, with a significantly lower peak plasma concentration.
Two major metabolites of TQ were also selectively increased in liver compared to blood compared with oral TQ. Hepatocyte exposure to the prodrug was thus comparable to that following oral administration.
A dose-dependent activity was observed, with complete eradication of parasites at 10 mg/kg, superior to oral TQ. Thus, the underlying mechanism proved to be the higher exposure in the liver.
Accordingly, hemotoxicity was also reduced more than twofold with pSVCTQ, using the industry standard for evaluation, a humanized G6PD-deficient mouse model. The prodrug binds to membrane receptors on the cell surface to enter the cell by endocytosis, with the level of ASGPR receptors varying over time.
COGS could be reduced to 36% by redesigning the prodrug, making the product more attractive in low-resource settings. Its manufacturing ability could be improved.
conclusions
“These results show how the polymer could be engineered and optimized for COGS requirements and health equity, and not just by therapeutic index..”
The prodrug should improve the prospects for mass eradication. In addition, the results could be used to design other treatments for multiple internal organs.
“Together, these results validate the liver-targeted TQ prodrug design platform as an important therapeutic approach to the spectacularly unmet need for radical malaria therapy.”
