Malaria continues to pose a significant threat to billions worldwide, with new therapies urgently needed to combat the infection and its various life stages. A promising new study published in Scientific Advances reports on the development of tafenoquine, a prodrug that could fulfill the criteria for a mass eradication campaign.
In 2021 alone, malaria caused nearly 250 million infections and over 600,000 deaths. According to African leaders, the world faces the potential for a major malaria-related public health emergency within the next two decades. While Plasmodium falciparum is the most lethal malaria parasite, Plasmodium vivax causes the majority of cases due to its wider distribution. Approximately 3,300 million people are at risk of P. vivax infection worldwide, with the parasite’s habitat spanning the Americas, India, Southeast Asia, and the Western Pacific regions. As this habitat is expected to expand, the situation is likely to worsen in the coming decades.
P. vivax’s dormant hypnozoite stage within liver cells poses a major challenge to malaria treatment, as it remains invulnerable to standard therapies. These hypnozoites not only carry the risk of relapse but also contribute to the ongoing transmission of the parasite, even after individuals have received treatment for active malaria. The need for new drugs suitable for mass administration and eradication campaigns is therefore evident.
Currently, only two 8-aminoquinoline (8-AQ) drugs, primaquine, and tafenoquine (TQ), have been approved for radical malaria cures, eliminating P. vivax hypnozoites from the liver. Tafenoquine offers the advantage of a single-dose oral administration, unlike primaquine’s 14-day regimen. However, its use is restricted in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, a common enzyme defect, or those with unknown G6PD status.
G6PD deficiency affects approximately 400 million people globally, providing some protection against severe malaria but also complicating treatment with tafenoquine. In affected individuals, the drug can induce toxic oxidation in red blood cells, leading to severe hemolytic anemia, renal failure, and potentially death in cases of severe deficiency. Ironically, the same oxidizing metabolites responsible for these effects are also what enable tafenoquine to kill malaria parasites.
Given the uneven access to G6PD testing, particularly in low-resource areas where malaria prevalence is high, tafenoquine remains unsuitable for many who need it. Additionally, individuals with G6PD deficiency serve as a reservoir for the parasite, hindering mass eradication efforts.
To address these challenges, research into prodrugs has been conducted to potentially broaden the therapeutic margin, even slightly. Prior studies suggest that these modifications may make tafenoquine safe for use in individuals with G6PD deficiency. However, a 300 mg TQ dose may not be sufficient to produce a radical cure.
Researchers have developed a polymeric prodrug to enhance the therapeutic index of tafenoquine (TQ) administered subcutaneously (SC). This modification results in lower peak blood concentrations, reducing hemolytic anemia risk. The prodrug is also engineered to optimize transport through liver cells, aiming to achieve a radical cure with a single dose while minimizing the production of hemotoxic metabolites in the liver. The prodrug remains stable in the bloodstream but is broken down by cathepsin enzymes within the body.
In comparative studies, this prodrug proved more effective against Plasmodium berghei sporozoites than oral TQ and exhibited reduced hemolysis in a humanized mouse model of G6PD deficiency. To evaluate the prodrug’s efficacy in the absence of non-8-aminoquinoline (non-8-AQ) options for radical cures, primary nonhuman primate hepatocytes with P. cynomolgi hypnozoites were utilized.
The researchers also assessed the cost of goods sold (COGS) and manufacturability to determine the feasibility of producing the prodrug on a mass scale. By modifying the blood-stable linker in the prodrug, researchers increased its stability fourfold on SC administration. The optimized pSVCTQ prodrug was easily cleaved within liver cells and selectively targeted the liver, resulting in significantly higher hepatocyte exposure compared to oral TQ. Simultaneously, it exhibited lower maximum concentrations in the plasma.
Two important TQ metabolites were also selectively increased in the liver compared to the blood compared to oral TQ. The exposure of liver cells to the prodrug was comparable to that following oral administration. A dose-dependent activity was observed, with complete elimination of parasites at 10 mg/kg, superior to oral TQ. This enhanced efficacy was attributed to the higher liver exposure.
Correspondingly, hemotoxicity was also reduced more than twofold with pSVCTQ, using the industry standard for evaluation, a humanized mouse model with G6PD deficiency. The prodrug binds to membrane receptors on the cell surface to enter the cell by endocytosis, along with the level of ASGPR receptors that vary over time.
The COGS could be reduced to 36% by the prodrug redesign, making the product more attractive to low-resource settings. Its manufacturability could also be improved. These results demonstrate the potential of polymer engineering to optimize COGS requirements and health equity, beyond solely considering the therapeutic index.
This liver-targeted TQ prodrug design platform represents a significant therapeutic approach to address the unmet need for radical cure malaria therapeutics. The findings hold promise for mass eradication campaigns and could also inform the design of therapies targeting multiple internal organs.
