Last Updated: 24/02/2025
Mechanistic assessment of hemolytic risk mitigation for a novel 8-aminoquinoline
Objectives
The research focuses on NPC1161B, a novel 8-aminoquinoline antiparasitic agent, which is being developed for treating vivax malaria, Pneumocystis pneumonia, and visceral leishmaniasis. The proposal sets to utilize the planning grant period to establish a research team and clinical sites, and develop an IND application with requisite supporting documents and protocols to bring NPC1161B into a `Phase 0′ clinical evaluation.
NPC1161B is an 8-aminoquinoline (8-AQ) antiparasitic agent in late preclinical development for three potential indications: radical cure of malaria due to Plasmodium vivax, Pneumocystis pneumonia, and visceral leishmaniasis. Primaquine (PQ), the prototype 8-AQ, and tafenoquine (TQ), under clinical development, are racemic mixtures of approximately equal proportions of the R-(-) and S-(+) forms. NPC1161B has a crucial differentiating feature: it is a single R-(-) enantiomer 8-AQ drug that exhibits different pharmacological and toxicological profiles than its opposite S-(+) enantiomer. This study posits that R-(-) NPC1161B confers a safety advantage within therapeutic dose ranges, compared with racemic 8-AQ drugs. In addition, because the 8-AQ drug class is associated with methemoglobinemia and hemolytic anemia in glucose-6-phosphate dehydrogenase (G6PD) deficient subjects, novel strategies are needed that mitigate 8- AQ-induced hemotoxicity and obviate the need for pre-treatment genetic testing for G6PD deficiency. It has been shown that R-(-) NPC1161B has a more favorable therapeutic index and less hemotoxicity vs. its opposite enantiomer. The hypotheses underlying the study to be planned are: (1) NPC1161B is well-tolerated with minimal liability in human subjects with glucose-6-phosphate dehydrogenase (G6PD) deficiency, in contrast to human experience with approved 8-AQ drugs contraindicated for use in G6PDd; and (2) NPC1161B-induced methemoglobin and other hematological responses will be correlated with the presence of specific drug metabolites in red blood cells. Studies are planned which evaluate, starting at low doses of the drug, hematological target effects, and correlate to pharmacokinetics and erythrocyte exposure to putative active metabolites. Assuming safety and tolerability are suitable in G6PD normal volunteers, the plan is for careful evaluation of the risk in mildly G6PDd subjects. In the process this project would develop relevant pharmacokinetic data on NPC1161B, including its metabolites, and their distribution in plasma and red cells, as well as ascertain their relation to relevant hematological endpoints. Should NPC1161B’s hematological safety profile warrant, the plan is that this IND would be withdrawn, and a full commercial development IND would be filed.
Jun 2020 — May 2021
$229,374
