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. We posit 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. We have shown that R-(-) NPC1161B has a more favorable therapeutic index and less hemotoxicity vs. its opposite enantiomer. We propose 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. 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. We will plan studies that 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, we would plan for careful evaluation of the risk in mildly G6PDd subjects. In the process we 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 Should NPC1161B's hematological safety profile warrant, the plan is that this IND would be withdrawn, and a full commercial development IND would be filed. 1
The application proposes the planning of a clinical trial to explore the hematological effects and mechanisms involved for a new 8-aminoquinoline (8-AQ) anti-infective (NPC1161B), with activity against malaria, pneumocystis and leishmaniasis. This is important because this class of drugs has uniquely useful activity profiles, but also shows serious toxicity in individuals with a deficiency of glucose-6-phosphate dehydrogenase, a very widespread genetic disorder. Thus, if successful, this planning grant would allow studies in humans to provide confirmation of the safety advantage of this drug, and open the way to safely use this highly important 8-AQ drug class in malaria and other infectious diseases world-wide.
