PROJECT SUMMARY
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would be withdrawn, and a full commercial development IND would be filed.
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