Objective: Efficacy of BBP-671 as a potential therapy for pantothenate kinase-associated neurodegeneration (PKAN) was evaluated in a PKAN mouse model. Safety, PK, and PD of BBP-671 were investigated in healthy subjects in a Phase 1 study (NCT04836494).

Background: PKAN is a rare neurodegenerative disease caused by mutations in pantothenate kinase 2 (PANK2). As an activator of human pantothenate kinases (PanKs), BBP-671 is anticipated to compensate for the loss of PanK2 in PKAN.

Method: Pank1,Pank2 neuronal double knock-out (dKO) mice were generated as described [1] and maintained on chow ± BBP-671. Analyses of BBP-671 in plasma and tissue, coenzyme-A (CoA) levels, and movement were performed as described [1]. Body weight gain and survival were assessed.
Five single and four multiple dose cohorts of healthy adults were administered BBP-671 in a double-blind manner, randomized 6:2 (BBP-671 : placebo). Vital signs, ECGs, AEs, and routine safety laboratory tests were utilized to interrogate safety and tolerability. Drug concentrations were measured in plasma and CSF and whole blood (WB) acetyl-CoA was measured to assess PD.

Results: Treatment of dKO mice with BBP-671 significantly increased brain CoA and improved survival, weight gain, and motor defects. Specifically, BBP-671-treated dKO mice spent more time moving and travelled a greater distance than untreated animals.
Single doses of 3 to 120 mg BBP-671, and 7-day courses of 30 mg, 60 mg, 70 mg and 100 mg total daily dosage, were studied in healthy subjects. BBP-671 was readily absorbed after oral dosing with a T_max of 1─2 hours and an elimination half-life of 6─9 hours. Increases in mean BBP-671 exposure were more than dose proportional and there was a 2.5 to 3-fold accumulation at steady state. BBP-671 was detected in human plasma and CSF. Increases in WB acetyl-CoA were observed with BBP-671.

Conclusion: In a PKAN mouse model, BBP-671 improved both survival and movement. In healthy human subjects, BBP-671 was generally well-tolerated and detected in plasma and CSF at concentrations at which efficacy was observed in dKO mice. Increases in WB acetyl-CoA observed with BBP-671 demonstrated target engagement and proof of mechanism. Together, these data support development of BBP-671 as a potential therapy for PKAN.

References: 1. Sharma et. al. 2018. Nat. Commun. 9:4399.

« Back to 2022 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/bbp-671-an-investigational-modulator-of-pantothenate-kinases-demonstrates-proof-of-concept-in-a-pkan-mouse-model-and-target-engagement-in-humans/