ESPN 54th Annual Meeting

ESPN 2022


 
A Randomized, Placebo -Controlled, Phase 2/3 study of glycolate oxidase (GO) inhibitor BBP-711 in Children and Adults with Primary Hyperoxaluria Type 1
SCOTT ADLER 1 JIA MA 1 RAMEI SANI-GROSSO 1 LILLIAN LEE 1 GUSTAVO LORENTE 1 JUSTIN LAFOUNTAINE 1 JONATHAN FOX 1

1- CANTERO THERAPEUTICS, A BRIDGEBIO COMPANY
 
Introduction:

Primary hyperoxaluria (PH) is a group of rare, autosomal recessive, inborn errors of metabolism resulting in excessive production of oxalate that can lead to nephrolithiasis, nephrocalcinosis, renal failure, and systemic oxalosis. PH Type 1 (PH1) is the most common and severe of the subtypes and is caused by a deficiency in the liver-specific peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT) due to mutations in the AGXT gene. Deficiency in AGT impairs the transamination of glyoxylate to glycine in hepatic peroxisomes and the accumulated glyoxylate is subsequently metabolized into oxalate. In the metabolic step preceding the transamination of glyoxylate, glycolate oxidase (GO) catalyzes the conversion of glycolate to glyoxylate.

Material and methods:

GO has been shown to be a safe and efficient target for substrate reduction therapy in PH1. BBP-711 is an oral, small molecule inhibitor of GO. Inhibition of GO is expected to reduce hepatic oxalate production in PH1, reducing hyperoxaluria and its sequelae.

Results:

In healthy adult volunteers, BBP-711 had a PK profile to support once daily dosing, and an acceptable safety profile.  BBP-711 is a potent inhibitor of GO, resulting in plasma glycolate concentrations comparable to case reports of individuals with germline HAO1 deletions, suggesting near complete GO inhibition.

Conclusions:

This global, seamless Phase 2/3 study will evaluate the safety and efficacy of BBP-711 in children and adults with PH1. The study will consist of two parts. Part A will include a dose-finding period to identify a well-tolerated therapeutic dose for Part B. Part B will be a randomized, placebo-controlled, trial in patients with PH1 not requiring renal replacement therapy. The primary endpoint will be a change from baseline in 24hr urinary oxalate (UOx) excretion corrected for body surface area (BSA). Key secondary endpoints include absolute change from baseline in 24hr UOx excretion corrected for BSA and percentage of participants with 24hr UOx below ULN.