CHK-336 is a first-in-class, liver-targeted, oral small molecule LDHA inhibitor being developed for the treatment of hyperoxalurias
CHK-336 is a novel, potent and selective small molecule lactate dehydrogenase A (LDHA) inhibitor with the potential for once-daily oral dosing. CHK-336 has an engineered liver-targeted tissue distribution profile, which targets its activity to the primary site of oxalate production and minimizes extra-hepatic LDH inhibition. Preclinical studies have demonstrated that CHK-336 produced significant and dose-dependent reductions in urinary oxalate in a primary hyperoxaluria type 1 (PH1) mouse model into the range observed in wild-type mice. Initial toxicity studies indicate wide safety margins, and CHK-336 is currently progressing through IND-enabling studies, with initiation of a Phase 1 clinical trial planned in 2H 2021.
Hyperoxalurias, including Primary Hyperoxaluria
Hyperoxalurias, including primary hyperoxaluria (PH), are diseases caused by excess oxalate, a potentially toxic metabolite. Oxalate is typically filtered through the kidneys and excreted as a waste product in urine. However, in patients with hyperoxalurias, excess oxalate combines with calcium to form calcium oxalate crystals that deposit in the kidney, resulting in the formation of painful kidney stones and driving progressive kidney damage over time. Primary hyperoxalurias (PH) 1-3 are ultra-rare diseases caused by genetic mutations which result in hepatic overproduction of oxalate. Symptoms of PH can include recurrent kidney stones, severe pain, blood in the urine and urinary tract infections, which when left untreated, can result in kidney failure requiring dialysis or dual kidney/liver transplantation.
Lactate Dehydrogenase A
Lactate dehydrogenase A (LDHA) catalyzes the terminal and committed step in hepatic oxalate synthesis from glycolate and is downstream from the genetic mutations causing PH, 1-3. Therefore, liver-targeted LDHA inhibition has the potential to treat all three forms of PH as well as other forms of hyperoxaluria resulting from endogenous oxalate overproduction.