At the 2023 ERA Congress, Chinook Therapeutics revealed Phase I data for its first-in-class oral small molecule LDHA inhibitor.
Phase I study data of a first-in-class oral small molecule lactate dehydrogenase A (LDHA) inhibitor demonstrated successful use of a novel 13C2-glycolate tracer.
Data successfully demonstrates hepatic LDH target engagement in healthy volunteers and establishes proof-of-mechanism for CHK-336 to decrease hepatic oxalate production”
The data presented at the 2023 European Renal Association (ERA) Congress “successfully demonstrates hepatic LDH target engagement in healthy volunteers and establishes proof-of-mechanism for CHK-336 to decrease hepatic oxalate production,” commented Andrew King, Chief Scientific Officer of Chinook Therapeutics.
CHK-336 is an LDHA inhibitor with liver-targeted tissue distribution in development for patients with primary hyperoxaluria (PH) and other kidney stone disorders driven by endogenous overproduction of oxalate.
CHK-336 Phase I study
There were 104 healthy volunteers in the single-ascending dose (SAD) and multiple-ascending dose (MAD) trial. Healthy volunteers in the SAD portion of the clinical study received placebo or a single dose of CHK-336 ranging from 15mg to 500mg on day one.
Participants in the MAD portion of the study received placebo or multiple doses of the oral small molecule CHK-336, ranging from 30mg to 500mg given daily for 14 days.
Key highlights from the presentation include:
- CHK-336 was generally well tolerated in HVs who received single doses up to 500mg and multiple doses (14 days) up to 60mg.
- There were no dose-related trends in adverse events, vital signs or EKG findings.
Pharmacokinetics (PK) was well characterised with dose proportional exposures, a plasma half-life consistent with once daily oral dosing and no exposure accumulation following repeat dosing.
How did the oral small molecule work?
CHK-336 effectively blocked conversion of a novel 13C2-glycolate tracer to 13C2-oxalate with maximal inhibition observed following a single dose of CHK-336 at 60-125mg.
However, due to a single serious adverse event (SAE) observed in the 125mg MAD cohort, at present, while the next steps are decided, “the CHK-336 program will remain paused,” according to King.
Accumulation of maladaptive tubular epithelial cells (TECs) ubiquitous in chronic kidney diseases
The company stated that disease-associated maladaptive TECs have been described in rodent models and are characterised by a failed repair phenotype that contributes to tubulointerstitial inflammation and fibrosis. This study explores the significance of maladaptive TECs in the NURTuRE chronic kidney disease (CKD) cohort to gain insights into mechanisms of CKD progression.
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