First-in-class oral small molecule trial data presented at 2023 ERA Congress

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.

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.

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