Chinook Therapeutics Presents Data from CHK-336 Phase 1 Trial in Healthy Volunteers and New Insights into the Role of Failed Repair in Chronic Kidney Disease at the 60th European Renal Association (ERA) Congress
- CHK-336 was generally well tolerated in healthy volunteers (HV) who received single doses up to 500 mg and multiple doses up to 60 mg for 14 days
- Pharmacokinetics (PK) was well characterized with dose-proportional exposures and a half-life that supports once-daily dosing
- Successful implementation of a novel 13C2-glycolate tracer established proof-of-mechanism of CHK-336 to block hepatic oxalate production in HVs
- One serious adverse event (SAE) of anaphylaxis occurred in a multiple ascending dose HV who received one 125 mg dose CHK-336, resulting in voluntary study pause
- Additional research presented on the impact of maladaptive tubular epithelial cells on progression of chronic kidney disease
“The data presented from the phase 1 study of CHK-336 at this year’s
CHK-336, A First-in-Class Orally Administered LDH Inhibitor: Safety, PK and Target Engagement in a First-in-Human Phase 1 Healthy Volunteer Study
CHK-336 is an oral small molecule LDHA inhibitor with liver-targeted tissue distribution in development for the treatment of patients with primary hyperoxaluria (PH) and other kidney stone disorders driven by endogenous overproduction of oxalate.
The phase 1 single-center trial (see www.clinicaltrials.gov, identifier NCT05367661) was designed to evaluate the safety, tolerability, pharmacokinetic profile of CHK-336 in 104 healthy volunteers in randomized, placebo-controlled, double-blinded, single-ascending dose (SAD) and multiple-ascending dose (MAD) settings. Healthy volunteers in the SAD portion of the study received placebo or a single dose of CHK-336 ranging from 15 mg to 500 mg on day 1. Healthy volunteers in the MAD portion of the study were to receive placebo or multiple doses of CHK-336 ranging from 30 mg to 500 mg given daily for 14 days.
Key highlights from the presentation include the following:
- CHK-336 was generally well tolerated in HVs who received single doses up to 500 mg and multiple doses (14 days) up to 60 mg.
- There were no dose-related trends in adverse events, vital signs or EKG findings.
- The most common treatment emergent adverse event was headache in six subjects receiving CHK-336 (8.8%) and no placebo subjects, with no dose-related trend.
- There was one serious adverse event (SAE) of anaphylaxis that occurred in a single HV following the first dose in the 125 mg MAD group. The SAE had a rapid onset within one hour following the first dose and rapidly resolved after treatment with an antihistamine, without requiring epinephrine administration. The HV had clinically significant elevations in serum tryptase levels during the event, confirming anaphylaxis. This SAE resulted in voluntary pausing of the trial to enable further investigation.
- PK was well characterized with dose proportional exposures, a plasma half-life consistent with once daily oral dosing and no exposure accumulation following repeat dosing.
- The successful utilization of a novel 13C2-glycolate tracer in the trial establishes proof-of-mechanism for CHK-336 as an orally administered small molecule inhibitor of hepatic LDH. CHK-336 effectively blocked conversion of the 13C2-glycolate tracer to 13C2-oxalate with maximal inhibition observed following a single dose of CHK-336 at 60-125 mg.
Accumulation of Maladaptive Tubular Epithelial Cells (TECs) is Ubiquitous in Chronic Kidney Diseases and Represents a Common Initiating Mechanism of Disease Progression
Disease-associated maladaptive TECs have been described in rodent models and are characterized 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 by integrating clinical, histological, transcriptomic and proteomic data from blood and urine to gain insights into mechanisms of CKD progression. The NURTuRE consortium biobank comprises patient samples from a broad range of CKD diagnoses and kidney functional states with rich clinical data from over 3,500 subjects.
Human gene signatures for two maladaptive tubule subtypes were identified in human CKD scRNA-Seq datasets. Based on unbiased analysis, maladaptive tubule signatures were found to be among the most highly associated with CKD progression in the NURTuRE cohort and a high maladaptive tubule gene signature score at time of biopsy was significantly associated with shorter renal event-free survival in the NURTuRE cohort (304 patients across 12 disease etiologies). The emergence of maladaptive tubules is associated with disease progression across multiple CKDs and targeting these cells may potentially be an effective strategy to preserve kidney function broadly in CKD.
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