Chinook Therapeutics Presents Updated Data from BION-1301 Phase 1/2 Trial in Patients with IgA Nephropathy (IgAN) and CHK-336 Preclinical Efficacy Data at the American Society of Nephrology (ASN) Kidney Week 2022
- The initial response to de novo subcutaneous (SC) BION-1301 treatment in Cohort 2 is highly consistent with Cohort 1 across both mechanistic biomarkers and proteinuria reductions
- BION-1301 is well-tolerated, with no serious adverse events (SAEs) and no treatment discontinuations due to adverse events (AEs) in patients with IgAN across Cohorts 1 and 2
- BION-1301 continues to demonstrate rapid and sustained reductions in mechanistic biomarkers, including IgA and Gd-IgA1 levels, in patients with IgAN across Cohorts 1 and 2
- In Cohort 1, BION-1301 demonstrated mean proteinuria reductions of 30.4% at 12 weeks of treatment, 48.8% at 24 weeks of treatment and 66.9% at 52 weeks of treatment, as well as 67.4% in four patients at 76 weeks of treatment and 71.0% in two patients at 100 weeks of treatment
- In Cohort 2, de novo SC BION-1301 treatment resulted in mean proteinuria reductions of 28.7% in 15 patients at 12 weeks of treatment and 53.8% in nine patients at 24 weeks of treatment
- CHK-336, a potent LDHA inhibitor with liver-targeted tissue distribution, demonstrated preclinical efficacy in PH1 and PH2 mouse models of primary hyperoxaluria (PH), and the potential for benefit in non-genetic hyperoxalurias caused by oxalate overproduction was also described.
Chinookto host investor conference call, webcast and in-person event today at 6:30 pm EDTwith Dr. Sreedhar A. Mandayam, Professor of Nephrology at the University of Texas MD Anderson Cancer Centerand Baylor College of Medicine, and Laura Kooienga, MD, practicing nephrologist and director of research at Colorado Kidney Care
“The strong data we presented today at ASN Kidney Week from the ongoing phase 1/2 study of BION-1301 continue to demonstrate its disease-modifying potential in patients with IgAN,” said
FR-PO659 – Updated Interim Results of a Phase 1/2 Study of BION-1301 in Patients with IgA Nephropathy
BION-1301 is a novel anti-APRIL monoclonal antibody currently in phase 2 clinical development for patients with IgAN. Blocking APRIL is a potentially disease-modifying approach to treating IgAN by reducing circulating levels of galactose-deficient IgA1 (Gd-IgA1).
Updated data from Cohort 1 and initial data from Cohort 2 were presented from Part 3 of the ongoing phase 1/2 multi-center trial (see www.clinicaltrials.gov, identifier NCT03945318) evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical responses of open-label BION-1301 treatment in patients with IgAN.
Key highlights from the presentation include the following:
Patients in Cohort 1 initially received a 450mg intravenous (IV) dose of BION-1301 every two weeks. After at least 24 weeks of IV dosing, patients in Cohort 1 transitioned to a 600 mg SC dose every two weeks for a total treatment duration of up to two years. Cohort 1 enrolled 10 patients, of which eight patients remain on treatment. All eight patients have transitioned from IV to SC administration, with a mean SC treatment duration of 40 weeks.
Patients in Cohort 2 are receiving a SC dose of 600 mg of BION-1301 every two weeks for a total treatment duration of up to two years. Cohort 2 has enrolled 24 of the planned 30 patients. Mean treatment duration was 17 weeks, with time on treatment ranging from two to 30 weeks.
Baseline 24-hour Urine Protein Excretion (g/day)
- The median baseline 24-hour urine protein excretion for patients enrolled in Cohort 1 was 1.2 g/day, with a range of 0.7 – 6.5 g/day, and the median baseline 24-hour urine protein excretion for patients enrolled in Cohort 2 was 1.0 g/day, with a range of 0.6 – 2.7 g/day. Cohorts 1 and 2 both represent a population of patients with IgAN at high risk of kidney disease progression.
Safety and Tolerability
- As of the
October 13, 2022data cutoff, BION-1301 has been well-tolerated, with no serious adverse events or treatment discontinuations due to adverse events. Of all 34 patients enrolled in both Cohorts 1 and 2:
- Eight patients experienced mild (Grade 1 or 2) treatment-related AEs, including three patients with fatigue and three patients with injection site reactions.
- Seventeen patients experienced mild (Grade 1 or 2) infections, of which only one Grade 1 infection was assessed as treatment-related.
- The PK profile demonstrated low inter-individual variability in BION-1301 serum concentrations and consistent trough concentrations following IV and SC administrations.
- To date, no anti-drug antibodies have been observed in patients.
- BION-1301’s effects on mechanistic biomarkers were highly consistent between Cohorts 1 and 2.
- In Cohort 1, reductions in IgA and Gd-IgA1 were maintained beyond 52 weeks of treatment. Reductions in IgM, and to a lesser extent IgG, were also observed (see figures below). Reductions in free APRIL confirm durable target neutralization sustained through one year.
- In Cohort 2, SC BION-1301 treatment resulted in rapid and sustained reductions in IgA and Gd-IgA1, IgM, and to a lesser extent IgG, through 24 weeks of treatment, consistent with Cohort 1 (see figures below).
- In Cohort 1, BION-1301 demonstrated mean reductions in 24-hour urine protein creatinine ratio (UPCR) of 30.4% in seven patients at 12 weeks of treatment, 48.8% in all eight patients at 24 weeks of treatment, 66.9% in all eight patients at 52 weeks of treatment, 67.4% in four patients at 76 weeks of treatment and 71.0% in two patients at 100 weeks of treatment (see figure below).
- Clinically meaningful reductions in UPCR from baseline were seen in patients with IgAN across a wide range of baseline proteinuria levels by Week 12.
- UPCR continued to decline through one year, and reductions were maintained through two years, providing evidence of sustained efficacy.
- Among patients with available data at Week 52, seven of eight patients demonstrated a greater than 50% mean reduction in 24-hour UPCR from baseline at Week 52
- In Cohort 2, BION-1301 demonstrated mean reductions in 24-hour UPCR of 28.7% in 15 patients at 12 weeks of treatment and 53.8% in 9 patients at 24 weeks of treatment, highly consistent with reductions observed at the same timepoints in Cohort 1 (see figure below).
FR-PO334 – Preclinical Efficacy of CHK-336: A First in Class, Liver-Targeted, Small Molecule Inhibitor of Lactate Dehydrogenase for the Treatment of Primary Hyperoxalurias (PH)
CHK-336 is a potent LDHA inhibitor with liver-targeted tissue distribution that is efficacious in PH1 and PH2 mouse models and has potential benefit in non-genetic hyperoxalurias caused by oxalate overproduction.
CHK-336 demonstrates potent inhibition of LDHA in enzyme assays (IC50 = 0.2-0.3 nM) and primary hepatocyte assays across multiple species (IC50 = 52-165 nM). CHK-336 also demonstrates tight LDHA binding with a very slow off-rate (hours to days). CHK-336 exhibits a liver-targeted tissue distribution profile in mice, rats and monkey with high liver concentrations and low extra-hepatic tissue exposures.
Since LDHA catalyzes the final step of oxalate production from glycolate, in vivo conversion of a 13C2-glycolate stable isotope tracer to 13C2-oxalate was dose-dependently blocked by CHK-336, demonstrating target engagement. Human PK predictions suggest CHK-336 has the potential to be a low, once-daily oral dose therapeutic in humans.
CHK-336 was dosed orally, once-daily for seven days in male Agxt KO mice, a PH1 mouse model, and urinary oxalate concentrations were compared to a vehicle control group. Low, oral, once-daily doses of CHK-336 significantly and dose-dependently reduced urinary oxalate; the majority of treated mice reached the normal range observed in wild-type mice. CHK-336 also had a more rapid onset of action and comparable magnitude of urinary oxalate reduction compared to a GO-targeting siRNA.
CHK-336 was dosed orally, once-daily for seven days at 25 mg/kg in male Grhpr KO mice, a PH2 mouse model, and significantly reduced urinary oxalate concentrations compared to the vehicle control group.
Increased urinary oxalate and altered hepatic expression of genes involved in oxalate synthesis were observed in obese, hypertensive and diabetic rats compared to controls. This supports the potential therapeutic benefit of CHK-336 in non-genetic oxalate nephropathies associated with increased endogenous production of oxalate.
The human safety and PK profiles of CHK-336 are currently under investigation in a phase 1 healthy volunteer SAD/MAD study (see www.clinicaltrials.gov, identifier NCT05367661) and data is expected to be presented in the first half of 2023. Administration of the 13C2-glycolate stable isotope tracer has been incorporated into the phase 1 study to assess LDHA target engagement in humans.
FR-OR60 – A Multi-Omics Approach to IgA Nephropathy Characterization in the NURTuRE Cohort Enables Precision-Based Treatment Approaches
An overview of the multi-omics analysis of the NURTuRE IgAN patient cohort will be delivered today as an oral presentation during the Glomerular Diseases: From Bench to Bedside session at 4:30 –
SA-PO1011 – Unsupervised Characterization of the NURTuRE Cohort Reveals Gene Expression and Tissue Remodeling Dynamics along a Synthetic CKD Progression Axis
An overview of the unsupervised characterization of the QUOD and NURTuRE patient cohorts will be delivered in collaboration with Evotec tomorrow (
Once published by ASN, all four presentations can be found in the
Live Conference Call and Webcast
Conference Call and Webcast Details
To access the call, please dial (800) 715-9871 (domestic) or (646) 307-1963 (international) and provide the Conference ID 7505851 to the operator.
To access the live webcast and subsequent archived recording of this and other company presentations, please visit the Investors section of Chinook’s website. The archived webcast will remain available for replay on Chinook’s website for 90 days.
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BION-1301 Treatment Results in Rapid and Durable Reductions in IgA and Gd-IgA1 in Patients with IgA Nephropathy
Following both IV and SC dosing, BION-1301 produced rapid and sustained reductions in IgA and Gd-IgA1, the pathogenic variant of IgA nephropathy
BION-1301 Treatment Results in Clinically Meaningful Proteinuria Reductions in Patients with IgAN
Mean reduction in UPCR of 53.8 % at 24 weeks in Cohort 2 with de novo SC administration of BION-1301 are consistent with those observed in Cohort 1
Source: Chinook Therapeutics, Inc.