Chinook Therapeutics, Inc. (NASDAQ: KDNY), a biopharmaceutical
company focused on the discovery, development and commercialization
of precision medicines for kidney diseases, today announced six
poster presentations at the ISN World Congress of Nephrology 2021
(WCN ’21).
“The depth and breadth of our presence at this year’s WCN ’21 is
a testament to Chinook’s role as a leading kidney disease company,”
said Eric Dobmeier, president and chief executive officer of
Chinook. “Our data demonstrating BION-1301’s ability to
significantly reduce Gd-IgA1 levels in healthy volunteers, as well
as the favorable pharmacodynamics of subcutaneous administration of
BION-1301, position the program well to move forward in
demonstrating its disease-modifying potential for IgA nephropathy
patients. In addition, our preclinical poster presentations on
atrasentan provide broader insights into its anti-fibrotic and
anti-inflammatory properties that are additive and complementary to
its proteinuria-lowering mechanism of action.”
WCN21-0706: A Phase 1, Open Label, Randomized, Single
Dose, Parallel Group Safety and Bioavailability Study of BION-1301
Administered by Intravenous (IV) and Subcutaneous (SC)
Routes
BION-1301 is a novel anti-APRIL monoclonal antibody currently in
phase 1 clinical development for IgAN. Blocking APRIL is a
potential disease-modifying approach to treating IgAN by reducing
circulating levels of Gd-IgA1 to prevent the formation of immune
complexes that deposit in the glomeruli of the kidney, causing
damage.
The ongoing phase 1 multi-center trial (see
www.clinicaltrials.gov, identifier NCT03945318) evaluated the
safety and tolerability of BION-1301 in 63 healthy volunteers in
double-blinded, placebo-controlled single-ascending dose (SAD) and
multiple-ascending dose (MAD) settings. Healthy volunteers in the
SAD portion of the study received placebo or a single intravenous
(IV) dose of BION-1301 ranging from 10 mg to 1350 mg on day 1.
Healthy volunteers in the MAD portion of the study received placebo
or IV doses of BION-1301 ranging from 50 mg to 450 mg on days 1, 15
and 29 (three doses total).
As previously presented, BION-1301 was well-tolerated with no
serious adverse events (SAEs), a pharmacokinetic (PK) half-life of
approximately 33 days and demonstrated dose-dependent
pharmacodynamic (PD) effects characterized by durable reductions in
serum levels of IgA and IgM, with a lesser reduction in IgG.
Recently analyzed data from this study in healthy volunteers also
demonstrated that BION-1301 produced dose-dependent reductions in
serum Gd-IgA1 levels that were greater in magnitude than previously
reported for total IgA concentrations. In the MAD cohort, BION-1301
reduced Gd-IgA1 levels by 39%, 51% and 55% on Day 29 following the
first two doses but prior to the third dose of BION-1301 at 50 mg,
150 mg and 450 mg, respectively, compared to a mean 6% increase in
Gd-IgA1 in the placebo group. Upon further follow-up on Day 85,
which was 56 days after the third and final dose of BION-1301,
Gd-IgA1 reductions were sustained, with mean reductions of 24%, 48%
and 70%, at 50 mg, 150 mg and 450 mg, respectively, compared to a
mean 4% increase in Gd-IgA1 in the placebo group. Data figures from
Day 85 were not included in the poster presentation, but can be
found in Chinook’s corporate presentation located on the Events and
Presentations section of Chinook’s website.
Part 3 of the phase 1 study is ongoing to evaluate BION-1301 in
adult IgAN patients in an open-label setting. Preliminary data from
Part 3 will be presented at nephrology conferences in 2021.
With the aim to reduce patient burden with a more convenient
alternative administration route, BION-1301 was further studied in
a single-dose phase 1 study to determine safety and bioavailability
of BION-1301 administered via IV infusion or SC injection in
healthy volunteers. This was a phase 1, open-label, randomized,
parallel group, safety and bioavailability study of 300 mg
BION-1301 administered intravenously or subcutaneously to adult
healthy volunteers in the United States.
Key highlights from the bioavailability study include the
following:
- BION-1301 was well tolerated when administered by both IV and
SC routes in healthy volunteers, and no injection site or
infusion-related reactions were reported.
- The PK profile of BION-1301 was consistent with previous
clinical studies and minimal differences in drug concentration were
observed between administration routes after one week, following
the absorption phase.
- After SC administration, BION-1301 absorption rate was typical
of a monoclonal antibody with bioavailability of approximately
50%.
- Magnitude of pharmacodynamic responses were largely retained
with SC dosing compared to IV dosing:
- SC administration generated approximately 81% of the maximum
free APRIL reduction;
- SC administration generated approximately 75% of the maximum
IgA reduction.
- No anti-drug antibodies (ADAs) were observed in the SC
cohort
Data generated in this study will be used to enable SC
administration of BION-1301 in ongoing and future clinical
studies.
WCN21-0358: Selective ETA Antagonist Atrasentan, Rapidly
Reduces Albuminuria and Downregulates Intra-renal Pro-Inflammatory
and Pro-Fibrotic Transcriptional Networks in the g-ddY Mouse Model
of Spontaneous IgA Nephropathy
The effect of short-term treatment of selective ETA antagonist
atrasentan was investigated in gddY mice, a spontaneous and
accelerated model of IgAN.
Four days of treatment with atrasentan reduced urinary albumin
to creatinine ratio (UACR) from baseline by 28%, 62% and 63% at 10
mg/kg/day, 20 mg/kg/day and 30 mg/kg/day, respectively. This effect
was statistically significant at the two higher doses.
Five days of treatment with atrasentan demonstrated
dose-dependent effects on intra-renal gene expression profiles,
assessed by RNA sequencing analysis of the kidney cortex. Gene set
enrichment analysis (GSEA) to define hallmark pathways was
performed and cross-validated to the transcriptome of kidney biopsy
samples from publicly available IgAN patient datasets. In the
biopsies of patients with IgAN, the gene pathways found to be
dysregulated in the glomeruli included a down-regulation of
oxidative metabolism and up-regulation of gene pathways associated
with proliferation, inflammation and fibrosis. GSEA showed that
treatment with 30 mg/kg of atrasentan in gddY mice consistently
reversed the gene pathways found to be dysregulated in IgAN
patients.
The dynamic transcriptional changes in the kidney, following
only five days of treatment and prior to sustained long-term
reductions in albuminuria and blood pressure that could mediate
this benefit, are consistent with direct anti-inflammatory and
antifibrotic effects of ETA blockade in IgAN. These results support
the therapeutic potential of atrasentan in IgAN to reduce
proteinuria and kidney inflammation and fibrosis, key drivers of
IgAN progression.
WCN21-0398: Human Renal Mesangial Cell Activation
Induced by Endothelin-1 or IgA Nephropathy Patient Immune Derived
Complexes is Blocked by Selective ETA Antagonist
Atrasentan
Human renal mesangial cell (HRMC) activation is considered the
initiating intra-renal event in the pathogenesis of IgAN and occurs
in response to the deposition of pathogenic galactose-deficient IgA
(Gd-IgA)-containing immune complexes. This activation results in
increased cellular proliferation and inflammatory cytokine
secretion. The role of ETA receptor activation in HRMC activation
in response to endothelin-1 (ET-1) and IgAN patient-derived immune
complexes was investigated.
ET-1 resulted in increased HRMC proliferation and IL-6
secretion, which was blocked by atrasentan in a
concentration-dependent manner. RNA sequencing and gene set
enrichment analysis of HRMCs following treatment with ET-1
identified upregulation of cell proliferation, pro-fibrotic and
pro-inflammatory pathways, which were reversed with atrasentan
treatment.
HRMCs cultured with purified IgA-containing immune complexes
isolated from IgAN patient serum, had five-fold higher
proliferation compared to treatment with IgA-complexes from matched
healthy controls. Atrasentan significantly attenuated the
proliferation induced by IgAN patient-derived IgA-containing immune
complexes.
Exogenous ET-1 directly stimulates mesangial cell activation,
inducing proliferative, pro-inflammatory and pro-fibrotic pathways,
which can be blocked by atrasentan. Atrasentan prevented HRMC
hyperproliferation in response to IgAN patient-derived immune
complexes. This suggests that the autocrine action of endogenously
produced ET-1 on ETA receptors contributes to mesangial cell
activation resulting from pathogenic IgA-containing immune
complexes. These results support the therapeutic potential of
atrasentan in patients with IgAN, not only via its well
characterized effect of reducing proteinuria, but also by
potentially reducing mesangial cell activation, a hallmark of IgA
nephropathy.
WCN21-0848: A Phase 3, Randomized, Double-Blind,
Placebo-Controlled Study of Atrasentan in Patients with IgA
Nephropathy (The ALIGN Study)
The ALIGN Study (see www.clinicaltrials.gov, identifier
NCT04573478) is a global, randomized, multicenter, double-blind,
placebo-controlled phase 3 clinical trial comparing the efficacy
and safety of atrasentan versus placebo in patients with IgAN at
risk of progressive loss of kidney function. Approximately 320
patients with biopsy-proven IgAN will be randomized to receive 0.75
mg atrasentan or placebo as a once-daily oral pill for
approximately 2.5 years. Patients will continue receiving an
optimized and stable dose of a RASi as standard of care. The study
will also include patients that are unable to tolerate RASi
therapy.
The primary efficacy endpoint of the ALIGN Study is to evaluate
the effect of atrasentan versus placebo on proteinuria as measured
by urine protein to creatinine ratio (UPCR) from baseline to 24
weeks. Secondary and exploratory objectives include evaluating the
change in kidney function over time as measured by eGFR, safety and
tolerability, as well as quality of life. Chinook expects to report
top-line data from the 24-week primary endpoint efficacy analysis
in 2023.
WCN21-0717: Atrasentan in Patients with Proteinuric
Glomerular Diseases (The AFFINITY Study)
The AFFINITY Study (see www.clinicaltrials.gov, identifier
NCT04573920) is a phase 2, open-label, basket study to evaluate the
efficacy and safety of atrasentan in patients with proteinuric
glomerular disease who are at risk of progressive loss of renal
function. Four initial cohorts will consist of patients with: IgAN
with UPCR of 0.5 to less than 1.0 g/g, focal segmental
glomerulosclerosis (FSGS), Alport syndrome and diabetic kidney
disease (DKD) in combination with an SGLT2 inhibitor. Additional
cohorts may be added to the study over time. Approximately 20
patients will be enrolled in each cohort to receive 0.75 mg
atrasentan for 52 weeks. Patients in all cohorts will continue
receiving an optimized and stable dose of a RAS inhibitor as
standard of care. The AFFINITY Study will enroll patients in the
United States, Australia, South Korea, the United Kingdom, Italy
and Spain.
The primary efficacy endpoint of the AFFINITY Study is the
effect on proteinuria as measured by UPCR in patients with IgAN,
FSGS and Alport syndrome and the change in albuminuria as measured
by urine albumin to creatinine (UACR) in patients with DKD, from
baseline to 12 weeks. Chinook expects to report data from initial
cohorts of patients in the AFFINITY Study during 2022.
WCN21-0612: Discovery of CHK-336: A First-in-Class,
Liver-Targeted, Small Molecule Inhibitor of Lactate Dehydrogenase
for the Treatment of Hyperoxaluria
CHK-336, is a first-in-class, liver-targeted oral small molecule
LDHA inhibitor for the treatment of PH. LDHA catalyzes the final
step in the production of oxalate in the liver, and therefore LDHA
inhibition has the potential to treat all forms of PH – PH1, PH2
and PH3 – as well as other disorders arising from excess oxalate.
As previously presented, CHK-336 demonstrates sub-nM enzyme potency
and a cellular IC50 in hepatocytes across multiple species ranging
from 50 to approximately 300 nM. CHK-336 demonstrates tight LDHA
binding and a very slow enzyme off-rate, to extend the duration of
action and enable the potential of once-daily dosing in humans.
CHK-336 was engineered with a liver-targeted distribution profile
to effectively block hepatic oxalate synthesis while minimizing
systemic exposures.
CHK-336, dosed orally, once-daily, produced significant
reductions in urinary oxalate in a mouse model of PH1, with the
majority of CHK-336-treated mice reaching the normal range seen in
wild-type mice. The non-clinical safety assessment of CHK-336
supports continued development and CHK-336 is currently progressing
through IND-enabling GLP studies with IND submission planned for
late 2021/early 2022.
About Chinook Therapeutics, Inc.Chinook
Therapeutics, Inc. is a clinical-stage biotechnology company
developing precision medicines for kidney diseases. Chinook’s
product candidates are being investigated in rare, severe chronic
kidney disorders with opportunities for well-defined clinical
pathways. Chinook’s lead program is atrasentan, a phase 3
endothelin receptor antagonist for the treatment of IgA nephropathy
and other proteinuric glomerular diseases. BION-1301, an anti-APRIL
monoclonal antibody is being evaluated in a phase 1b trial for IgA
nephropathy. In addition, Chinook is advancing CHK-336, an oral
small molecule LDHA inhibitor for the treatment of primary
hyperoxaluria, as well as research programs for other rare, severe
chronic kidney diseases. Chinook is building its pipeline by
leveraging insights in kidney single cell RNA sequencing,
human-derived organoids and new translational models, to discover
and develop therapeutics with differentiating mechanisms of action
against key kidney disease pathways. To learn more, visit
www.chinooktx.com.
Cautionary Note on Forward-Looking Statements
Certain of the statements made in this press release are forward
looking, including those relating to Chinook’s business, future
operations, advancement of its product candidates and product
pipeline, clinical development of its product candidates, including
expectations regarding timing of initiation and results of clinical
trials. In some cases, you can identify these statements by
forward-looking words such as “may,” “will,” “continue,”
“anticipate,” “intend,” “could,” “project,” “expect” or the
negative or plural of these words or similar expressions.
Forward-looking statements are not guarantees of future performance
and are subject to risks and uncertainties that could cause actual
results and events to differ materially from those anticipated,
including, but not limited to, our ability to develop and
commercialize our product candidates, including initiation of
clinical trials, whether results of early clinical trials or
preclinical studies, such as those described in this press release,
will be indicative of the results of future trials, our ability to
obtain and maintain regulatory approval of our product candidates,
our ability to operate in a competitive industry and compete
successfully against competitors that may be more advanced or have
greater resources than we do, our ability to obtain and adequately
protect intellectual property rights for our product candidates and
the effects of COVID-19 on our clinical programs and business
operations. Many of these risks are described in greater detail in
our filings with the SEC. Any forward-looking statements in this
press release speak only as of the date of this press release.
Chinook assumes no obligation to update forward-looking statements
whether as a result of new information, future events or otherwise,
after the date of this press release.
Contact:Noopur LiffickVice President, Investor
Relations & Corporate Communicationsinvestors@chinooktx.com
media@chinooktx.com
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