SAN DIEGO, June 25, 2021 /PRNewswire/ -- Regulus
Therapeutics Inc. (Nasdaq: RGLS), a biopharmaceutical company
focused on the discovery and development of innovative medicines
targeting microRNAs (the "Company" or "Regulus"), today announced
the presentation of additional data from the first cohort of
patients in the Company's Phase 1b
clinical trial of RGLS4326 for the treatment of autosomal dominant
polycystic kidney disease (ADPKD), as well as new preclinical data
from relevant animal models of the disease. The E-poster
presentation, titled "Preclinical Evaluation and Results from the
First Cohort of Phase 1b Clinical
Trial of RGLS4326 for the Treatment of Patients with Autosomal
Dominant Polycystic Kidney Disease (ADPKD)," is available to
attendees of the PKD Connect Conference 2021, on Friday, June 25, from 2-3
p.m. CDT.
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The poster presents results from the Company's ongoing Phase
1b study evaluating the safety,
pharmacokinetics, and effects on pharmacodynamic biomarkers of
multiple doses of RGLS4326 in patients with ADPKD. The data
demonstrate clinical proof of mechanism by showing target
engagement in the kidneys through a statistically significant
increase in urinary biomarkers PC1 and PC2, validating miR-17 as a
target for ADPKD treatment. Levels of PC1 and PC2 have previously
been shown to be inversely correlated with disease severity.
RGLS4326 was well-tolerated with no serious adverse events. The
poster also describes new data from relevant preclinical models
showing treatment with RGLS4326 results in increased gene and
polycystin levels in vitro. In addition, improvements
in key disease markers including serum creatinine and BUN were
demonstrated in the Pkd1(F/RC) mouse model that harbors
Pkd1 mutation equivalent to human ADPKD.
"These exciting results lend further support to the therapeutic
potential of RGLS4326 in ADPKD and also bring us a step closer to
our mission to improve the lives of patients suffering from this
disease," commented Jay Hagan,
President and Chief Executive Officer of Regulus. "The data from
the first cohort of patients in this clinical study suggest that
further increases in polycystin levels may be achievable with
longer term and, potentially, less frequent, dosing and reinforce
our belief that RGLS4326 represents an innovative approach to the
treatment of underlying genetic drivers of ADPKD."
Clinical study details:
RGLS4326 is currently being evaluated in a Phase 1b, multicenter, open-label, adaptive design
dose-ranging study to evaluate its safety, tolerability,
pharmacokinetics and pharmacodynamics in patients with ADPKD. In
the first cohort of the Phase 1b
study, nine patients were enrolled and received 4 doses of 1 mg/kg
of RGLS4326 administered every other week.
Clinical study results:
- The data demonstrate clinical proof of mechanism by showing
target engagement in the kidneys through statistically significant
increases in urinary biomarkers, PC1 and PC2, at study completion
compared to baseline.
- In addition, one patient with pre-study levels uNGAL almost
twice the upper limit of normal saw their uNGAL levels drop into
the normal range during the course of the study.
- Administration of RGLS4326 was well-tolerated with no serious
adverse events.
The study is continuing to enroll patients with ADPKD in
additional cohorts to evaluate different doses of RGLS4326. The
second cohort of patients are receiving a dose of 0.3mg/kg
administered every other week and is nearing completion of
enrollment.
Preclinical study details:
Pkd1(RC/-) cells were treated with either vehicle,
control or RGL4326 for 2 days prior to measuring changes in
Pkd1 and Pkd2 genes, and for 3 days prior to
measuring changes in PC1 and PC2 proteins. In addition,
Pkd1(F/RC) mice were dosed with either a control or RGLS4326
for four doses prior to assessment of efficacy.
Preclinical study results:
- RGLS4326 treatment led to increased Pkd1 and Pkd2
gene expression (>100% increase) and increased levels of their
encoded proteins PC1 and PC2 (~50% increase) in Pkd1(RC/-)
cells in vitro.
- RGLS4326 treatment demonstrated improvement in key efficacy
parameters including kidney-weight-to-body-weight ratio (~75%
decrease), serum creatinine (~50% decrease) and BUN (~60% decrease)
in Pkd1(F/RC) mice compared to control.
About RGLS4326 Phase 1b
The Phase 1b is an adaptive
design, open-label, multiple dose study in up to three cohorts of
patients with ADPKD. The study is designed to evaluate the
safety, pharmacokinetics, and changes in levels of PC1 and PC2 in
patients with ADPKD administered RGLS4326 every other week for a
total of four doses. To characterize the effect of RGLS4326
within each cohort, biomarker values at the end of study are
compared to baseline values using a two-sided paired t-test.
P-values less than 0.05 are considered statistically significant
with no adjustment for multiplicity. The dose level for the first
cohort is 1mg/kg of RGLS4326 and the dose level for the second
cohort is 0.3mg/kg. The third and final cohort will be dosed
at a level to be determined based on the results of the first two
cohorts.
For more information about the clinical trial design, please
visit www.clinicaltrials.gov (NCT04536688).
About RGLS4326
RGLS4326 is a novel oligonucleotide designed to inhibit miR-17
and designed to preferentially target the kidney. Preclinical
studies with RGLS4326 have demonstrated direct regulation of
Pkd1 and Pkd2, reduction of cyst growth in human
in vitro ADPKD models, and attenuation of cyst proliferation
and improvement of kidney function in mouse models of
ADPKD. The RGLS4326 IND is currently on a partial clinical
hold for treatment of extended duration by FDA until the
second set of requirements outlined by the agency have been
satisfactorily addressed. The Company will use information from the
Phase 1 clinical studies, including the first cohort of the Phase
1b study together with information
from the recently completed additional nonclinical studies
generated in 2020, in its plan to address the second set of
requirements outlined in the partial clinical hold letter to
support studies of extended duration. Regulus plans to discuss its
approach to addressing the remaining partial clinical hold
requirements with FDA in mid-2021. RGLS4326 has received
orphan drug designation from FDA in July
2020.
About ADPKD
ADPKD, caused by the mutations in the PKD1 or PKD2
genes, is among the most common human monogenic disorders and a
leading cause of end-stage renal disease. The disease is
characterized by the development of multiple fluid filled cysts
primarily in the kidneys, and to a lesser extent in the liver and
other organs. Excessive kidney cyst cell proliferation, a central
pathological feature, ultimately leads to end-stage renal disease
in approximately 50% of ADPKD patients by age 60.
About Regulus
Regulus Therapeutics Inc. (Nasdaq: RGLS) is a biopharmaceutical
company focused on the discovery and development of innovative
medicines targeting microRNAs. Regulus has leveraged its
oligonucleotide drug discovery and development expertise to develop
a pipeline complemented by a rich intellectual property estate in
the microRNA field. Regulus maintains its corporate
headquarters in San Diego,
CA.
Forward-Looking Statements
Statements contained in this press release regarding matters
that are not historical facts are "forward-looking statements"
within the meaning of the Private Securities Litigation Reform Act
of 1995, including statements associated with the clinical
activities concerning the RGLS4326 program, including the
preliminary biomarker, pharmacokinetic and safety data resulting
from the first cohort of patients from the ongoing clinical study,
the sufficiency of the data required to recommence clinical studies
for extended duration dosing, the timing of the Company's
interactions with FDA regarding the clinical hold and the timing
and of other preclinical and clinical activities. Because
such statements are subject to risks and uncertainties, actual
results may differ materially from those expressed or implied by
such forward-looking statements. Words such as "believes,"
"anticipates," "plans," "expects," "intends," "will," "goal,"
"potential" and similar expressions are intended to identify
forward-looking statements. These forward-looking statements are
based upon Regulus' current expectations and involve assumptions
that may never materialize or may prove to be incorrect.
Actual results and the timing of events could differ materially
from those anticipated in such forward-looking statements as a
result of various risks and uncertainties, which include, without
limitation, risks associated with the process of discovering,
developing and commercializing drugs that are safe and effective
for use as human therapeutics and in the endeavor of building a
business around such drugs, and feedback from the FDA. In
addition, while Regulus expects the COVID-19 pandemic to adversely
affect its business operations and financial results, the extent of
the impact on Regulus' ability to achieve its preclinical and
clinical development objectives and the value of and market for its
common stock, will depend on future developments that are highly
uncertain and cannot be predicted with confidence at this time,
such as the ultimate duration of the pandemic, travel restrictions,
quarantines, social distancing and business closure requirements in
the U.S. and in other countries, and the effectiveness of actions
taken globally to contain and treat the disease. These
and other risks are described in additional detail in Regulus'
filings with the Securities and Exchange Commission. All
forward-looking statements contained in this press release speak
only as of the date on which they were made. Regulus undertakes no
obligation to update such statements to reflect events that occur
or circumstances that exist after the date on which they were
made.
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SOURCE Regulus Therapeutics Inc.