LA JOLLA, Calif., May 3, 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
top-line results from the first cohort of patients with ADPKD in
its ongoing Phase 1b clinical trial
of RGLS4326. The study is evaluating the safety, pharmacokinetics,
and effects on pharmacodynamic biomarkers of multiple doses of
RGLS4326 in patients with ADPKD.
In the first cohort, nine patients were enrolled and received 1
mg/kg of RGLS4326 subcutaneously every other week for four
doses. Safety, pharmacokinetics, and certain disease related
biomarkers were evaluated through the course of the study.
The biomarkers included: Polycystin 1 (PC1) and Polycystin 2 (PC2)
which are the protein products of the PKD1 and PKD2 genes
respectively, kidney injury marker 1 (KIM-1), neutrophil
gelatinase-associated lipocalin (NGAL), as well as urea and
creatinine and were chosen to evaluate changes in disease related
measures.
RGLS4326 was well tolerated by all nine patients with no serious
adverse events reported. All reported adverse events were
mild and generally transient in nature.
Overall, the pharmacokinetic profile of RGLS4326 in patients
with ADPKD was similar to the pharmacokinetic profile observed in a
prior healthy volunteer study with the following observations:
- The half-life of RGLS4326 in plasma was slightly longer in
patients with impaired renal function and did not exhibit any signs
of accumulation in plasma.
- RGLS4326 plasma concentrations in patients were elevated
relative to healthy volunteers with mean plasma AUC levels after
the first and fourth dose approximately two-fold higher in
patients.
- Higher plasma exposure is anticipated to lead to higher kidney
exposure allowing for potential dose reductions needed to achieve
desired kidney exposure.
A statistically significant increase in the PC1 biomarker was
observed in the first cohort of this study. The mean increase
at Day 71 (n=8) compared to baseline was greater than 50% and all
patients had double digit increases in PC1 levels with an
overall trend showing increasing levels of both PC1 and PC2 over
time. Mean PC2 levels increased compared to baseline levels
(>20%) however the results did not reach statistical
significance. Importantly, at the time of the analysis, mutational
status was not known and may further contribute to understanding
differences in response rates. Approximately 85% of patients with
ADPKD are reported to have a mutation in the PKD1 gene, while the
remaining 15% have a mutation in the PKD2 gene. Measured
levels of these biomarkers (PC1 and PC2) inversely correlate with
disease severity and are believed to be directly linked to the
underlying genetic drivers of the disease. Regulus believes these
initial data demonstrate that RGLS4326 engages the target miR-17
leading to de-repression of the PKD1 and PKD2 genes and the
resultant increases in measured polycystin levels. In
addition to polycystin changes, one other notable improvement was
observed in NGAL levels for one patient in the first cohort.
As anticipated, NGAL levels for nearly all patients in this study
were within the normal range. However, one patient had levels
that were approximately twice the normal range at baseline and that
individual saw NGAL levels drop to within the normal range by the
end of study. Further analyses of the data are ongoing to
better understand drivers of response and correlations with
baseline characteristics and other parameters. Data from this
first cohort is planned to be submitted for presentation at Kidney
Week, the American Society of Nephrology annual meeting being held
in November 2021.
"We are very pleased with these data as it provides the safety
and pharmacokinetic data needed to complete the modeled safety
margins and engage FDA on the remaining partial clinical hold
requirements. We believe it also demonstrates clinical proof
of mechanism by showing target engagement through increases in a
biomarker that inversely correlates with disease severity with a
promising trend of increasing levels over time, suggesting that
with extended dosing, further increases in polycystin may be
attainable," said Jay Hagan, CEO of
Regulus. "These results validate our efforts in targeting miR-17 in
the kidney and give us confidence in our overall program, with our
lead molecule, RGLS4326, now in the second cohort of this Phase
1b study and our next generation
compound in IND preparation. We want to thank all of the patients,
investigators and collaborators we continue to work with in
advancing this novel program designed to address this significant
disease at the genetic level."
Conference Call & Webcast Information
Regulus will host a conference call and webcast at 8:30 a.m. Eastern Time today to discuss the
top-line results from the available data at the time of this
analysis from the first cohort of patients in our ongoing Phase
1b study of RGLS4326 in patients with
ADPKD. To access the call, please dial (877) 257-8599
(domestic) or (970) 315-0459 (international) and refer to
conference ID 9988705. To access the telephone replay of the
call, dial (855) 859-2056 (domestic) or (404) 537-3406
(international), passcode ID 9988705. The webcast and
telephone replay will be archived on the company's website at
www.regulusrx.com for ninety days following the call.
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 polycystin 1
(PC1) and polycystin 2 (PC2) in patients with ADPKD administered
RGLS4326 every other week for a total of four doses. 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 La Jolla,
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.
View original content to download
multimedia:http://www.prnewswire.com/news-releases/regulus-therapeutics-announces-top-line-data-from-the-first-cohort-of-phase-1b-clinical-trial-of-rgls4326-for-the-treatment-of-patients-with-autosomal-dominant-polycystic-kidney-disease-adpkd-301281847.html
SOURCE Regulus Therapeutics Inc.