Statistically significant increase in urinary
polycystin 1(PC1) after treatment with RGLS8429
Urinary polycystin exhibits anticipated
pharmacokinetics/pharmacodynamics (PK/PD) correlation in patients
with ADPKD
Company to hold conference call at
8:30 a.m. EDT today
SAN
DIEGO, Sept. 20, 2023 /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
positive topline results from the first cohort of patients in its
Phase 1b MAD study of RGLS8429 for
the treatment of ADPKD.
In the first cohort, 12 subjects were randomized 3:1 to receive
either 1 mg/kg of RGLS8429 or placebo every other week for three
months. The study is designed to evaluate safety, pharmacokinetics,
disease related urinary biomarkers, including urinary polycystin 1
(PC1) and polycystin 2 (PC2), height-adjusted total kidney volume
(htTKV), and novel cyst imaging biomarkers. PC1 and PC2 are the
protein products of the PKD1 and PKD2 genes respectively and have
been shown to inversely correlate with disease severity.
RGLS8429 was well tolerated by all 9 subjects receiving active
drug with no safety findings.
Increases in both PC1 and PC2 biomarkers were
observed. Statistically significant increases in mean PC1
levels were observed at Day 85 and Day 86 (n=9) compared to
baseline (36%-41%). Numeric increases in PC2 were observed during
the treatment period, although not statistically significant.
These data are consistent with what was observed with the
Company's first-generation compound, RGLS4326, which showed a
significant dose response between 0.3mg/kg and 1mg/kg of RGLS4326.
Furthermore, the correlation between PK and urinary PC1 response at
1mg/kg is comparable between RGLS4326 and RGLS8429.
Urinary polycystin exhibits an appropriate PK/PD correlation to
potentially serve as a key pharmacodynamic biomarker for the
Company's program targeting miR-17 to treat ADPKD. Furthermore, the
data suggest the opportunity to demonstrate increased urinary
polycystin response at the higher doses being tested in subsequent
cohorts in Phase 1b. Data from the
second cohort, dosed at 2mg/kg, are anticipated in the first
quarter of 2024.
"RGLS8429 continues to prove itself as a potential treatment for
ADPKD. These data are encouraging and support that we are another
step closer to establishing the optimal dosing range for the
compound," said Preston Klassen,
M.D., President and Head of Research & Development. "Cohort 1
meets expectations and continues to validate polycystin as a key
pharmacodynamic marker for appropriate dose-ranging prior to a
potential pivotal Phase 2 trial."
"These data strengthen our conviction in the potential of our
lead compound, RGLS8429, to address the underlying genetic drivers
of ADPKD," said Jay Hagan, CEO of
Regulus Therapeutics. "Additionally, this study has increased our
experience by incorporating renal imaging into our clinical study
including the use of novel imaging biomarkers. We would like to
thank everyone who has contributed to this study, most importantly
the patients, their families, study investigators and
collaborators. We look forward to providing additional updates as
we continue to make progress with the second cohort of this Phase
1b study and initiate recruitment for
the third cohort next month."
Approximately 80% of patients with ADPKD are reported to have a
mutation in the PKD1 gene, 15% have a mutation in the PKD2 gene,
and the remaining 5% have other mutations. 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 RGLS8429 engages the target miR-17 leading to
de-repression of the PKD1 and PKD2 genes and the resultant
increases in measured polycystin levels. Recent independent
studies have shown dramatic improvements in mouse models of the
disease including kidney function and cyst number when polycystin
can be re-expressed.
The Phase 1b MAD study is a
double-blind, placebo-controlled trial evaluating the safety,
tolerability, pharmacokinetics and pharmacodynamics (PK/PD) of
RGLS8429 in adult patients with ADPKD. The study will evaluate
RGLS8429 treatment across three different dose levels, including
measuring changes in polycystins, height-adjusted total kidney
volume (htTKV), cyst architecture, and overall kidney function. The
first cohort was dosed at 1 mg/kg of RGLS8429 or placebo every
other week for three months. RGLS8429 was well tolerated with no
significant safety findings in cohort 1. Patients in the second
cohort are receiving 2 mg/kg of RGLS8429 or placebo every other
week for three months. The Company also completed the 27-week
chronic toxicity study of RGLS8429 in mice. No RGLS8429-related
toxicity, including CNS adverse effects, was observed at any dose
level up to the top dose of 300 mg/kg administered every other
week.
More information about the MAD clinical trial is available at
clinicaltrials.gov (NCT05521191).
Conference Call Information
The Company will host a
conference call and live audio webcast on Wednesday, September
20, 2023 at 8:30 a.m. Eastern Daylight Time. To
access the call, please dial (866) 652-5200 (domestic) or
(412) 317-6060 (international). To access the telephone
replay of the call, dial (877) 344-7529 (domestic) or (412)
317-0088 (international), passcode ID 6807709. The webcast
and telephone replay will be archived on the Company's website
at www.regulusrx.com following the call.
About ADPKD
Autosomal Dominant Polycystic Kidney
Disease (ADPKD), caused by 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. Approximately
160,000 individuals are diagnosed with the disease in the United States alone, with an estimated
global prevalence of 4 to 7 million.
About RGLS8429
RGLS8429 is a novel, next
generation oligonucleotide for the treatment of ADPKD designed
to inhibit miR-17 and to preferentially target the kidney.
Administration of RGLS8429 has shown robust data in preclinical
models, where clear improvements in kidney function, size, and
other measures of disease severity have been demonstrated along
with a superior pharmacologic profile in preclinical studies
compared to Regulus' first-generation compound, RGLS4326. Regulus
announced completion of the Phase 1 SAD study in September 2022. The Phase 1 SAD study
demonstrated that RGLS8429 has a favorable safety and PK profile.
RGLS8429 was well-tolerated with no serious adverse events reported
and plasma exposure was approximately linear across the four doses
tested and is similar to the PK data from the first-generation
compound. In April 2023, Regulus
announced completion of enrollment for the first cohort of patients
in the Phase 1b MAD study. The first
cohort was dosed at 1 mg/kg of RGLS8429 or placebo every other week
for three months. RGLS8429 was well tolerated with no significant
safety findings in cohort 1. Patients in the second cohort are
receiving 2 mg/kg of RGLS8429 or placebo every other week for three
months. The Company also completed the 27-week chronic toxicity
study of RGLS8429 in mice. No RGLS8429-related toxicity, including
CNS adverse effects, was observed at any dose level up to the top
dose of 300 mg/kg administered every other week.
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 presentation 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 Company's RGLS8429 program, the expected timing
for initiating clinical studies, potentially achieving therapeutic
efficacy and clinical translation for ADPKD patients, the expected
timing for reporting topline data from the ongoing clinical study
and the timing and future occurrence 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, the approach we are taking to discover
and develop drugs is novel and may never lead to marketable
products, preliminary or initial results may not be indicative of
future results, preclinical and clinical studies may not be
successful, risks related to regulatory review and approval, risks
related to our reliance on third-party collaborators and other
third parties, risks related to intellectual property, 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 the risk additional toxicology data may be negative and
our need for additional capital. These and other risks are
described in additional detail in Regulus' filings with the
Securities and Exchange Commission, including under the "Risk
Factors" heading of Regulus' most recently filed quarterly report
on Form 10-Q. 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.