Pliant Therapeutics, Inc. (Nasdaq: PLRX) today announced 12-week
interim data from the 320 mg dose group of INTEGRIS-PSC, a
multinational, randomized, double-blind, placebo-controlled Phase
2a clinical trial of bexotegrast in patients with primary
sclerosing cholangitis (PSC) and suspected moderate to severe liver
fibrosis. The 320 mg group met its primary and secondary endpoints
demonstrating that bexotegrast was well tolerated over a 12-week
treatment period and its plasma concentrations increased with dose.
There was no dose relationship for adverse events. Pruritus and
cholangitis occurred less frequently on bexotegrast than on
placebo.
The trial’s exploratory efficacy endpoints assessed changes in
the liver fibrosis markers, Enhanced Liver Fibrosis (ELF) score and
PRO-C3 levels, as well as liver biochemistry and magnetic resonance
imaging (MRI) of the liver. Consistent with the results from the
lower doses tested, bexotegrast-treated patients at the 320 mg dose
showed a reduction in both ELF score and PRO-C3 levels relative to
placebo at Week 12. Bexotegrast-treated patients also showed
stabilization of alkaline phosphatase (ALP) levels, relative to an
increase on placebo at Week 12. In addition, MRI imaging continued
to show evidence of improved hepatocyte function and bile flow with
bexotegrast at the 320 mg dose relative to placebo.
INTEGRIS-PSC is a multinational, randomized, dose-ranging,
double-blind, placebo-controlled Phase 2a trial evaluating
bexotegrast at once-daily oral doses of 40 mg, 80 mg, 160 mg, 320
mg or placebo for 12 weeks in 121 patients with PSC. The 320 mg
group enrolled 27 patients in the active arm and added 9 new
patients to the pooled placebo arm. We believe INTEGRIS-PSC to be
the first randomized clinical trial to use an enrichment strategy
to enroll patients with suspected moderate to severe liver fibrosis
based on liver stiffness measure, ELF score or historical liver
biopsy. Baseline characteristics of the trial population reflected
this enrichment. The 320 mg dose group will continue until all
patients have been treated for at least 24 weeks, with final data
expected in mid-2024.
“Results from INTEGRIS-PSC continue to build on the favorable
safety and tolerability data for bexotegrast which is critically
important in the setting of vulnerable patient populations and the
need for chronic therapies,” said Éric Lefebvre, M.D., Chief
Medical Officer of Pliant. “As the therapeutic profile of
bexotegrast comes into focus with these data, it’s encouraging to
see bexotegrast’s treatment effects manifested across multiple
endpoints, suggesting its potential to impact PSC where therapies
are urgently needed. I look forward to additional data from this
trial in mid-2024 and upcoming discussions with regulatory
authorities surrounding potential next steps.”
Bexotegrast 320 mg was Well Tolerated with No
Drug-Related Severe or Serious Adverse Events
The primary endpoint of the INTEGRIS-PSC trial is the evaluation
of the safety and tolerability of bexotegrast. The secondary
endpoint is an assessment of its pharmacokinetics.
Bexotegrast at the 320 mg dose was well tolerated with no dose
relationship observed for adverse events. Of the 27 patients
treated with bexotegrast at the 320 mg dose, 26 (96%) completed 12
weeks of treatment with no drug-related severe or serious adverse
events (SAE). Most treatment-emergent adverse events (TEAEs) were
mild or moderate in severity and consistent with PSC disease
symptoms. In addition, adverse events of pruritus and cholangitis
occurred less frequently on all doses of bexotegrast relative to
placebo. Patients in the trial who had concomitant inflammatory
bowel disease (IBD) saw no change in their IBD symptoms as measured
by partial Mayo Score while on treatment.
Bexotegrast total and unbound plasma concentrations increased
with dose.
Bexotegrast 320 mg Demonstrated Antifibrotic Activity in
a PSC Population with Suspected Moderate to Severe Liver Fibrosis
at Week 12
The exploratory endpoints of the INTEGRIS-PSC trial include
changes in liver fibrosis markers, ELF and PRO-C3, liver
biochemistry and MRI imaging.
Figure 1. ELF Score – Change from Baseline at Week 12
Consistent with the lower doses tested, bexotegrast at 320 mg
reduced ELF score relative to placebo at Week 12. The ELF score is
a well-established prognostic marker of liver disease severity and
liver-related events in patients with advanced fibrosis.1 ELF is
strongly associated with transplant‐free survival in PSC and may be
useful as a surrogate marker in clinical trials.2
Consistent with the lower doses tested, bexotegrast at 320 mg
reduced PRO-C3 levels relative to placebo. PRO-C3 is a biomarker of
active fibrogenesis with higher levels associated with greater
disease activity.3
MRI relative enhancement using gadoxetate contrast is a measure
of hepatocyte function, with increased enhancement suggesting
improved hepatocyte function.4,5 Consistent with the lower doses
tested, bexotegrast at the 320 mg dose showed an increase in
relative enhancement on contrast MRI compared to a decrease
observed in the placebo group at Week 12. In addition, consistent
with the lower doses tested, bexotegrast at the 320 mg dose reduced
time to arrival to the common bile duct compared to placebo,
suggesting improved bile flow.6
Patients with PSC often experience pruritus, or itch, as part of
their disease.7 Bexotegrast at the 320 mg dose demonstrated
statistically significant reductions in the Itch Numerical Rating
Scale relative to placebo at Week 12.
“Consistent with prior observations from the INTEGRIS-PSC
trial, bexotegrast continues to demonstrate a very favorable safety
profile while also maintaining efficacy signals,” said Kris V.
Kowdley MD, AGAF, FAASLD, FACP, FACG, Director, Liver Institute
Northwest and Professor of Medicine, Elson S. Floyd College of
Medicine at Washington State University. “These promising results
present a strong rationale for the further study of bexotegrast in
patients with PSC as part of a larger late-stage trial.”
Bexotegrast in PSC Clinical Development Next
Steps
The Company is planning to share these data from the
INTEGRIS-PSC trial with regulatory authorities to discuss the
potential path to registration.
We would like to thank our INTEGRIS-PSC investigators and their
study teams for their dedication in support of the successful
execution of this trial. Special thanks to the INTEGRIS-PSC
clinical trial participants, their families and support networks
for helping us advance this promising program.
Background on Primary Sclerosing
Cholangitis
PSC is a rare, progressive liver disease of unknown origin,
which frequently occurs in the setting of inflammatory bowel
disease. PSC affects more than 30,000 patients in the United States
and over 100,000 patients worldwide. The disease can occur in all
ages, genders, and races. PSC is characterized by inflammation and
fibrosis, with progressive liver and biliary damage leading to
cirrhosis and liver failure. Currently there are no FDA or
EMA-approved therapies for patients with PSC. Therefore, there is a
high unmet need for new therapeutic options to address the symptoms
and modify the disease progression of this grievous illness.
INTEGRIS-PSC Multinational Phase 2a Trial of Bexotegrast
(NCT04480840)
INTEGRIS-PSC is a Phase 2a, multinational randomized,
dose-ranging, double-blind, placebo-controlled trial evaluating the
safety, tolerability, and pharmacokinetics of bexotegrast
administered over 12 weeks in patients with IPF. Patients were
enrolled in doses of 40 mg, 80 mg, 160 mg or 320 mg, with a 3:1
randomization ratio (active:placebo) and stratification based on
use of ursodeoxycholic acid (UDCA). The primary endpoint is the
evaluation of bexotegrast safety and tolerability and the secondary
endpoint is the assessment of pharmacokinetics across the range of
doses. Exploratory endpoints will measure changes in liver fibrosis
markers, ELF and PRO-C3, liver biochemistry and liver imaging.
Conference Call and Webcast Information
The Company will host a conference call and webcast with a slide
presentation tomorrow, Monday, February 5, 2024, at 8:00 a.m. ET |
5:00 a.m. PT to discuss this update. Members of Pliant’s management
team will be joined by Gideon Hirshfield, FRCP, Ph.D., Lily and
Terry Horner Chair in Autoimmune Liver Disease at the University of
Toronto. Interested parties may access the live webcast on Pliant’s
website at Pliant Therapeutics INTEGRIS-PSC Webcast or
may participate via telephone by registering in advance at the
following link: Pliant Therapeutics INTEGRIS-PSC Conference
Call. Upon registration, all telephone participants will receive
the dial-in number along and a unique passcode to access the call.
An archived replay of the webcast will be available on Pliant’s
website for 60 days following completion of the event.
About Pliant Therapeutics, Inc.
Pliant Therapeutics is a clinical-stage biopharmaceutical
company and leader in the discovery and development of novel
therapeutics for the treatment of fibrotic diseases. Pliant's lead
product candidate, bexotegrast (PLN-74809), is an oral, small
molecule, dual selective inhibitor of αvß6 and αvß1 integrins that
is in development in the lead indications for the treatment of
idiopathic pulmonary fibrosis, or IPF, and primary sclerosing
cholangitis, or PSC. Bexotegrast has received Fast Track
Designation and Orphan Drug Designation from the U.S. Food and Drug
Administration (FDA) in IPF and PSC and Orphan Drug Designation
from the European Medicines Agency in IPF and PSC. Pliant has
initiated BEACON-IPF, a Phase 2b trial of bexotegrast in IPF.
Pliant has also developed PLN-1474, a small molecule, selective
inhibitor of αvß1 integrin for the treatment of nonalcoholic
steatohepatitis, or NASH with liver fibrosis. Pliant has initiated
a Phase 1 study for its third clinical program, PLN-101095, a small
molecule, dual-selective inhibitor of αvß8 and αvß1 integrins, that
is being developed for the treatment of solid tumors. In addition
to clinical-stage programs, Pliant currently has a preclinical
program targeting muscular dystrophies. For additional information,
please visit: www.PliantRx.com. Follow us on social
media X, LinkedIn, Facebook and YouTube.
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. Words such as "may," "will," "expect," "anticipate,"
"estimate," "intend," and similar expressions (as well as other
words or expressions referencing future events, conditions, or
circumstances) are intended to identify forward-looking statements.
These statements include those regarding the safety, tolerability,
pharmacodynamics and therapeutic potential of bexotegrast; our
plans for the future development of bexotegrast; bexotegrast’s
potential to become a treatment for IPF or PSC; the anticipated
timing of data and progress from our clinical studies; including
the timing of 24-week data from the 320 mg dose cohort of the
INTEGRIS-PSC Phase 2a trial in mid-2024; and discussions and
interactions with regulatory authorities, including regarding a
potential path to registration. Because such statements deal with
future events and are based on our current expectations, they are
subject to various risks and uncertainties and actual results,
performance or achievements of Pliant Therapeutics could differ
materially from those described in or implied by the statements in
this press release. These forward-looking statements are subject to
risks and uncertainties, including those related to the development
and commercialization of our product candidates, including any
delays in our ongoing or planned preclinical or clinical trials,
the impact of current macroeconomic and marketplace conditions, our
reliance on third parties for critical aspects of our development
operations, the risks inherent in the drug development process, the
risks regarding the accuracy of our estimates of expenses and
timing of development, our capital requirements and the need for
additional financing, including the availability of additional term
loans under our loan facility, and our ability to obtain and
maintain intellectual property protection for our product
candidates. These and additional risks are discussed in the
sections titled "Risk Factors" and "Management's Discussion and
Analysis of Financial Condition and Results of Operations" in our
Quarterly Report on Form 10-Q for the period ended September 30,
2023 which is available on the SEC's website at www.sec.gov. Unless
otherwise noted, Pliant is providing this information as of the
date of this news release and does not undertake any obligation to
update any forward-looking statements contained in this document as
a result of new information, future events or otherwise.
Investor and Media Contact:
Christopher KeenanVice President, Investor Relations and
Corporate CommunicationsPliant Therapeutics,
Inc.ir@pliantrx.com
1 Vesterhus M, et al. Hepatology. 2019 69(2):684-698.2 Bowlus
CL, et al. Hepatology. 2023 Feb 1;77(2):659-702.3 Nielsen MJ, et
al. Aliment Pharmacol Ther. 2018 Jul;48(2):179-189.4 Schulze J, et
al. Clin Gastroenterol Hepatol. 2019 Jan;17(1):192-199.5 Nilsson H,
et al. J Magn Reson Imaging. 2014 Apr;39(4):879-86.6 Elkilany A, et
al. Abdom Radiol (NY). 2021 Mar;46(3):979-991.7 Karlsen TH, et al.
J Hepatol. 2017 Dec;67(6):1298-1323.
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