Pliant Therapeutics, Inc. (Nasdaq: PLRX), today announced positive
data from INTEGRIS-PSC, a Phase 2a clinical trial of bexotegrast in
patients with primary sclerosing cholangitis (PSC) and suspected
moderate to severe liver fibrosis. The trial 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. 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. Results at the initial three doses tested showed bexotegrast
reduced both ELF scores and PRO-C3 levels at Week 12 at all doses
relative to placebo with statistically significant differences at
the 160 mg dose relative to placebo at Week 12. Patients also
showed stabilization of liver chemistry, including a dose-dependent
trend in reduction of alkaline phosphatase (ALP) levels, relative
to placebo at Week 12. In addition, preliminary MRI imaging results
suggest improved hepatocyte function and bile flow with bexotegrast
160 mg. Twelve-week interim data from the high-dose 320 mg cohort
is expected in the first quarter of 2024.
INTEGRIS-PSC is a multinational, randomized, dose-ranging,
double-blind, placebo-controlled Phase 2a trial evaluating
bexotegrast at once-daily doses of 40 mg, 80 mg, 160 mg or placebo
for 12 weeks in 85 patients with PSC. 64 patients were enrolled in
the active arms and 21 patients were enrolled in the 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 INTEGRIS-PSC interim data has surpassed our expectations,
providing hope to patients with PSC who currently have no approved
therapeutic options available to them,” said Éric Lefebvre, M.D.,
Chief Medical Officer of Pliant. “Today marks a new chapter for the
bexotegrast platform, having now shown meaningful antifibrotic
effects across multiple tissues and indications. The
INTEGRIS-PSC and INTEGRIS-IPF trials provide further evidence that
localized inhibition of TGF-β by bexotegrast blocks a profibrotic
pathway that is common in multiple fibrotic diseases without
affecting TGF-β signaling systemically. This, coupled with the
favorable safety and tolerability profile seen to date, gives us
great confidence in bexotegrast as we look to broaden future
development into additional pulmonary and liver indications.”
Bexotegrast Was Well Tolerated Across All
Doses
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 was well tolerated at all three doses tested. Of the
64 patients treated with bexotegrast, 60 (94%) completed 12 weeks
of treatment with no deaths or 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. 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 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.
ELF: enhanced liver fibrosis score; All participants had
baseline ELF > 7.7 (moderate to severe liver fibrosis)21
Hepatology 2015 62(1):188-197 2 Hepatology 2015 62(1):188-197
Figure 1. Change in ELF Score at 12 Weeks in
INTEGRIS-PSC
A treatment effect was observed on ELF score in all bexotegrast
dose groups. 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 Bexotegrast reduced ELF scores relative to placebo at all
doses, with a statistical significance achieved at the 160 mg dose.
The bexotegrast 160 mg dose group demonstrated an 84% reduction of
the change in ELF score relative to placebo at Week 12.
Importantly, at the 160 mg dose group, statistically significant
reductions were observed across all three components of the ELF
score (tissue inhibitor of metalloproteinase 1 (TIMP-1),
procollagen III N-terminal propeptide (PIIINP) and hyaluronic acid
(HA)). Similarly, the bexotegrast 160 mg dose showed a
statistically significant reduction in PRO-C3 level relative to
placebo at Week 12. PRO-C3 is a biomarker of active fibrogenesis
with higher levels associated with greater disease activity.3
Patients with PSC tend to have elevated or fluctuating liver
biochemistry levels.4 Patients treated with bexotegrast showed
stabilization of liver chemistry levels, including alanine
aminotransferase (ALT) and aspartate aminotransferase (AST), as
well as total and direct bilirubin, at all doses versus increases
in placebo at Week 12. Additionally, bexotegrast-treated patients
with elevated baseline ALP levels (ie, > upper limit of normal)
showed a dose-dependent trend in reduction in ALP relative to
placebo at Week 12.
Preliminary MRI imaging of the liver using gadoxedate contrast
showed small increases in MRI relative enhancement from baseline
across all dose groups, compared to a decrease observed in the
placebo group to Week 12. MRI relative enhancement using gadoxedate
contrast is a measure of hepatocyte function, with increased
enhancement suggesting improved hepatocyte function.5,6 Similarly,
the change in time of arrival of gadoxedate in the common bile duct
from baseline to Week 12 was shorter in the bexotegrast arms
compared to the placebo group. Time to arrival is a measure of bile
flow with shorter times suggestive of improved bile flow.7
Patients with PSC often experience pruritus, or itch, as part of
their disease.8 Treatment with bexotegrast demonstrated dose
dependent reductions in the Itch Numerical Rating Scale relative to
placebo with statistical significance achieved at the 160 mg dose
at Week 12.
“The INTEGRIS-PSC data is compelling, with bexotegrast
demonstrating a favorable tolerability profile, and showing
antifibrotic activity across all doses,” said Cynthia Levy, M.D.,
Professor of Medicine at the University of Miami School of
Medicine, and INTEGRIS-PSC trial investigator. “I am encouraged by
the clear reduction in serum ELF score, a well-established
prognostic biomarker in PSC, at all doses compared to placebo.
Given the lack of pharmaceutical treatment options, our imperative
is to identify novel therapies that slow or prevent disease
progression. I look forward to seeing additional data from
INTEGRIS-PSC.”
INTEGRIS-PSC Next Steps
Pliant has recently completed enrollment of the high-dose 320 mg
dose cohort of the INTEGRIS-PSC Phase 2a trial. Interim 12-week
data from the 320 mg dose is expected in the first quarter of 2024,
with 24-week data from this dose expected in mid-2024.
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.
INTEGRIS-PSC Multinational Phase 2 Trial of Bexotegrast
(NCT04480840)
INTEGRIS-PSC is a Phase 2a, 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 a dose range. Exploratory
endpoints will measure changes in liver fibrosis markers, ELF and
PRO-C3, liver biochemistry and liver imaging.
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, gender, and race. 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.
Conference Call and Webcast
The Company will host a conference call and webcast with a slide
presentation today, Tuesday September 26 at 8:00 a.m. ET to discuss
this update. 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 focused on discovering and developing novel therapies for
the treatment of fibrosis. 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 Twitter, 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 12-week and 24-week data from the 320 mg dose cohort
of the INTEGRIS-PSC Phase 2a trial in the first quarter of 2024 and
mid-2024, respectively. 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 June 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. 2015 Jul;62(1):188-97.2 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 Karlsen TH, et
al. J Hepatol. 2017 Dec;67(6):1298-1323.5 Schulze J, et al. Clin
Gastroenterol Hepatol. 2019 Jan;17(1):192-199.6 Nilsson H, et al. J
Magn Reson Imaging. 2014 Apr;39(4):879-86.7 Elkilany A, et al.
Abdom Radiol (NY). 2021 Mar;46(3):979-991.8 Karlsen TH, et al. J
Hepatol. 2017 Dec;67(6):1298-1323.
A photo accompanying this announcement is available at
https://www.globenewswire.com/NewsRoom/AttachmentNg/c694776f-ffc7-48b2-85e9-685fd5930f59
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