Intercept Pharmaceuticals, Inc. (Nasdaq: ICPT), a biopharmaceutical
company focused on the development and commercialization of novel
therapeutics to treat rare and serious liver diseases, today
announced new results from a planned interim analysis of its
ongoing Phase 2 study 747-213 assessing improvements in serum
biomarkers of hepatic function, cholestasis and inflammation in
patients with primary biliary cholangitis (PBC) after treatment
with an investigational combination of obeticholic acid (OCA) and
bezafibrate. Results from the full interim data set, shared in a
podium presentation today at the European Association for the Study
of the Liver (EASL) Congress 2023 in Vienna, Austria, showed that
the combination of OCA 5-10 mg and bezafibrate 400 mg was effective
in normalizing multiple biochemical markers associated with
PBC-induced liver damage.
“The results of this interim analysis, specifically the
normalization of key biochemistries in nearly 60 percent of
patients in the OCA 5-10 mg and bezafibrate 400 mg combination arm,
demonstrate the potential for synergy between the mechanisms of FXR
and PPAR agonists,” said M. Michelle Berrey, M.D., M.P.H.,
President of Research & Development and Chief Medical Officer
of Intercept. “We have an opportunity to build on the improved
transplant-free survival seen in patients with PBC taking OCA
across multiple real-world studies. We are encouraged by the
best-in-class potential of our novel combination with rapid
biochemical responses that have predicted improved clinical
outcomes and believe that a fixed-dose combination of OCA and
bezafibrate could reframe the parameters for efficacy in PBC.”
“Results of this planned interim analysis of the combination of
OCA and bezafibrate represent a milestone for the PBC community,”
said Frederik Nevens, M.D., Ph.D., Professor at University
Hospitals KU Leuven, Belgium. “The potential of this therapy to
deliver such broad biochemical responses in a large percentage of
patients across serum markers associated with outcomes in PBC
suggests that this combination can provide a new level of clinical
benefit.”
In this planned interim analysis from the first of two Phase 2
studies, 62 patients with PBC were randomized to receive 12 weeks
of once-daily oral therapy in addition to ongoing ursodeoxycholic
acid (UDCA) treatment (if any) in one of four treatment arms:
- bezafibrate 200 mg (B200) (n=16)
- OCA 5 mg titrated to 10 mg at week 4 + bezafibrate 200 mg
(OCA5-10/B200) (n=16)
- bezafibrate 400 mg (B400) (n=15)
- OCA 5 mg titrated to 10 mg at week 4 + bezafibrate 400 mg
(OCA5-10/B400) (n=15)
The goal of this interim analysis was to assess improvements in
serum biomarkers of PBC-induced liver damage including alanine
transaminase (ALT) and aspartate aminotransferase (AST) as well as
markers shown to predict transplant-free survival including
alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT) and
total bilirubin. Safety was assessed by monitoring of adverse
events (AEs) and laboratory values. The primary efficacy endpoint
of Study 747-213 is change in ALP from baseline to week 12.
Preliminary data from the abstract accepted by EASL were previously
reported on June 7.
EfficacyBiochemical remission, defined as
normalization of ALP, GGT, ALT, AST (all ≤ULN) and total bilirubin
(≤0.6xULN), was induced in 58% of patients on OCA5-10/B400 at 12
weeks vs 7% (B200), 27% (B400) and 31% (OCA5-10/B200) in the other
treatment arms. Further, patients in the OCA5-10/B400 arm
experienced consistently high levels of normalization of individual
biomarkers ALP (75% normalized), GGT (75% normalized), total
bilirubin (≤0.6xULN, 100% normalized), ALT (100% normalized) and
AST (92% normalized). The lower target for total bilirubin was
selected as it is associated with the lowest risk for liver
transplant or death.
Patients in the OCA5-10/B400 arm demonstrated the highest rates
of reduction from baseline in ALP, ALT, total bilirubin and GGT
with a clear dose response seen in total bilirubin and GGT.
SafetyTreatment-emergent adverse events (TEAEs)
were generally balanced across all arms (8 in B200, 11 in
OCA5-10/B200, 12 in B400, 9 in OCA5-10/B400) with the majority
being mild and not related to study drug. No deaths occurred in the
study.
Pruritus events were low across all study arms with the lowest
rate in the OCA5-10/B400 arm (2 events, 13.3%). Observed pruritus
in the other arms were 4 events (25%) in B200; 4 events (25%) in
OCA5-10/B200; and 3 events (20%) in B400. One serious
treatment-related pruritus TEAE leading to discontinuation was
reported in the OCA5-10/B400 arm.
There was a reduction from baseline in mean cholesterol levels
at 4 weeks in the combination arms and relative to the active
control, bezafibrate. Patients in the two OCA-bezafibrate treatment
arms demonstrated the largest reductions in cholesterol at 12 weeks
with a clear dose response.
Intercept has two ongoing Phase 2 studies (747-213 /
NCT04594694, 747-214 / NCT05239468) that are exploring a range of
therapeutic doses for the fixed-dose combination of OCA and
bezafibrate. Intercept expects to complete planned interim analyses
from both ongoing Phase 2 studies this year. Analyses from these
Phase 2 studies, in addition to Phase 1 and preclinical data, will
serve as the basis of an end-of-phase 2 meeting with FDA.
About the Investigational OCA-bezafibrate Fixed-Dose
CombinationIntercept is investigating a fixed-dose
combination of OCA and bezafibrate for the potential treatment of
individuals with PBC. OCA, a farnesoid X receptor (FXR) agonist, is
marketed by Intercept as Ocaliva in the United States for the
treatment of PBC (see below for full indication and Important
Safety Information). Bezafibrate, a pan-peroxisome
proliferator-activated receptor (pan-PPAR) agonist, is not approved
in the United States for any indication.
FXR and PPAR are distinct pathways that each play a role in PBC.
Simultaneously targeting both pathways may offer the greatest
potential to impact bile acid synthesis, metabolism, and clearance
that underly cholestatic liver diseases. Published studies
establish a clinical proof-of-concept which suggests that the
combination of OCA and bezafibrate may provide additive clinical
efficacy and tolerability benefits in the treatment of PBC.
OCA-bezafibrate combination therapy is investigational; safety and
efficacy have not been established.
About Primary Biliary CholangitisPrimary
biliary cholangitis (PBC) is a rare, progressive, and chronic
autoimmune disease that affects the bile ducts in the liver and is
most prevalent (approximately 1 in 10,000) in women over the age of
40. PBC causes bile acid to build up in the liver, resulting in
inflammation and scarring (fibrosis), which, if left untreated, can
lead to cirrhosis, a liver transplant, or death.
About InterceptIntercept is a biopharmaceutical
company focused on the development and commercialization of novel
therapeutics to treat rare and serious liver diseases, including
primary biliary cholangitis (PBC) and severe alcohol-associated
hepatitis (sAH). For more information, please visit
www.interceptpharma.com or connect with the Company on Twitter and
LinkedIn.
About Ocaliva® (obeticholic
acid)OCALIVA, a farnesoid X receptor (FXR) agonist, is
indicated for the treatment of adult patients with primary biliary
cholangitis (PBC)
- without cirrhosis or
- with compensated cirrhosis who do not have evidence of portal
hypertension,
either in combination with ursodeoxycholic acid (UDCA) with an
inadequate response to UDCA or as monotherapy in patients unable to
tolerate UDCA.
This indication is approved under accelerated approval based on
a reduction in alkaline phosphatase (ALP). An improvement in
survival or disease-related symptoms has not been established.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in confirmatory
trials.
IMPORTANT SAFETY INFORMATION
WARNING: HEPATIC DECOMPENSATION AND FAILURE IN PRIMARY
BILIARY CHOLANGITIS PATIENTS WITH CIRRHOSIS
- Hepatic decompensation and
failure, sometimes fatal or resulting in liver transplant, have
been reported with OCALIVA treatment in primary biliary cholangitis
(PBC) patients with either compensated or decompensated
cirrhosis.
- OCALIVA is contraindicated
in PBC patients with decompensated cirrhosis, a prior
decompensation event, or with compensated cirrhosis who have
evidence of portal hypertension.
- Permanently discontinue
OCALIVA in patients who develop laboratory or clinical evidence of
hepatic decompensation; have compensated cirrhosis and develop
evidence of portal hypertension; or experience clinically
significant hepatic adverse reactions while on
treatment.
Contraindications
OCALIVA is contraindicated in patients with:
- decompensated cirrhosis (e.g.,
Child-Pugh Class B or C) or a prior decompensation event
- compensated cirrhosis who have
evidence of portal hypertension (e.g., ascites, gastroesophageal
varices, persistent thrombocytopenia)
- complete biliary obstruction
Warnings and Precautions
Hepatic Decompensation and Failure in PBC Patients with
CirrhosisHepatic decompensation and failure, sometimes
fatal or resulting in liver transplant, have been reported with
OCALIVA treatment in PBC patients with cirrhosis, either
compensated or decompensated. Among post-marketing cases reporting
it, median time to hepatic decompensation (e.g., new onset ascites)
was 4 months for patients with compensated cirrhosis; median time
to a new decompensation event (e.g., hepatic encephalopathy) was
2.5 months for patients with decompensated cirrhosis.
Some of these cases occurred in patients with decompensated
cirrhosis when they were treated with higher than the recommended
dosage for that patient population; however, cases of hepatic
decompensation and failure have continued to be reported in
patients with decompensated cirrhosis even when they received the
recommended dosage.
Hepatotoxicity was observed in the OCALIVA clinical trials. A
dose-response relationship was observed for the occurrence of
hepatic adverse reactions including jaundice, worsening ascites,
and primary biliary cholangitis flare with dosages of OCALIVA of 10
mg once daily to 50 mg once daily (up to 5-times the highest
recommended dosage), as early as one month after starting treatment
with OCALIVA in two 3-month, placebo-controlled clinical trials in
patients with primarily early stage PBC.
Routinely monitor patients for progression of PBC, including
hepatic adverse reactions, with laboratory and clinical assessments
to determine whether drug discontinuation is needed. Closely
monitor patients with compensated cirrhosis, concomitant hepatic
disease (e.g., autoimmune hepatitis, alcoholic liver disease),
and/or with severe intercurrent illness for new evidence of portal
hypertension (e.g., ascites, gastroesophageal varices, persistent
thrombocytopenia), or increases above the upper limit of normal in
total bilirubin, direct bilirubin, or prothrombin time to determine
whether drug discontinuation is needed. Permanently discontinue
OCALIVA in patients who develop laboratory or clinical evidence of
hepatic decompensation (e.g., ascites, jaundice, variceal bleeding,
hepatic encephalopathy), have compensated cirrhosis and develop
evidence of portal hypertension (e.g., ascites, gastroesophageal
varices, persistent thrombocytopenia), experience clinically
significant hepatic adverse reactions, or develop complete biliary
obstruction. If severe intercurrent illness occurs, interrupt
treatment with OCALIVA and monitor the patient’s liver function.
After resolution of the intercurrent illness, consider the
potential risks and benefits of restarting OCALIVA treatment.
Severe PruritusSevere pruritus was
reported in 23% of patients in the OCALIVA 10 mg arm, 19% of
patients in the OCALIVA titration arm, and 7% of patients in the
placebo arm in a 12-month double-blind randomized controlled
clinical trial of 216 patients. Severe pruritus was defined as
intense or widespread itching, interfering with activities of daily
living, or causing severe sleep disturbance, or intolerable
discomfort, and typically requiring medical interventions. Consider
clinical evaluation of patients with new onset or worsening severe
pruritus. Management strategies include the addition of bile acid
binding resins or antihistamines, OCALIVA dosage reduction, and/or
temporary interruption of OCALIVA dosing.
Reduction in HDL-CPatients with PBC generally
exhibit hyperlipidemia characterized by a significant elevation in
total cholesterol primarily due to increased levels of high-density
lipoprotein-cholesterol (HDL-C). Dose-dependent reductions from
baseline in mean HDL-C levels were observed at 2 weeks in
OCALIVA-treated patients, 20% and 9% in the 10 mg and titration
arms, respectively, compared to 2% in the placebo arm. Monitor
patients for changes in serum lipid levels during treatment. For
patients who do not respond to OCALIVA after 1 year at the highest
recommended dosage that can be tolerated (maximum of 10 mg once
daily), and who experience a reduction in HDL-C, weigh the
potential risks against the benefits of continuing treatment.
Adverse ReactionsThe most common adverse
reactions (≥5%) are: pruritus, fatigue, abdominal pain and
discomfort, rash, oropharyngeal pain, dizziness, constipation,
arthralgia, thyroid function abnormality, and eczema.
Drug Interactions
- Bile Acid Binding ResinsBile acid binding resins such as
cholestyramine, colestipol, or colesevelam adsorb and reduce bile
acid absorption and may reduce the absorption, systemic exposure,
and efficacy of OCALIVA. If taking a bile acid binding resin, take
OCALIVA at least 4 hours before or 4 hours after taking the bile
acid binding resin, or at as great an interval as possible.
- WarfarinThe International Normalized Ratio (INR) decreased
following coadministration of warfarin and OCALIVA. Monitor INR and
adjust the dose of warfarin, as needed, to maintain the target INR
range when co-administering OCALIVA and warfarin.
- CYP1A2 Substrates with Narrow Therapeutic IndexObeticholic acid
may increase the exposure to concomitant drugs that are CYP1A2
substrates. Therapeutic monitoring of CYP1A2 substrates with a
narrow therapeutic index (e.g., theophylline and tizanidine) is
recommended when co-administered with OCALIVA.
- Inhibitors of Bile Salt Efflux PumpAvoid concomitant use of
inhibitors of the bile salt efflux pump (BSEP) such as
cyclosporine. Concomitant medications that inhibit canalicular
membrane bile acid transporters such as the BSEP may exacerbate
accumulation of conjugated bile salts including taurine conjugate
of obeticholic acid in the liver and result in clinical symptoms.
If concomitant use is deemed necessary, monitor serum transaminases
and bilirubin.
Please click here for Full
Prescribing Information, including Boxed
WARNING.To report SUSPECTED ADVERSE REACTIONS,
contact Intercept Pharmaceuticals, Inc. at 1-844-782-ICPT
or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Forward Looking StatementsThis press release
contains forward-looking statements (“FLS”), including regarding
the progress, timing, and results of our clinical trials; drug
efficacy, safety, and tolerability; and the timing and subject
matter of our meetings and other interactions with regulators.
Important factors could cause actual results to differ materially
from the FLS. For example, there could be efficacy, safety, or
tolerability concerns about our product candidates; or we could
have problems with our research and development activities and
clinical trials, including their initiation, timing, cost, conduct,
progress, and results, due to delays or failures in identifying,
enrolling, treating, and retaining patients, meeting specific
endpoints, or completing and reporting results.
ContactFor more information about Intercept,
please contact:
For investors:Nareg Sagherian, Executive Director, Global
Investor Relationsinvestors@interceptpharma.com
For media:Karen Preble, Executive Director, Global Corporate
Communicationsmedia@interceptpharma.com
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