Intercept Pharmaceuticals, Inc., a biopharmaceutical company and
wholly owned subsidiary of Alfasigma S.p.A. focused on the
development and commercialization of novel therapeutics to treat
rare and serious liver diseases, today announced new data from two
Phase 2 studies, including a topline full data analysis (Study
747-213) and an interim analysis (Study 747-214), evaluating the
effects of the investigational combination of farnesoid X receptor
(FXR) agonist, obeticholic acid (OCA) and peroxisome
proliferator-activated receptor (PPAR) agonist, bezafibrate, on
multiple key serum biomarkers in primary biliary cholangitis (PBC)
that have been shown to predict clinical outcomes. These data will
be presented on Monday, November 13, 2023, at the American
Association for the Study of Liver Diseases’ (AASLD) The Liver
Meeting® in Boston (poster #5019-C).
“The results of both Phase 2 studies reinforce our excitement
for the combination of OCA-bezafibrate to build on the improved
transplant-free survival seen in patients with PBC taking OCA
across multiple real-world studies,” said M. Michelle Berrey, M.D.,
M.P.H., President of Research & Development and Chief Medical
Officer of Intercept. “These data support progression to Phase 3
trials of the sustained release formulation of bezafibrate with low
doses of OCA, an important step as we continue to prioritize
Intercept’s investment in PBC.”
Patients with PBC in Study 747-213 were randomized 1:1:1:1 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 immediate release (B200 IR) (n=19)
- bezafibrate 400 mg sustained release (B400 SR) (n=19)
- bezafibrate 200 mg IR + OCA 5 mg titrated to 10 mg at week 4
(OCA5-10/B200 IR) (n=19)
- bezafibrate 400 mg SR + OCA 5 mg titrated to 10 mg at week
4 (OCA5-10/B400 SR) (n=18)
Patients with PBC in Study 747-214 were randomized 1:1:1:1 to
receive 12 weeks of once-daily oral therapy in addition to ongoing
UDCA treatment (if any) in one of four treatment arms:
- bezafibrate 100 mg IR (B100 IR) (n=11)
- bezafibrate 400 mg IR (B400 IR) (n=11)
- bezafibrate 100 mg IR + OCA 5 mg (OCA5/B100 IR) (n=9)
- bezafibrate 400 mg IR + OCA 5 mg (OCA5/B400 IR) (n=10)
The primary endpoint of both studies is change in alkaline
phosphatase (ALP) from baseline to Week 12. The study also assessed
percentage change and normalization rates of several serum
biomarkers of PBC-induced liver damage, such as alanine
transaminase (ALT) and aspartate aminotransferase (AST), as well as
markers shown to predict transplant-free survival beyond ALP,
including gamma-glutamyl transferase (GGT) and total bilirubin.
Safety was assessed by monitoring of adverse events (AEs) and
laboratory values.
Efficacy Results
Study 747-213
- OCA5-10/B400 SR showed a −60.6% change in ALP from baseline at
week 12 (primary endpoint)
- At week 12, OCA5-10/B400 SR induced biochemical remission,
defined as normalization of ALP, GGT, ALT, AST (all ≤ULN) and total
bilirubin (≤0.6xULN), in 44.4% of patients compared to 31.6% in
B400 SR, 31.6% in OCA5-10/B200 IR and 15.8% in B200 IR
- 66.7% of patients in the OCA5-10/B400 SR arm achieved
normalization of ALP (≤ULN) and 100% achieved TB ≤0.6xULN at week
12
- Normalization rates of GGT, ALT and AST (≤ULN) for OCA5-10/B400
SR at week 12 were 58.86%, 94.1% and 82.4% respectively
Study 747-214
- OCA5/B400 IR showed a −65.4% change in ALP from baseline at
week 12 (primary endpoint)
- At week 12, OCA5/B400 IR induced biochemical remission in 40.0%
of patients compared to 18.2% in B400 IR, 11.1% in OCA5/B100 IR and
9.1% in B100 IR
- 70.0% of patients in the OCA5/B400 IR arm achieved
normalization of ALP (≤ULN) and 90.0% achieved TB ≤0.6xULN at week
12
- Normalization rates of GGT, ALT and AST (≤ULN) for OCA/B400 IR
at week 12 were 40.0%, 100%, and 90.0%, respectively
Safety Results
The frequency of treatment-emergent adverse events (TEAEs)
reported was generally balanced across all arms in both studies.
Two severe TEAEs (pruritus [OCA5-10/B400 SR] and hypertension [B200
IR]) occurred in Study 213; the severe TEAE of pruritus led to
study discontinuation. One severe TEAE (pruritus, OCA5/B100 IR)
occurred in Study 214; no TEAEs led to study discontinuation in
Study 214.
The rate of new events of pruritus or worsening of baseline
pruritus was very low in the OCA5-10/B400 SR arm of Study 747-213
(2/18 patients). Preliminary data from the OCA5/B400 IR arm of
Study 747-214 showed a higher rate of new events of pruritus (7/10
patients), likely due to pharmacokinetic differences between the IR
formulation of bezafibrate compared to the SR formulation used in
Study 747-213.
“Results from these studies illustrate the OCA-bezafibrate
combination’s potential to deliver biochemical responses across a
range of biomarkers that predict improved clinical outcomes in
PBC,” said Cynthia Levy, M.D., Hepatologist at the University of
Miami Hospital and Professor of Medicine at the University of
Miami. “These positive findings, including low rates of pruritus,
are an important milestone for the PBC community.”
The company is continuing its two ongoing Phase 2 studies
(747-213 / NCT04594694, 747-214 / NCT05239468) that are exploring a
range of therapeutic doses and formulations for the combination of
OCA and bezafibrate. The Company expects to have the necessary data
from the OCA-bezafibrate combination program to submit a request in
2023 for an End-of-Phase 2 meeting with the FDA. These data include
analyses from both Phase 2 studies, in addition to Phase 1 and
preclinical data.
Poster Presentation“Combined Effect of
Obeticholic Acid and Bezafibrate in Patients with Primary Biliary
Cholangitis and Inadequate Response to Or Intolerance of
Ursodeoxycholic Acid: Results from Two Phase 2 Clinical Trials”
Poster #5019-CMonday, November 13, 1-2 PM ETCynthia Levy,
Vaclav Hejda, Alexandre Louvet, Ziad Younes, Manuel Mendizabal,
Alan Bonder, Heng Zou, Antonio Civitarese, Alejandra Villamil and
Frederik Nevens
A full list of sessions at The Liver Meeting® 2023 is available
at https://www.aasld.org/the-liver-meeting.
About the Investigational OCA-Bezafibrate Fixed-Dose
CombinationIntercept, a wholly owned subsidiary of
Alfasigma S.p.A., 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 common and 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 that are unmatched 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 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.
About InterceptIntercept is a biopharmaceutical
company and a wholly owned subsidiary of Alfasigmna S.p.A. 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 LinkedIn, Threads, and X (formerly Twitter).
ContactFor more information about Intercept,
please contact:
For media:media@interceptpharma.com
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