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, is presenting new data from a
planned six-month analysis of its ongoing Phase 2 study 747-213
evaluating a fixed-dose combination of obeticholic acid (OCA) and
bezafibrate in patients with primary biliary cholangitis (PBC) at
Digestive Disease Week® (DDW) 2024 in Washington, D.C. Results from
the study show that six-month administration of OCA and bezafibrate
has the potential to normalize alkaline phosphatase (ALP), a serum
biomarker of PBC-related liver damage that has been correlated with
improved transplant-free and decompensation-free survival.
“I am encouraged by the findings from this six-month analysis of
the fixed-dose combination of OCA and bezafibrate,” said Alan
Bonder, MD, Medical Director of Liver Transplant, BIDMC, and
Associate Professor of Medicine, Harvard Medical School. “As a
clinician, normalizing ALP is a key component of pharmacological
therapy in PBC, and the impact of this combination on ALP, coupled
with its ability to normalize total and LDL cholesterol, gives me
confidence in this investigational therapy.”
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)
Following the 12-week double-blind treatment period,
OCA-bezafibrate dosage could be optimized in the long-term safety
extension.
The objectives of this study were to evaluate change in ALP from
baseline to Month 6, as well as changes in lipid panel over the
same time period.
Six-Month Results on ALP Reduction
- OCA/B400 SR induced the greatest percent change from baseline
of ALP, resulting in a -65.3% reduction (p<0.05 vs. B400
SR)
- B400 resulted in a -49.0% change from baseline
- OCA/B200 IR induced a -42.4% reduction from baseline
- B200 IR induced a -39.3% change from baseline
Six-Month Results on Metabolic OutcomesMean
total cholesterol was reduced to less than 200 mg/dl in the
OCA/B400 SR arm along with 19% mean reduction in LDL cholesterol.
HDL levels remained within normal range.
Total Cholesterol
- Only the OCA/B400 SR arm resulted in normalization of total
mean cholesterol levels at Month 6 to less than 200 mg/dL
- OCA/B400 SR induced a -19.6% reduction from baseline (p=0.004
vs. B400 SR, which induced a -6.8% reduction from baseline)
- OCA/B200 IR resulted in a -14.5% reduction from baseline
(p<0.05 vs. B200 IR, which induced a -5.9% reduction from
baseline)
LDL Cholesterol
- OCA/B400 SR induced a -18.7% change from baseline
- OCA/B200 IR resulted in a -9.6% reduction from baseline
- B400 SR and B200 IR induced a -11.1% and -9.5% reduction from
baseline, respectively
HDL Cholesterol
OCA/B400 SR and OCA/B200 IR both induced reductions in HDL
cholesterol; however, levels remained within a normal range as
defined by the U.S. National Library of Medicine.
- OCA/B400 SR induced a -17.9% reduction from baseline (p<0.05
vs. B400 SR, which induced a 7.5% increase from baseline)
- OCA/B200 IR resulted in a -14.9% reduction from baseline
(p<0.05 vs. B200 IR, which induced a 5.9% increase from
baseline)
“The results from this analysis provide important insights on
the potential benefits of OCA-bezafibrate combination therapy in
PBC,” said Sangeeta Sawhney, Senior Vice President and Head of U.S.
Research & Development. “We have conducted multiple studies
demonstrating the value of OCA – namely, transplant-free survival –
and we are eager to continue innovating on behalf of people living
with PBC by studying OCA’s apparent synergy with bezafibrate to
further improve clinical outcomes. We look forward to presenting
these data in further depth at DDW 2024.”
The company is continuing its two ongoing Phase 2 studies
(747-213 / NCT04594694, 747-214 / NCT05239468),
which are exploring a range of therapeutic doses and formulations
for the combination of OCA and bezafibrate.
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
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
Cirrhosis Hepatic 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 Pruritus Severe 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-C Patients 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 Reactions The 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 Resins Bile 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.
- Warfarin The 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
Index Obeticholic 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 Pump Avoid 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.
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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 Alfasigma 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).
Intercept owns the commercial rights to Ocaliva in the U.S. market.
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