NEW YORK, Aug. 17, 2016 (GLOBE
NEWSWIRE) -- Intercept Pharmaceuticals, Inc. (Nasdaq:ICPT), a
biopharmaceutical company focused on the development and
commercialization of novel therapeutics to treat non-viral,
progressive liver diseases, today announced that
the New England Journal of
Medicine published the key results of the Phase 3 POISE
trial of Ocaliva (obeticholic acid) for the treatment of patients
with primary biliary cholangitis, formerly known as primary biliary
cirrhosis (PBC). On a background of standard of care or given as
monotherapy, Ocaliva met the primary endpoint of the POISE trial
and improved multiple biochemical disease markers as compared to
placebo with high statistical significance.
The POISE trial evaluated the safety and efficacy
of once-daily treatment with Ocaliva in PBC patients with an
inadequate therapeutic response to, or who are unable to tolerate,
ursodeoxycholic acid (UDCA). The trial's primary endpoint was a
reduction in alkaline phosphatase (ALP) to below a threshold of
1.67 times the upper limit of the normal range, with a reduction of
at least 15% from baseline, and a total bilirubin level at or below
the upper limit of the normal range after 12 months of Ocaliva
therapy. These liver biomarkers have been shown to be reasonably
likely to predict progression to liver failure and resulting liver
transplant or premature death in patients with PBC. Ocaliva 5-10 mg
(46%) and Ocaliva 10 mg (47%) were both statistically superior to
placebo (10%) in achieving the primary endpoint (p<0.001). Most
Ocaliva-treated patients had liver biochemical improvements even if
they did not achieve the composite primary endpoint, with a
significantly higher percent of patients achieving greater than or
equal to 15% ALP reduction with Ocaliva 5-10 mg and Ocaliva 10
mg (both groups 77%) compared to placebo (29%) (p<0.001). The
majority of patients (93%) continued receiving UDCA therapy during
the trial.
"The POISE data support Ocaliva as an important
new treatment option for the substantial group of PBC patients who
have an inadequate response to, or cannot tolerate, UDCA and
therefore remain at risk of adverse outcomes," said Frederik
Nevens, M.D., Ph.D., University Hospitals Leuven & KU Leuven,
Belgium, and the lead author of the paper. "For nearly 20 years, we
only had one option to help our PBC patients. The introduction of
Ocaliva provides physicians and patients with an opportunity to
rethink treatment goals and take action when ALP and/or bilirubin
remain elevated despite UDCA therapy."
On May 27, 2016, the U.S. Food and Drug
Administration (FDA) granted accelerated approval to Ocaliva for
the treatment of PBC in combination with UDCA in adults with an
inadequate response to UDCA, or as monotherapy in adults unable to
tolerate UDCA. An improvement in survival or disease-related
symptoms has not been established.
Efficacy
In addition to the primary composite endpoint, the
POISE study evaluated the effect of Ocaliva on biochemical disease
markers of PBC using descriptive statistics with nominal p-values.
ALP improved in both Ocaliva groups versus placebo at all visits
(p<0.001), with reductions from baseline of -113±14 U/L in the
Ocaliva 5-10 mg group and -130±15 U/L in the Ocaliva 10 mg group,
compared to -14±15 U/L for placebo at 12 months. Reductions were
observed as early as two weeks and were maintained at each time
point thereafter. There was additional benefit observed in patients
who titrated from 5 mg to 10 mg, compared to those who remained on
a 5 mg dose.
An exploratory secondary analysis showed that
patients treated with placebo experienced total bilirubin increases
over the 12-month study period, while Ocaliva-treated patients
experienced decreases in total bilirubin. While the changes in
total bilirubin were within the normal range, the difference
between groups was statistically significant (p<0.001).
Additional exploratory secondary analyses
indicated that other liver enzymes (gamma-glutamyl transferase,
alanine transaminase, aspartate transaminase and conjugated
bilirubin) all improved from baseline in both Ocaliva groups
(p<0.001 for all end of study evaluations compared with
placebo).
Safety and
Tolerability
Pruritus (itch) is the most common symptom in
patients with PBC and was also the most common adverse event in the
trial, with a higher incidence reported in the Ocaliva 5-10 mg
(56%) and Ocaliva 10 mg (68%) groups, compared to placebo (38%).
The implementation of the Ocaliva 5-10 mg titration strategy
decreased the incidence of pruritus and was associated with a lower
discontinuation rate due to pruritus (one patient, 1%) compared
with starting at a higher dose of 10 mg (seven patients, 10%).
Additional side effects observed during the trial included fatigue,
abdominal pain and discomfort, rash, oropharyngeal pain, dizziness,
constipation, arthralgia, thyroid function abnormality, and
eczema.
High density lipoprotein cholesterol, which was
elevated at baseline (consistent with PBC-associated
hyperlipidemia), decreased within two weeks in Ocaliva-treated
patients, but stabilized and remained within the normal range after
12 months.
In an exploratory assessment, the rates of bone
fracture were similar among the trial groups, but dual energy X-ray
absorption indicated a smaller decrease in femoral bone mineral
density T-score in both Ocaliva groups versus placebo
(p<0.05).
Open-Label
Extension
The majority (97%) of the patients who completed
the double-blind phase of the POISE trial entered an open-label
extension (which will continue for five years). Patients who had
received Ocaliva in the double-blind phase experienced sustained
improvements in ALP and bilirubin, demonstrating a durable response
through two years of treatment. Placebo patients initiating
treatment with Ocaliva in the open-label extension demonstrated
similar improvements in ALP and bilirubin to the Ocaliva-treated
patients in the double-blind phase, including reversal of previous
increases in total bilirubin to levels comparable to baseline.
The severity and incidence of pruritus were
reduced in the open-label extension compared to the double-blind
phase in patients originally randomized to Ocaliva. Other adverse
events during the open-label extension were observed at comparable
rates to the double-blind phase and no new safety findings were
observed.
About
Primary Biliary Cholangitis, Formerly Known as Primary Biliary
Cirrhosis
Primary biliary cholangitis (PBC) is a rare, autoimmune cholestatic
liver disease that puts patients at risk for life-threatening
complications. PBC is primarily a disease of women, afflicting
approximately one in 1,000 women over the age of 40. If left
untreated, survival of PBC patients is significantly worse than the
general population.
About the
POISE Trial
The POISE trial studied the safety and efficacy of once-daily
treatment with Ocaliva in PBC patients with an inadequate
therapeutic response to, or who are unable to tolerate UDCA, the
current standard of care. Of 216 patients randomized to three
treatment arms-placebo, Ocaliva 5 mg titrated to 10 mg or Ocaliva
10 mg-93% continued receiving UDCA. The Ocaliva 5-10 mg titration
group received Ocaliva 5 mg for six months, after which dosing was
increased to 10 mg based on tolerability and biochemical response.
The trial's primary endpoint was a reduction in ALP to below a
threshold of 1.67 times the upper limit of normal, with a minimum
of 15% reduction in ALP level from baseline, and a normal bilirubin
level after 12 months of therapy.
About
Ocaliva® (obeticholic
acid)
Ocaliva is an agonist for FXR, a nuclear receptor expressed in the
liver and intestine. FXR is a key regulator of bile acid,
inflammatory, fibrotic, and metabolic pathways.
Ocaliva is indicated in the United States for the
treatment of primary biliary cholangitis (PBC) in combination with
ursodeoxycholic acid (UDCA) in adults with an inadequate response
to UDCA, or as monotherapy in adults unable to tolerate UDCA.
This indication is approved under accelerated
approval based on a reduction in alkaline phosphatase (ALP), as a
surrogate endpoint which is reasonably likely to predict clinical
benefit, including an improvement in liver transplant
free-survival. 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. Intercept is currently
enrolling COBALT, a Phase 4 clinical outcomes trial of Ocaliva in
patients with PBC with the goal of confirming clinical benefit on a
post-marketing basis.
A marketing authorization application for Ocaliva
for the treatment of PBC was accepted by the European Medicines
Authority (EMA) in June 2015 and is currently under review. The
brand name Ocaliva has been provisionally approved by the EMA.
IMPORTANT SAFETY
INFORMATION
Contraindications
Ocaliva is contraindicated in patients with
complete biliary obstruction.
Warnings and
Precautions
Liver-Related Adverse
Reactions
In two 3-month, placebo-controlled clinical
trials, a dose-response relationship was observed for the
occurrence of liver-related adverse reactions including jaundice,
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 a pooled analysis of three placebo-controlled
trials in patients with PBC, the exposure-adjusted incidence rates
for all serious and otherwise clinically significant liver-related
adverse reactions, and isolated elevations in liver biochemical
tests, per 100 patient exposure years (PEY) were: 5.2 in the
Ocaliva 10 mg group (highest recommended dosage), 19.8 in the
Ocaliva 25 mg group (2.5 times the highest recommended dosage) and
54.5 in the Ocaliva 50 mg group (5 times the highest
recommended dosage) compared to 2.4 in the placebo group.
Monitor patients during treatment with Ocaliva for
elevations in liver biochemical tests and for the development of
liver-related adverse reactions. Weigh the potential risks against
the benefits of continuing treatment with Ocaliva in patients who
have experienced clinically significant liver-related adverse
reactions. The maximum recommended dosage of Ocaliva is 10 mg once
daily. Adjust the dosage for patients with moderate or severe
hepatic impairment.
Discontinue Ocaliva in patients who develop
complete biliary obstruction.
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 the POISE trial, a
12-month double-blind randomized controlled 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. In the subgroup of patients
in the Ocaliva titration arm who increased their dosage from 5 mg
once daily to 10 mg once daily after 6 months of treatment (n=33),
the incidence of severe pruritus was 0% from months 0 to 6 and 15%
from months 6 to 12. The median time to onset of severe pruritus
was 11, 158 and 75 days for patients in the Ocaliva 10 mg, Ocaliva
titration and placebo arms, respectively.
Management strategies include the addition of bile
acid 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). In the POISE trial, 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. At
month 12, the reduction from baseline in mean HDL-C level was 19%
in the Ocaliva 10 mg arm, 12% in the Ocaliva titration arm and 2%
in the placebo arm. Nine patients in the Ocaliva 10 mg arm and six
patients in the Ocaliva titration arm, versus three patients in the
placebo arm, had reductions in HDL-C to less than
40 mg/dL.
Monitor patients for changes in serum lipid levels
during treatment. For patients who do not respond to Ocaliva after
one 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 from subjects
taking Ocaliva (greater than or equal to 5%) were pruritus,
fatigue, abdominal pain and discomfort, rash, oropharyngeal pain,
dizziness, constipation, arthralgia, thyroid function abnormality
and eczema.
Drug
Interaction
Bile Acid Binding Resins
Bile acid binding resins such as cholestyramine, colestipol or
colesevelam absorb and reduce bile acid absorption and may reduce
the absorption, systemic exposure and efficacy of Ocaliva. If
taking bile acid binding resins, take Ocaliva at least 4 hours
before or 4 hours after (or at as great an interval as possible)
taking a bile acid binding resin.
Please see Full Prescribing
Information for Ocaliva (obeticholic acid) 5 mg and 10 mg
tablets.
About
Intercept
Intercept is a biopharmaceutical company focused on the development
and commercialization of novel therapeutics to treat non-viral,
progressive liver diseases, including primary biliary cholangitis
(PBC), nonalcoholic steatohepatitis (NASH), primary sclerosing
cholangitis (PSC) and biliary atresia. Founded in 2002 in New York,
Intercept now has operations in the United States, Europe and
Canada. For more information about Intercept, please
visit www.interceptpharma.com.
Safe
Harbor Statements
This press release contains "forward-looking
statements" within the meaning of the Private Securities Litigation
Reform Act of 1995, including, but not limited to, statements
regarding the clinical relevance and
utility of ALP and the surrogate endpoint used in the Phase 3 POISE
trial to predict clinical outcomes, the acceptance of Ocaliva®
(obeticholic acid) as a treatment for PBC by healthcare providers,
patients and payors, the potential
regulatory approval and launch of OCA in PBC outside the United
States and the timelines related thereto, the anticipated prevalence of and other epidemiological
estimates and market data related to PBC, the continued
development of OCA and Intercept's other product candidates, and
our strategic directives under the caption "About Intercept." These
"forward-looking statements" are based on management's current
expectations of future events and are subject to a number of
important risks and uncertainties that could cause actual results
to differ materially and adversely from those set forth in or
implied by such forward-looking statements. These risks and uncertainties include, but are not limited
to: Intercept's ability to successfully commercialize
Ocaliva in PBC, and Intercept's ability to maintain its
regulatory approval of Ocaliva in the United States for Ocaliva in
PBC; the initiation, cost, timing, progress and results of
Intercept's development activities, preclinical studies and
clinical trials; the timing of and Intercept's ability to obtain
and maintain regulatory approval of OCA in PBC in countries outside
the United States and in indications other than PBC and any other
product candidates it may develop such as INT-767; conditions that
may be imposed by regulatory authorities on Intercept's marketing
approvals for its product candidates such as the need for clinical
outcomes data (and not just results based on achievement of a
surrogate endpoint), and any related restrictions, limitations,
and/or warnings in the label of any approved product candidates;
Intercept's plans to research, develop and commercialize its
product candidates; Intercept's ability to obtain and maintain
intellectual property protection for its product candidates;
Intercept's ability to successfully commercialize OCA in
indications other than PBC and its other product candidates; the
size and growth of the markets for Intercept's product candidates
and its ability to serve those markets; the rate and degree of
market acceptance of any of Intercept's products, which may be
affected by the reimbursement that it may receive for its products
from payors; the success of competing drugs that are or become
available; the election by Intercept's collaborators to pursue
research, development and commercialization activities; Intercept's
ability to attract collaborators with development, regulatory and
commercialization expertise; regulatory developments in the United
States and other countries; the performance of third-party
suppliers and manufacturers; Intercept's need for and ability to
obtain additional financing; Intercept's estimates regarding
expenses, future revenues and capital requirements and the accuracy
thereof; Intercept's use of cash, short-term investments and the
proceeds from the offering; Intercept's ability to attract and
retain key scientific or management personnel; and other
factors discussed under the heading "Risk Factors" contained in our
annual report on Form 10-K for the year ended December 31, 2015
filed on February 29, 2016 as well as any updates to these risk
factors filed from time to time in our other filings with the
Securities and Exchange Commission. All information in this press
release is as of the date of the release, and Intercept undertakes
no duty to update this information unless required by
law.
Contact
For more information about Intercept Pharmaceuticals, please contact:
Mark Vignola
+1-646-747-1000
investors@interceptpharma.com
Christopher Frates
+1-646-757-2371
media@interceptpharma.com
This
announcement is distributed by NASDAQ OMX Corporate Solutions on
behalf of NASDAQ OMX Corporate Solutions clients.
The issuer of this announcement warrants that they are solely
responsible for the content, accuracy and originality of the
information contained therein.
Source: Intercept Pharmaceuticals, Inc. via
Globenewswire
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