Inrebic, a once-daily, oral therapy, is the
first new treatment option approved in Europe for myelofibrosis in
nearly a decade
Inrebic demonstrated clinically meaningful
spleen and symptom response in myelofibrosis patients where
treatment with ruxolitinib has failed, who are intolerant to
ruxolitinib or who are JAK inhibitor naïve, based on results from
JAKARTA and JAKARTA2 studies
Bristol Myers Squibb (NYSE: BMY) today announced that the
European Commission (EC) has granted full Marketing Authorization
for Inrebic ® (fedratinib) for the treatment of disease-related
splenomegaly (enlarged spleen) or symptoms in adult patients with
primary myelofibrosis, post-polycythaemia vera myelofibrosis or
post-essential thrombocythaemia myelofibrosis, who are Janus
Associated Kinase (JAK) inhibitor naïve or have been treated with
ruxolitinib. Inrebic is the first, once-daily oral therapy to
significantly reduce spleen volume and symptom burden for patients
with myelofibrosis where treatment with ruxolitinib has failed, who
are intolerant to ruxolitinib or who are JAK inhibitor naïve. The
centralized Marketing Authorization approves use of Inrebic in all
European Union (EU) member states, as well as Norway, Iceland and
Liechtenstein.* Inrebic was granted orphan drug designation in the
United States and is also approved in the United States and Canada.
1,2
“Myelofibrosis is a serious and often debilitating bone marrow
disorder for which there has only been one approved treatment
option for nearly a decade,” said Claire Harrison, M.D., FRCP,
FRCPath, JAKARTA and JAKARTA2 study investigator and professor of
hematology at Guy's and St. Thomas' NHS Foundation Trust, London,
United Kingdom. “Inrebic showed clinically meaningful reductions in
spleen volume and symptoms in patients who progressed on
ruxolitinib or who are JAK inhibitor naïve. Approximately one out
of every 100,000 people in the EU will be diagnosed with
myelofibrosis each year, and today’s approval provides an important
new option for patients who have remained in urgent need of new
therapies.”
The EC approval of Inrebic was based on results from the JAKARTA
and JAKARTA2 studies, which included patients from 14 countries in
the EU. The pivotal JAKARTA study evaluated the efficacy of
once-daily oral doses of Inrebic compared with placebo in 289
patients with intermediate-2 or high-risk primary or secondary
myelofibrosis with splenomegaly. The JAKARTA2 study evaluated the
efficacy of once-daily oral doses of Inrebic in 97 patients with
intermediate or high-risk primary or secondary myelofibrosis with
splenomegaly previously treated with ruxolitinib.3 In the clinical
development program of Inrebic, which included 608 patients,
serious and fatal cases of encephalopathy, including Wernicke’s,
occurred in Inrebic-treated patients. Serious cases were reported
in 1.3% (8/608) of patients treated with Inrebic in clinical trials
and 0.16% (1/608) of cases were fatal.1
“With today’s EC approval of Inrebic, patients with
myelofibrosis throughout Europe will now have a critical new option
for a rare bone marrow disorder that’s seen little progress in
several years,” said Diane McDowell, M.D., vice president,
Hematology Global Medical Affairs, Bristol Myers Squibb. “We’re
committed to improving on standards of care for patients living
with hard-to-treat blood diseases and are working collaboratively
with European member states to make Inrebic available to patients
as quickly as possible.”
*Centralized Marketing Authorization does not include approval
in Great Britain (England, Scotland and Wales).
About JAKARTA and JAKARTA2
The Inrebic development program consisted of multiple studies
(including JAKARTA and JAKARTA2) in 608 patients who received more
than one dose (ranging from 30 mg to 800 mg), of whom 459 had
myelofibrosis, including 97 previously treated with ruxolitinib.3
JAKARTA was a pivotal Phase 3, multicenter, randomized,
double-blind, placebo-controlled trial evaluating the efficacy of
once-daily oral doses of Inrebic compared with placebo in patients
with intermediate-2 or high-risk primary or secondary
(post-polycythemia vera or post-essential thrombocythemia)
myelofibrosis with splenomegaly and a platelet count of ≥50 x 109/L
who were previously untreated with a JAK inhibitor. The study
included 289 patients randomized to receive either Inrebic 500 mg
(n=97) or 400 mg (n=96) or placebo (n=96) across 94 sites in 24
countries.1 JAKARTA2 was a Phase 2, open-label, single arm study of
Inrebic in myelofibrosis patients previously treated with
ruxolitinib with a diagnosis of intermediate-1 with symptoms,
intermediate-2 or high-risk myelofibrosis, post-polycythemia vera
myelofibrosis or post-essential thrombocythemia myelofibrosis with
splenomegaly and platelet count ≥50 x 109/L. The study included 97
patients who started Inrebic at 400 mg once daily across 10
countries.3
The primary endpoint of JAKARTA and JAKARTA2 was spleen response
rate, defined as the proportion of patients achieving greater than
or equal to a 35% reduction from baseline in spleen volume at the
end of cycle 6 as measured by magnetic resonance imaging (MRI) or
computerized tomography (CT) with a follow-up scan 4 weeks later in
the JAKARTA study. Secondary endpoints of the studies included
symptom response rate, defined as the proportion of patients with a
50% or greater reduction in Total Symptom Score when assessed from
baseline to the end of cycle 6 as measured by the modified
Myelofibrosis Symptoms Assessment Form (MFSAF) v2.0 diary2 (night
sweats, itching, abdominal discomfort, early satiety, pain under
ribs on left side, bone or muscle pain).1,3
About Myelofibrosis
Myelofibrosis is a serious and rare bone marrow disorder that
disrupts the body’s normal production of blood cells. Bone marrow
is gradually replaced with fibrous scar tissue, which limits the
ability of the bone marrow to make blood cells. The disorder can
lead to anemia, weakness, fatigue and enlargement of the spleen and
liver, among other symptoms.4 Myelofibrosis is classified as a
myeloproliferative neoplasm, a group of rare blood cancers that are
derived from blood-forming stem cells.5 In the EU, approximately 1
of every 100,000 people will be diagnosed with myelofibrosis each
year.6 Both men and women are affected, and while the disease can
affect people of all ages, the median age at diagnosis ranges from
60 to 67 years.7,8 Median survival after ruxolitinib
discontinuation is generally poor, ranging from 6 months to 2
years, representing a significant need for alternative treatment
options.9
About Inrebic Inrebic®
(fedratinib) is an oral kinase inhibitor with activity against wild
type and mutationally activated Janus Associated Kinase 2 (JAK2)
and FMS-like tyrosine kinase 3 (FLT3). Inrebic is a JAK2-selective
inhibitor with higher potency for JAK2 over family members JAK1,
JAK3 and TYK2. Abnormal activation of JAK2 is associated with
myeloproliferative neoplasms, including myelofibrosis and
polycythemia vera. In cell models expressing mutationally active
JAK2 or FLT3, Inrebic reduced phosphorylation of signal transducer
and activator of transcription (STAT3/5) proteins, inhibited cell
proliferation, and induced apoptotic cell death. In mouse models of
JAK2V617F-driven myeloproliferative disease, Inrebic blocked
phosphorylation of STAT3/5, increased survival and improved
disease-associated symptoms, including reduction of white blood
cells, hematocrit, splenomegaly and fibrosis.1
U.S. INDICATION INREBIC®
(fedratinib) is indicated for the treatment of adult patients with
intermediate-2 or high-risk primary or secondary (post-polycythemia
vera or post-essential thrombocythemia) myelofibrosis (MF).
U.S. IMPORTANT SAFETY
INFORMATION
WARNING: ENCEPHALOPATHY INCLUDING WERNICKE’S
Serious and fatal encephalopathy, including Wernicke’s, has
occurred in patients treated with INREBIC. Wernicke’s
encephalopathy is a neurologic emergency. Assess thiamine levels in
all patients prior to starting INREBIC, periodically during
treatment, and as clinically indicated. Do not start INREBIC in
patients with thiamine deficiency; replete thiamine prior to
treatment initiation. If encephalopathy is suspected, immediately
discontinue INREBIC and initiate parenteral thiamine. Monitor until
symptoms resolve or improve and thiamine levels normalize.
WARNINGS AND PRECAUTIONS Encephalopathy, including
Wernicke’s: Serious and fatal encephalopathy, including
Wernicke’s encephalopathy, has occurred in INREBIC-treated
patients. Serious cases were reported in 1.3% (8/608) of patients
treated with INREBIC in clinical trials and 0.16% (1/608) of cases
were fatal.
Wernicke’s encephalopathy is a neurologic emergency resulting
from thiamine (Vitamin B1) deficiency. Signs and symptoms of
Wernicke’s encephalopathy may include ataxia, mental status
changes, and ophthalmoplegia (e.g., nystagmus, diplopia). Any
change in mental status, confusion, or memory impairment should
raise concern for potential encephalopathy, including Wernicke’s,
and prompt a full evaluation including a neurologic examination,
assessment of thiamine levels, and imaging. Assess thiamine levels
in all patients prior to starting INREBIC, periodically during
treatment, and as clinically indicated. Do not start INREBIC in
patients with thiamine deficiency; replete thiamine prior to
treatment initiation. If encephalopathy is suspected, immediately
discontinue INREBIC and initiate parenteral thiamine. Monitor until
symptoms resolve or improve and thiamine levels normalize.
Anemia: New or worsening Grade 3 anemia occurred in 34%
of INREBIC-treated patients. The median time to onset of the first
Grade 3 anemia was approximately 2 months, with 75% of cases
occurring within 3 months. Mean hemoglobin levels reached nadir
after 12 to 16 weeks with partial recovery and stabilization after
16 weeks. Red blood cell transfusions were received by 51% of
INREBIC-treated patients and permanent discontinuation of INREBIC
occurred due to anemia in 1% of patients. Consider dose reduction
for patients who become red blood cell transfusion dependent.
Thrombocytopenia: New or worsening Grade ≥3
thrombocytopenia during the randomized treatment period occurred in
12% of INREBIC-treated patients. The median time to onset of the
first Grade 3 thrombocytopenia was approximately 1 month; with 75%
of cases occurring within 4 months. Platelet transfusions were
received by 3.1% of INREBIC-treated patients. Permanent
discontinuation of treatment due to thrombocytopenia and bleeding
that required clinical intervention both occurred in 2.1% of
INREBIC-treated patients. Obtain a complete blood count (CBC) at
baseline, periodically during treatment, and as clinically
indicated. For Grade 3 thrombocytopenia with active bleeding or
Grade 4 thrombocytopenia, interrupt INREBIC until resolved to less
than or equal to Grade 2 or baseline. Restart dose at 100 mg daily
below the last given dose and monitor platelets as clinically
indicated.
Gastrointestinal Toxicity: Gastrointestinal toxicities
are the most frequent adverse reactions in INREBIC-treated
patients. During the randomized treatment period, diarrhea occurred
in 66% of patients, nausea in 62% of patients, and vomiting in 39%
of patients. Grade 3 diarrhea 5% and vomiting 3.1% occurred. The
median time to onset of any grade nausea, vomiting, and diarrhea
was 1 day, with 75% of cases occurring within 2 weeks of treatment.
Consider providing appropriate prophylactic anti-emetic therapy
(e.g., 5-HT3 receptor antagonists) during INREBIC treatment. Treat
diarrhea with anti-diarrheal medications promptly at the first
onset of symptoms. Grade 3 or higher nausea, vomiting, or diarrhea
not responsive to supportive measures within 48 hours, interrupt
INREBIC until resolved to Grade 1 or less or baseline. Restart dose
at 100 mg daily below the last given dose. Monitor thiamine levels
and replete as needed.
Hepatic Toxicity: Elevations of ALT and AST (all grades)
during the randomized treatment period occurred in 43% and 40%,
respectively, with Grade 3 or 4 in 1% and 0%, respectively, of
INREBIC-treated patients. The median time to onset of any grade
transaminase elevation was approximately 1 month, with 75% of cases
occurring within 3 months. Monitor hepatic function at baseline,
periodically during treatment, and as clinically indicated. For
Grade 3 or higher ALT and/or AST elevations (greater than 5 × ULN),
interrupt INREBIC dose until resolved to Grade 1 or less or to
baseline. Restart dose at 100 mg daily below the last given dose.
If re-occurrence of a Grade 3 or higher elevation of ALT/AST,
discontinue treatment with INREBIC.
Amylase and Lipase Elevation: Grade 3 or higher amylase
2% and/or lipase 10% elevations developed in INREBIC-treated
patients. The median time to onset of any grade amylase or lipase
elevation was 15 days, with 75% of cases occurring within 1 month
of starting treatment. One patient developed pancreatitis in the
fedratinib clinical development program (n=608) and pancreatitis
resolved with treatment discontinuation. Monitor amylase and lipase
at baseline, periodically during treatment, and as clinically
indicated. For Grade 3 or higher amylase and/or lipase elevations,
interrupt INREBIC until resolved to Grade 1 or less or to baseline.
Restart dose at 100 mg daily below the last given dose.
ADVERSE REACTIONS: The most common adverse reactions for
INREBIC treated vs. placebo were diarrhea (66% vs. 16%), nausea
(62% vs. 15%), anemia (40% vs. 14%), and vomiting (39% vs. 5%).
Dosage interruptions due to an adverse reaction during the
randomized treatment period occurred in 21% of patients who
received INREBIC. Adverse reactions requiring dosage interruption
in >3% of patients who received INREBIC included diarrhea and
nausea. Dosage reductions due to an adverse reaction during the
randomized treatment period occurred in 19% of patients who
received INREBIC. Adverse reactions requiring dosage reduction in
>2% of patients who received INREBIC included anemia (6%),
diarrhea (3%), vomiting (3%), and thrombocytopenia (2%).
DRUG INTERACTIONS: Coadministration of INREBIC with a
strong CYP3A4 inhibitor increases fedratinib exposure. Increased
exposure may increase the risk of adverse reactions. Consider
alternative therapies that do not strongly inhibit CYP3A4 activity.
Alternatively, reduce the dose of INREBIC when administering with a
strong CYP3A4 inhibitor. Avoid INREBIC with strong and moderate
CYP3A4 inducers. Avoid INREBIC with dual CYP3A4 and CYP2C19
inhibitor. Coadministration of INREBIC with drugs that are CYP3A4
substrates, CYP2C19 substrates, or CYP2D6 substrates increases the
concentrations of these drugs, which may increase the risk of
adverse reactions of these drugs. Monitor for adverse reactions and
adjust the dose of drugs that are CYP3A4, CYP2C19, or CYP2D6
substrates as necessary when coadministered with INREBIC.
PREGNANCY/LACTATION: Consider the benefits and risks of
INREBIC for the mother and possible risks to the fetus when
prescribing INREBIC to a pregnant woman. Due to the potential for
serious adverse reactions in a breastfed child, advise patients not
to breastfeed during treatment with INREBIC, and for at least 1
month after the last dose.
RENAL IMPAIRMENT: Reduce INREBIC dose when administered
to patients with severe renal impairment. No modification of the
starting dose is recommended for patients with mild to moderate
renal impairment. Due to potential increase of exposure, patients
with preexisting moderate renal impairment require more intensive
safety monitoring, and if necessary, dose modifications based on
adverse reactions.
HEPATIC IMPAIRMENT: Avoid use of INREBIC in patients with
severe hepatic impairment.
Please see full Prescribing Information, including Boxed
WARNING, and Summary of Product Characteristics for
INREBIC.
Bristol Myers Squibb: Creating a Better
Future for People with Cancer Bristol Myers Squibb is
inspired by a single vision—transforming patients’ lives through
science. The goal of the company’s cancer research is to deliver
medicines that offer each patient a better, healthier life and to
make cure a possibility. Building on a legacy across a broad range
of cancers that have changed survival expectations for many,
Bristol Myers Squibb researchers are exploring new frontiers in
personalized medicine, and through innovative digital platforms,
are turning data into insights that sharpen their focus. Deep
scientific expertise, cutting-edge capabilities and discovery
platforms enable the company to look at cancer from every angle.
Cancer can have a relentless grasp on many parts of a patient’s
life, and Bristol Myers Squibb is committed to taking actions to
address all aspects of care, from diagnosis to survivorship.
Because as a leader in cancer care, Bristol Myers Squibb is working
to empower all people with cancer to have a better future.
About Bristol Myers Squibb
Bristol Myers Squibb is a global biopharmaceutical company whose
mission is to discover, develop and deliver innovative medicines
that help patients prevail over serious diseases. For more
information about Bristol Myers Squibb, visit us at BMS.com or
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Celgene and Juno Therapeutics are wholly owned subsidiaries of
Bristol-Myers Squibb Company. In certain countries outside the
U.S., due to local laws, Celgene and Juno Therapeutics are referred
to as, Celgene, a Bristol Myers Squibb company and Juno
Therapeutics, a Bristol Myers Squibb company.
Bristol Myers Squibb Cautionary
Statement Regarding Forward-Looking Statements This
press release contains “forward-looking statements” within the
meaning of the Private Securities Litigation Reform Act of 1995
regarding, among other things, the research, development and
commercialization of pharmaceutical products. All statements that
are not statements of historical facts are, or may be deemed to be,
forward-looking statements. Such forward-looking statements are
based on historical performance and current expectations and
projections about our future financial results, goals, plans and
objectives and involve inherent risks, assumptions and
uncertainties, including internal or external factors that could
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are difficult to predict, may be beyond our control and could cause
our future financial results, goals, plans and objectives to differ
materially from those expressed in, or implied by, the statements.
These risks, assumptions, uncertainties and other factors include,
among others, that the outcome of pricing and reimbursement
negotiations in individual countries in Europe may delay or limit
the commercial potential of Inrebic® (fedratinib) for the
additional indication described in this release, that continued
approval of such product candidate for such additional indication
described in this release may be contingent upon verification and
description of clinical benefit in confirmatory trials, and whether
such product candidate for such additional indication described in
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market, particularly those identified in the cautionary statement
and risk factors discussion in Bristol Myers Squibb’s Annual Report
on Form 10-K for the year ended December 31, 2019, as updated by
our subsequent Quarterly Reports on Form 10-Q, Current Reports on
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corporatefinancial-news
References:
- INREBIC U.S. Prescribing Information. Accessed January
2021.
- INREBIC Canada Product Monograph. Accessed January 2021.
- Clinical Trials.gov. Phase II, Open Label, Single Arm Study of
SAR302503 In Myelofibrosis Patients Previously Treated With
Ruxolitinib (JAKARTA2). Available at
https://clinicaltrials.gov/ct2/show/NCT01523171. Accessed January
2021.
- Mayo Clinic. Myelofibrosis. Available at:
https://www.mayoclinic.org/diseases-conditions/myelofibrosis/symptomscauses/syc-20355057.
Accessed January 2021.
- Leukemia & Lymphoma Society. Myelofibrosis. Available at:
https://www.lls.org/myeloproliferativeneoplasms/myelofibrosis.
Accessed January 2021.
- Moulard O, et al. Epidemiology of myelofibrosis, essential
thrombocythemia, and polycythemia vera in the European Union.
European Journal of Haematology. 2013;92:289/297.
- Mesa RA, Silverstein MN, Jacobsen SJ, et al. Population-based
incidence and survival figures in essential thrombocythemia and
agnogenic myeloid metaplasia: an Olmsted County Study, 1976-1995.
Am J Hematol. 1999;61(1):10-15.
- Abdel-Wahab O and Levine R. Primary myelofibrosis: Updates on
Definition, Pathogenesis and Treatment. Annual Review of Medicine.
2009;60:233-245.
- Harrison, C.N., Schaap, N. & Mesa, R.A. Management of
myelofibrosis after ruxolitinib failure. Ann Hematol 99,
1177–1191 (2020). https://doi.org/10.1007/s00277-020-04002-9.
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