INREBIC provides new, once-daily oral option
for patients affected by rare bone marrow cancer
Celgene Corporation (NASDAQ: CELG) today
announced the U.S. Food and Drug Administration (FDA) has approved
INREBIC® (fedratinib) for the treatment of adult patients with
intermediate-2 or high-risk primary or secondary (post-polycythemia
vera or post-essential thrombocythemia) myelofibrosis.1
“The approval of INREBIC is another important milestone for
Celgene and underscores our commitment to people living with blood
cancers,” said Jay Backstrom, M.D., M.P.H., Chief Medical Officer
for Celgene. “We are excited to provide INREBIC as a new treatment
option that may be used in patients with myelofibrosis, including
patients previously treated with ruxolitinib.”
“Myelofibrosis can cause patients to suffer in many ways,
including experiencing debilitating symptoms,” said Ruben Mesa,
M.D., FACP, Director of the Mays Cancer Center at UT Health San
Antonio Cancer Center MD Anderson. “There has not been a new
treatment approved for this disease in nearly a decade. With
INREBIC, physicians and patients now have another option available
for myelofibrosis.”
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),1 of whom 459 had
myelofibrosis,1 including 97 previously treated with ruxolitinib.1
The JAKARTA study evaluated the efficacy and safety 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 who were previously untreated with a JAK inhibitor,
had enlarged spleens (a condition known as splenomegaly), and had a
platelet count of ≥50 x 109/L (median baseline platelet count was
214 x 109/L; 16% <100 x 109/L and 84% ≥100 x 109/L).1,2 In the
JAKARTA study, spleen volume was reduced by 35% or greater, when
assessed from baseline to the end of cycle 6 (week 24), with a
4-week follow-up scan, in 37% (35 of 96) of patients treated with
INREBIC 400 mg versus 1% (1 of 96) of patients who received placebo
(p<0.0001).1 INREBIC also improved the Total Symptom Score 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)
by 50% or greater when assessed from baseline to the end of cycle 6
in 40% of (36 of 89) patients treated with 400 mg, versus 9% (7 of
81) of patients who received placebo (p<0.0001).1
INREBIC has a Boxed Warning for serious and fatal
encephalopathy, including Wernicke’s. Serious encephalopathy was
reported in 1.3% (8 of 608) of patients treated with INREBIC in
clinical trials and 0.16% (1 of 608) of the cases were fatal.
Wernicke’s encephalopathy is a neurologic emergency resulting from
thiamine (Vitamin B1) deficiency. Thiamine levels should be
assessed in all patients prior to starting INREBIC, periodically
during treatment, and as clinically indicated.1 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.
In the JAKARTA study, serious adverse reactions occurred in 21%
of patients treated with INREBIC 400 mg once daily (n=96), with the
most common (≥2%) being cardiac failure (5%) and anemia (2%).1
Fatal adverse reactions of cardiogenic shock occurred in 1% of
patients.1 Permanent discontinuation due to an adverse reaction
occurred in 14% of patients. The most frequent reasons for
permanent discontinuation in ≥2% of patients receiving INREBIC
included cardiac failure (3%), thrombocytopenia, myocardial
ischemia, diarrhea, and increased blood creatinine (2% each).1
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%).
“INREBIC is a much-welcomed new treatment for the myelofibrosis
community,” said Ann Brazeau, Chief Executive Officer and Founder,
MPN Advocacy and Education International. “This FDA approval marks
an important milestone for people living with myelofibrosis as we
embark on making greater strides in the diagnosis, understanding
and treatment of this disease.”
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.3 The disorder can
lead to anemia, weakness, fatigue and enlargement of the spleen and
liver, among other symptoms.3 Myelofibrosis is classified as a
myeloproliferative neoplasm, a group of rare blood cancers that are
derived from blood-forming stem cells.4 In the U.S., between 16,000
and 18,500 are living with myelofibrosis,5 and 1.5 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
About JAKARTA
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/L2 (median baseline platelet count was 214 x 109/L; 16% of
patients had a platelet count <100 x 109/L and 84% of patients
had a platelet count ≥100 x 109/L) who were previously untreated
with a JAK inhibitor.1,2 The study included 289 patients randomized
to receive either INREBIC 500 mg (n=97) or 400 mg (n=96) or placebo
(n=96)1 across 94 sites in 24 countries.
The primary endpoint 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. Secondary
endpoints 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
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
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).
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% 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 patient 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.
About Celgene
Celgene Corporation, headquartered in Summit, New Jersey, is an
integrated global biopharmaceutical company engaged primarily in
the discovery, development and commercialization of innovative
therapies for the treatment of cancer and inflammatory diseases
through next-generation solutions in protein homeostasis,
immuno-oncology, epigenetics, immunology and neuro-inflammation.
For more information, please visit www.celgene.com.
Follow Celgene on Social Media: @Celgene,
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Facebook and YouTube.
Forward-Looking Statements
This press release contains forward-looking statements, which
are generally statements that are not historical facts.
Forward-looking statements can be identified by the words
"expects," "anticipates," "believes," "intends," "estimates,"
"plans," "will," "outlook" and similar expressions. Forward-looking
statements are based on management's current plans, estimates,
assumptions and projections, and speak only as of the date they are
made. We undertake no obligation to update any forward-looking
statement in light of new information or future events, except as
otherwise required by law. Forward-looking statements involve
inherent risks and uncertainties, most of which are difficult to
predict and are generally beyond our control. Actual results or
outcomes may differ materially from those implied by the
forward-looking statements as a result of the impact of a number of
factors, many of which are discussed in more detail in our Annual
Report on Form 10-K and our other reports filed with the U.S.
Securities and Exchange Commission, including factors related to
the proposed transaction between Bristol-Myers Squibb and Celgene,
such as, but not limited to, the risks that: management’s time and
attention is diverted on transaction related issues; disruption
from the transaction make it more difficult to maintain business,
contractual and operational relationships; legal proceedings are
instituted against Bristol-Myers Squibb, Celgene or the combined
company that could delay or prevent the proposed transaction; and
Bristol-Myers Squibb, Celgene or the combined company is unable to
retain key personnel.
Hyperlinks are provided as a convenience and for informational
purposes only. Celgene bears no responsibility for the security or
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All trademarks are the property of their respective owners.
1 INREBIC U.S. Prescribing Information. Accessed August 2019. 2
Clinical Trials.gov. Phase III Study of SAR302503 in Intermediate-2
and High Risk Patients with Myelofibrosis (JAKARTA). Available at
https://clinicaltrials.gov/ct2/show/NCT01437787. Accessed May 2019.
3 Mayo Clinic. Myelofibrosis. Available at:
https://www.mayoclinic.org/diseases-conditions/myelofibrosis/symptoms-causes/syc-20355057.
Accessed July 2019. 4 Leukemia & Lymphoma Society.
Myelofibrosis. Available at:
https://www.lls.org/myeloproliferative-neoplasms/myelofibrosis.
Accessed July 2019. 5 Voices of MPN. About Myelofibrosis. Available
at
https://www.voicesofmpn.com/myelofibrosis-information.aspx.
Accessed July 2019. 6 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. 7 Abdel-Wahab O
and Levine R. Primary myelofibrosis: Updates on Definition,
Pathogenesis and Treatment. Annual Review of Medicine.
2009;60:233-245. 8 Mesa R, Niblack J, Wadleigh M, et al. The burden
of fatigue and quality of life in myeloproliferative disorders
(MPDs). Cancer. 2007;109:68-76.
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