Zeposia offers relapsing remitting multiple
sclerosis (RRMS) patients with active disease in the European Union
a new oral option to help address the disease’s hallmark relapses
and brain lesions
Zeposia is the only approved
sphingosine-1-phosphate (S1P) receptor modulator for RRMS patients
with active disease
Zeposia adds to Bristol Myers Squibb’s
immunology franchise and marks the first European Commission
marketing authorization since the Celgene acquisition
Bristol Myers Squibb (NYSE:BMY) today announced that the
European Commission (EC) has approved Zeposia (ozanimod) for the
treatment of adult patients with relapsing remitting multiple
sclerosis (RRMS) with active disease as defined by clinical or
imaging features. With the EC marketing authorization, Zeposia, an
oral medication taken once daily, becomes the only approved
sphingosine-1-phosphate (S1P) receptor modulator for RRMS patients
with active disease. The approval is based on data from the
SUNBEAM™ and RADIANCE™ Part B clinical trials showing that, as
compared to AVONEX® (interferon beta-1a), Zeposia delivered
powerful efficacy as measured by annualized relapse rate (ARR), as
well as on the number and size of brain lesions.
“Today’s European Commission approval provides the opportunity
for patients with RRMS with active disease to be offered Zeposia as
a new first-line treatment option, which is an important
advancement based on Phase 3 trial results showing significant
improvements in relapses and brain lesions caused by this
devastating disease,” said Samit Hirawat, M.D., chief medical
officer, Bristol Myers Squibb. “We share this achievement with the
courageous multiple sclerosis patient community in Europe and
around the globe, and are working closely with all stakeholders to
ensure that eligible European patients can start benefitting from
Zeposia as quickly as possible.”
Multiple sclerosis (MS) is a disease in which the immune system
attacks the protective myelin sheath that covers the nerves,
creating damaging lesions that make it harder for signals to travel
between each nerve cell. This “signal breakdown” can lead to
symptoms and relapses.
The approval was based on data from the randomized,
active-controlled Phase 3 SUNBEAM and RADIANCE Part B clinical
trials, which enrolled more than 2,600 patients across 150 sites in
more than 20 countries. Key findings from the trials include:
- Zeposia demonstrated a relative reduction in ARR versus AVONEX
of 48% through one year in the SUNBEAM study and 38% at two years
in the RADIANCE study (absolute ARR of 0.18 versus 0.35 and 0.17
versus 0.28, respectively).
- At one year in the SUNBEAM study, treatment with Zeposia
reduced the number of T1‑weighted gadolinium-enhanced (GdE) brain
lesions more than AVONEX (0.16 vs 0.43), a relative reduction of
63%, and reduced the number of new or enlarging T2 brain lesions
(1.47 versus 2.84), a relative reduction of 48%.
- At two years in the RADIANCE study, treatment with Zeposia
reduced the number of T1‑weighted GdE brain lesions more than
AVONEX (0.18 versus 0.37), a relative reduction of 53%. Zeposia
also reduced the number of new or enlarging T2 lesions versus
AVONEX (1.84 versus 3.18), a relative reduction of 42%.
- Zeposia demonstrated a reduction in percent change from
baseline in whole brain volume as compared to AVONEX at one year in
the SUNBEAM study (-0.41% versus -0.61%) and at two years in the
RADIANCE study (-0.71% versus -0.94%).
“There is no one-size-fits-all approach to treating MS. Patients
respond differently to currently available therapies, which is why
having options that address the hallmark characteristics of RRMS is
so important,” said Giancarlo Comi, M.D., Honorary Professor of
Neurology, Director of the Institute of Experimental Neurology at
the Vita-Salute San Raffaele University in Milan. “Given its
demonstrated efficacy and safety profile, Zeposia represents an
important new treatment option that I am excited to offer my
patients.”
Zeposia is the only approved S1P receptor modulator that offers
RRMS patients with active disease an initiation with no first-dose
observation required for the majority of patients.1 First-dose
monitoring is only recommended for high-risk patients with certain
pre-existing cardiac conditions. A dose escalation regimen from day
1 to day 7 should be used to reach the maintenance dose of Zeposia,
as a transient decrease in heart rate and atrioventricular
conduction delays may occur.
Zeposia demonstrated manageable safety and tolerability in the
Phase 3 SUNBEAM and RADIANCE Part B trials. Zeposia is
contraindicated in patients with hypersensitivity to the active
substance or to any of the excipients, as listed in the Summary of
Product Characteristics (SmPC); immunodeficient state; patients who
in the last six months experienced myocardial infarction, unstable
angina, stroke, transient ischemic attack, decompensated heart
failure requiring hospitalization or New York Heart Association
(NYHA) Class III/IV heart failure; patients with history or
presence of second-degree atrioventricular (AV) block Type II or
third-degree AV block or sick sinus syndrome unless the patient has
a functioning pacemaker; severe active infections, active chronic
infections such as hepatitis and tuberculosis; active malignancies;
severe hepatic impairment (Child-Pugh class C); and during
pregnancy and in women of childbearing potential not using
effective contraception. Zeposia is associated with the following
Special Warnings and Precautions for Use: bradyarrhythmia, liver
injury, immunosuppressive effects, increased risk of infections,
progressive multifocal leukoencephalopathy, cutaneous neoplasms,
macular oedema, posterior reversible encephalopathy syndrome,
increased blood pressure, respiratory effects and severe increase
in disability after stopping Zeposia. The most common adverse
reactions (incidence ≥4%) were upper respiratory infection, hepatic
transaminase elevation, orthostatic hypotension, urinary tract
infection, back pain and hypertension.
“Multiple sclerosis is an unpredictable and often disabling
disease that affects about 700,000 people in Europe. We are
delighted by the news that there is now another treatment option
available to potentially delay the progression of this debilitating
disease,” said Pedro Carrascal, President of the European Multiple
Sclerosis Platform.
About SUNBEAM™
SUNBEAM is a pivotal, Phase 3, multicenter, randomized,
double-blind, double-dummy, active-controlled trial evaluating the
efficacy, safety and tolerability of two doses of oral Zeposia
(0.92 mg and 0.46 mg, equivalent to 1 mg and 0.5 mg ozanimod HCI,
respectively) against weekly intramuscular AVONEX® (interferon
beta-1a) for at least a 12-month treatment period. The study
included 1,346 people living with relapsing forms of multiple
sclerosis (RMS) across 152 sites in 20 countries.
The primary endpoint of the trial was ARR during the treatment
period. The secondary MRI endpoints included the number of new or
enlarging hyperintense T2-weighted brain MRI lesions over 12
months, number of gadolinium-enhanced brain MRI lesions at month 12
and percent change from baseline in whole brain volume at month 12.
Cortical grey and thalamic volume changes were also prospectively
assessed versus active comparator.
An analysis of the time to onset of three-month confirmed
disability progression was pre-specified using pooled data from
both the SUNBEAM and RADIANCE Part B Phase 3 trials.
About RADIANCE™
RADIANCE Part B is a pivotal, Phase 3, multicenter, randomized,
double-blind, double-dummy, active-controlled trial evaluating the
efficacy, safety and tolerability of two doses of oral Zeposia
(0.92 mg and 0.46 mg, equivalent to 1 mg and 0.5 mg ozanimod HCI,
respectively) against weekly intramuscular AVONEX® (interferon
beta-1a) over a 24-month treatment period. The study included 1,320
people living with RMS across 150 sites in 21 countries.
The primary endpoint of the trial was ARR over 24 months. The
secondary MRI endpoints included the number of new or enlarging
hyperintense T2-weighted brain MRI lesions over 24 months, number
of gadolinium-enhanced brain MRI lesions at month 24 and percent
change from baseline in whole brain volume at month 24. Cortical
grey and thalamic volume changes were also prospectively assessed
versus active comparator.
An analysis of the time to onset of three-month confirmed
disability progression was pre-specified using pooled data from
both the SUNBEAM and RADIANCE Part B Phase 3 trials.
About Multiple Sclerosis
Multiple sclerosis (MS) is a disease in which the immune system
attacks the protective myelin sheath that covers the nerves. The
myelin damage disrupts communication between the brain and the rest
of the body. Ultimately, the nerves themselves may deteriorate — a
process that's currently irreversible. MS affects 700,000 people in
Europe and approximately 2.5 million people worldwide.
Relapsing remitting MS (RRMS) is characterized by clearly
defined attacks of worsening neurologic function. These attacks —
often called relapses, flare-ups or exacerbations — are followed by
partial or complete recovery periods (remissions), during which
symptoms improve partially or completely with no apparent
progression of disease. At different points in time, RRMS can be
characterized as active (with relapses and/or evidence of new MRI
activity) or not active, as well as worsening (a confirmed increase
in disability over a specified period of time following a relapse)
or not worsening. RRMS is the most common disease course at the
time of diagnosis. Approximately 85 percent of patients are
initially diagnosed with RRMS, compared with 10-15 percent with
progressive forms of the disease.
About Zeposia (ozanimod)
Zeposia (ozanimod) is an oral, sphingosine 1-phosphate (S1P)
receptor modulator that binds with high affinity to S1P receptors 1
and 5. Zeposia blocks the capacity of lymphocytes to egress from
lymph nodes, reducing the number of lymphocytes in peripheral
blood. The mechanism by which Zeposia exerts therapeutic effects in
multiple sclerosis is unknown but may involve the reduction of
lymphocyte migration into the central nervous system.
The U.S. Food and Drug Administration (FDA) approved Zeposia for
the treatment of adults with relapsing forms of multiple sclerosis
(RMS) in March 2020. Zeposia is also in development for additional
immune-inflammatory indications, including ulcerative colitis and
Crohn's disease.
U.S. FDA-APPROVED INDICATION FOR ZEPOSIA
ZEPOSIA is indicated for the treatment of relapsing forms of
multiple sclerosis (MS), to include clinically isolated syndrome,
relapsing-remitting disease, and active secondary progressive
disease, in adults.
IMPORTANT SAFETY INFORMATION
Contraindications:
- Patients who in the last 6 months, experienced myocardial
infarction, unstable angina, stroke, transient ischemic attack
(TIA), decompensated heart failure requiring hospitalization, or
Class III/IV heart failure or have a presence of Mobitz type II
second or third-degree atrioventricular (AV) block, sick sinus
syndrome, or sino-atrial, unless the patient has a functioning
pacemaker
- Patients with severe untreated sleep apnea
- Patients taking a monoamine oxidase (MAO) inhibitor
Infections: ZEPOSIA may increase the susceptibility to
infections. Life-threatening and rare fatal infections have
occurred in patients receiving ZEPOSIA. Obtain a recent (i.e.,
within 6 months or after discontinuation of prior MS therapy)
complete blood count (CBC) including lymphocyte count before
initiation of ZEPOSIA. Delay initiation of ZEPOSIA in patients with
an active infection until the infection is resolved. Consider
interruption of treatment with ZEPOSIA if a patient develops a
serious infection. Continue monitoring for infections up to 3
months after discontinuing ZEPOSIA
- Herpes zoster was reported as an adverse reaction in
ZEPOSIA-treated patients. Herpes simplex encephalitis and varicella
zoster meningitis have been reported with sphingosine 1-phosphate
(S1P) receptor modulators. Patients without a healthcare
professional-confirmed history of varicella (chickenpox), or
without documentation of a full course of vaccination against
varicella zoster virus (VZV), should be tested for antibodies to
VZV before initiating ZEPOSIA. A full course of vaccination for
antibody-negative patients with varicella vaccine is recommended
prior to commencing treatment with ZEPOSIA
- Cases of fatal cryptococcal meningitis (CM) were reported in
patients treated with another S1P receptor modulator. If CM is
suspected, ZEPOSIA should be suspended until cryptococcal infection
has been excluded. If CM is diagnosed, appropriate treatment should
be initiated.
- Progressive Multifocal Leukoencephalopathy (PML) is an
opportunistic viral infection of the brain that typically occurs in
patients who are immunocompromised, and that usually leads to death
or severe disability. No cases of PML were identified in
active-controlled MS clinical trials with ZEPOSIA. PML has been
reported in patients treated with S1P receptor modulators and other
MS therapies and has been associated with some risk factors. If PML
is suspected, withhold ZEPOSIA and perform an appropriate
diagnostic evaluation. If confirmed, treatment with ZEPOSIA should
be discontinued
- In clinical studies, patients who received ZEPOSIA were not to
receive concomitant treatment with antineoplastic,
non-corticosteroid immunosuppressive, or immune-modulating
therapies used for treatment of MS. Concomitant use of ZEPOSIA with
any of these therapies would be expected to increase the risk of
immunosuppression. When switching to ZEPOSIA from immunosuppressive
medications, consider the duration of their effects and their mode
of action to avoid unintended additive immunosuppressive
effects
- Use of live attenuated vaccines should be avoided during and
for 3 months after treatment with ZEPOSIA. If live attenuated
vaccine immunizations are required, administer at least 1 month
prior to initiation of ZEPOSIA
Bradyarrhythmia and Atrioventricular Conduction Delays:
Since initiation of ZEPOSIA may result in a transient decrease in
heart rate and atrioventricular conduction delays, dose titration
is recommended to help reduce cardiac effects. Initiation of
ZEPOSIA without dose escalation may result in greater decreases in
heart rate. If treatment with ZEPOSIA is considered, advice from a
cardiologist should be sought for those individuals:
- with significant QT prolongation
- with arrhythmias requiring treatment with Class 1a or III
anti-arrhythmic drugs
- with ischemic heart disease, heart failure, history of cardiac
arrest or myocardial infarction, cerebrovascular disease, and
uncontrolled hypertension
- with a history of Mobitz type II second-degree or higher AV
block, sick-sinus syndrome, or sinoatrial heart block
Liver Injury: Elevations of aminotransferases may occur
in patients receiving ZEPOSIA. Obtain liver function tests, if not
recently available (i.e., within 6 months), before initiation of
ZEPOSIA. Patients who develop symptoms suggestive of hepatic
dysfunction should have hepatic enzymes checked and ZEPOSIA should
be discontinued if significant liver injury is confirmed. Caution
should be exercised when using ZEPOSIA in patients with history of
significant liver disease
Fetal Risk: There are no adequate and well-controlled
studies in pregnant women. Based on animal studies, ZEPOSIA may
cause fetal harm. Women of childbearing potential should use
effective contraception to avoid pregnancy during treatment and for
3 months after stopping ZEPOSIA
Increased Blood Pressure: Increase in systolic pressure
was observed after about 3 months of treatment and persisted
throughout treatment. Blood pressure should be monitored during
treatment and managed appropriately. Certain foods that may contain
very high amounts of tyramine could cause severe hypertension in
patients taking ZEPOSIA. Patients should be advised to avoid foods
containing a very large amount of tyramine while taking ZEPOSIA
Respiratory Effects: ZEPOSIA may cause a decline in
pulmonary function. Spirometric evaluation of respiratory function
should be performed during therapy, if clinically indicated
Macular edema: S1P modulators have been associated with
an increased risk of macular edema. Patients with a history of
uveitis or diabetes mellitus are at increased risk. Patients with a
history of these conditions should have an ophthalmic evaluation of
the fundus, including the macula, prior to treatment initiation and
regular follow-up examinations. An ophthalmic evaluation is
recommended in all patients at any time if there is a change in
vision. Continued use of ZEPOSIA in patients with macular edema has
not been evaluated; potential benefits and risks for the individual
patient should be considered if deciding whether ZEPOSIA should be
discontinued
Posterior Reversible Encephalopathy Syndrome (PRES): Rare
cases of PRES have been reported in patients receiving a S1P
receptor modulator. If a ZEPOSIA-treated patient develops
unexpected neurological or psychiatric symptoms or any symptom/sign
suggestive of an increase in intracranial pressure, a complete
physical and neurological examination should be conducted. Symptoms
of PRES are usually reversible but may evolve into ischemic stroke
or cerebral hemorrhage. Delay in diagnosis and treatment may lead
to permanent neurological sequelae. If PRES is suspected, treatment
with ZEPOSIA should be discontinued
Unintended Additive Immunosuppressive Effects From Prior
Immunosuppressive or Immune-Modulating Drugs: When switching
from drugs with prolonged immune effects, the half-life and mode of
action of these drugs must be considered to avoid unintended
additive immunosuppressive effects while at the same time
minimizing risk of disease reactivation. Initiating treatment with
ZEPOSIA after treatment with alemtuzumab is not recommended
Severe Increase in Disability After Stopping
ZEPOSIA: Severe exacerbation of disease, including disease
rebound, has been rarely reported after discontinuation of a S1P
receptor modulator. The possibility of severe exacerbation of
disease should be considered after stopping ZEPOSIA treatment so
patients should be monitored upon discontinuation
Immune System Effects After Stopping ZEPOSIA:
After discontinuing ZEPOSIA, the median time for lymphocyte counts
to return to the normal range was 30 days with approximately 90% of
patients in the normal range within 3 months. Use of
immunosuppressants within this period may lead to an additive
effect on the immune system, therefore caution should be applied
when initiating other drugs 4 weeks after the last dose of
ZEPOSIA
Most common Adverse Reactions (≥ 4%): upper respiratory
infection, hepatic transaminase elevation, orthostatic hypotension,
urinary tract infection, back pain, and hypertension.
For additional safety information, please see the full
Prescribing Information and Medication Guide.
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
follow us on LinkedIn, Twitter, YouTube, Facebook and
Instagram.
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.
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
delay, divert or change any of them in the next several years, that
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 Zeposia (ozanimod) for the indication
described in this release, and whether Zeposia (ozanimod) for the
indication described in this release will be commercially
successful. No forward-looking statement can be guaranteed.
Forward-looking statements in this press release should be
evaluated together with the many risks and uncertainties that
affect Bristol Myers Squibb’s business and 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 Form 8-K and
other filings with the Securities and Exchange Commission. The
forward-looking statements included in this document are made only
as of the date of this document and except as otherwise required by
applicable law, Bristol Myers Squibb undertakes no obligation to
publicly update or revise any forward-looking statement, whether as
a result of new information, future events, changed circumstances
or otherwise.
References
- Zeposia [Summary of Product Characteristics]. Bristol Myers
Squibb. Available at: www.ema.europa.eu.
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