Zeposia brings a new way of treating this
chronic immune-mediated disease, approved for adults with
moderately to severely active ulcerative colitis (UC) who have had
an inadequate response, lost response, or were intolerant to either
conventional therapy or a biologic agent
Zeposia is the first and only oral
sphingosine 1-phosphate (S1P) receptor modulator for UC, with this
approval marking its second indication in the European
Union
Zeposia approval is based on the
Phase 3 True North trial, which demonstrated clinically
meaningful improvements in key clinical, endoscopic and mucosal
healing endpoints, with no new safety signals observed
Bristol Myers Squibb (NYSE:BMY) today announced the European
Commission has granted a Marketing Authorization for Zeposia
(ozanimod) for the treatment of adults with moderately to severely
active ulcerative colitis (UC) who have had an inadequate response,
lost response, or were intolerant to either conventional therapy or
a biologic agent. Zeposia, an oral medication taken once daily, is
a sphingosine 1-phosphate (S1P) receptor modulator that binds with
high affinity selectively to S1P subtypes 1 (S1P1) and 5 (S1P5).
Zeposia is the first and only oral S1P receptor modulator approved
for UC, and represents a new way of treating this chronic
immune-mediated disease.
“With today’s European Commission approval of Zeposia for
ulcerative colitis, patients and physicians now have a once-daily
oral treatment option to help address this debilitating disease,
with a demonstrated efficacy and safety profile and a different
mechanism of action than other available therapies,” said Jonathan
Sadeh, M.D., MSc., senior vice president of Immunology and Fibrosis
Development, Bristol Myers Squibb. “We are proud of our heritage in
transformational science and innovative medicines that has brought
us to this stage and look forward to offering appropriate patients
in Europe a new therapy that provides significant symptom relief
and lasting clinical remission.”
The approval was based on data from True North, a pivotal Phase
3 trial evaluating Zeposia as an induction and maintenance therapy
versus placebo in adult patients with moderately to severely active
UC. Key findings from the trial include:
- During induction at Week 10 (Zeposia N=429 versus placebo
N=216) the trial met its primary endpoint of clinical remissiona
(18% versus 6%, p<0.0001) as well as key secondary endpoints,
including clinical responseb (48% versus 26%, p<0.0001),
endoscopic improvementc (27% versus 12%, p<0.0001) and
endoscopic-histologic mucosal improvementd (13% versus 4%,
p<0.001) for Zeposia versus placebo, respectively.
- During maintenance at Week 52 (Zeposia N=230 versus placebo
N=227) the trial met its primary endpoint of clinical remissiona
(37% versus 19%, p<0.0001) as well as key secondary endpoints,
including clinical response (60% versus 41%, p<0.0001),
endoscopic improvement (46% versus 26%, p<0.001),
corticosteroid-free clinical remissione (32% versus 17%,
p<0.001) and endoscopic-histologic mucosal improvement (30%
versus 14%, p<0.001) for Zeposia versus placebo, respectively.
Decreases in rectal bleeding and stool frequency subscores were
observed as early as Week 2 (i.e., 1 week after completing the
required 7-day dosage titration) in patients treated with
Zeposia.
- In the induction and maintenance phases of the True North
trial, the overall safety profile was consistent with the known
safety profile for Zeposia and patients with moderate to severe
UC.
“The findings from the True North trial show that Zeposia
demonstrated significant, durable efficacy in patients with
moderate to severe ulcerative colitis across multiple key endpoints
such as clinical improvement, endoscopic and mucosal healing and
clinical remission,” said Dr. Silvio Danese, M.D., Director,
Gastroenterology and Endoscopy, IRCCS, San Raffaele Hospital and
University Vita-Salute San Raffaele in Milan. “The results for
endoscopic improvement and histologic remission are particularly
meaningful because they can be very difficult to achieve,
indicating that Zeposia has the potential to be an effective and
safe oral treatment option for clinicians treating adults living
with this serious, chronic disease.”
“In Europe, over 3 million people are affected by inflammatory
bowel disease, which includes ulcerative colitis, a challenging and
often debilitating form of the disease,” said Luisa Avedano, CEO,
European Federation of Crohn's & Ulcerative Colitis
Associations. “I’m thrilled that we now have a new treatment option
for patients and their caregivers as they manage the symptoms of a
disease that can have a such detrimental impact on quality of
life.”
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. The most commonly reported adverse
reactions (>5%) in controlled periods of the adult multiple
sclerosis (MS) and UC clinical studies are nasopharyngitis, alanine
aminotransferase (ALT) increased, and gamma-glutamyl transferase
(GGT) increased. The most common adverse reactions leading to
discontinuation were related to liver enzyme elevations (1.1%) in
the MS clinical studies. Liver enzyme elevations leading to
discontinuation occurred in 0.4% of patients, in UC controlled
clinical studies. The overall safety profile was similar for
patients with MS and UC.
Bristol Myers Squibb thanks the patients and investigators
involved in the True North clinical trial.
About True North
True North is a Phase 3, multicenter, randomized, double-blind,
placebo-controlled clinical trial assessing the efficacy and safety
of Zeposia 0.92 mg in patients with moderately to severely active
ulcerative colitis (UC) who had an inadequate response or were
intolerant to any of the following: oral aminosalicylates,
corticosteroids, immunomodulators or a biologic. Patients were to
be receiving treatment with oral aminosalicylates and/or
corticosteroids prior to and during the induction period. A total
of 30% of patients had previously failed or were intolerant to TNF
blockers. Of these patients, 63% received at least two biologics
including TNF blockers. At study entry, mean age was 42 years, 60%
were male and mean disease duration was 7 years; patient
characteristics were well-balanced across treatment groups. In the
10-week induction study (UC Study 1), a total of 645 patients were
randomized 2:1 to receive Zeposia (n=429) or placebo (n=216), of
whom 94% and 89%, respectively, completed the induction study. No
new safety signals were observed in the induction phase.
In maintenance, UC Study 2, a total of 457 patients who received
Zeposia in either UC Study 1 or in an open-label arm and achieved
clinical response at Week 10 were re-randomized 1:1 and were
treated with either Zeposia 0.92 mg (n=230) or placebo (n=227) for
42 weeks (UC Study 2), for a total of 52 weeks of treatment.
Concomitant aminosalicylates were required to remain stable through
week 52. Patients on concomitant corticosteroids were to taper
their dose upon entering the maintenance study. Of these, 80% and
54.6% of patients who received Zeposia and placebo, respectively,
completed the study. In the maintenance phase, the overall safety
profile was consistent with the known safety profile for Zeposia
and patients with moderate to severe UC. More information about the
True North trial can be found on www.clinicaltrials.gov,
NCT02435992.
The clinical findings from True North, entitled “Ozanimod as
Induction and Maintenance Therapy for Ulcerative Colitis,” were
published in the September 30th issue of The New England Journal of
Medicine.
All eligible patients were rolled into an open-label extension
trial, which is ongoing and designed to assess the longer-term
profile of Zeposia for the treatment of moderately to severely
active UC. Among patients who entered the trial clinical remission,
clinical response, endoscopic improvement, and symptomatic
remission were generally maintained through week 142. No new safety
concerns were identified in this study extension in patients with
UC. More information about the open-label extension trial can be
found on www.clinicaltrials.gov, NCT02531126.
About Ulcerative Colitis
Ulcerative colitis, a chronic inflammatory bowel disease (IBD),
is characterized by an irregular, chronic immune response that
creates inflammation and ulcers (sores) in the mucosa (lining) of
the large intestine (colon) or rectum. Symptoms include bloody
stools, severe diarrhea and frequent abdominal pain. Ulcerative
colitis has a major impact on patients' health-related quality of
life, including physical functioning, social and emotional
well-being and ability to go to work/school. Many patients have an
inadequate response or do not respond at all to currently available
therapies. It is estimated that approximately 12.6 million people
worldwide are living with IBD.
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 reduces the capacity of lymphocytes to migrate from
lymphoid tissue, reducing the number of circulating lymphocytes in
peripheral blood. The mechanism by which Zeposia exerts therapeutic
effects in UC is unknown but may involve the reduction of
lymphocyte migration into the intestines.
Bristol Myers Squibb is continuing to evaluate Zeposia in an
open-label extension trial, which is ongoing and designed to assess
the longer-term profile of Zeposia for the treatment of moderately
to severely active UC. The company is also investigating Zeposia
for the treatment of moderately to severely active Crohn’s disease
in the ongoing Phase 3 YELLOWSTONE clinical trial program.
The U.S. Food and Drug Administration (FDA) approved Zeposia for
the treatment of adults with moderately to severely active UC on
May 27, 2021, and for the treatment of adults with relapsing forms
of multiple sclerosis (RMS) in March 2020. The European Commission
approved Zeposia for the treatment of adult patients with relapsing
remitting multiple sclerosis (RRMS) with active disease as defined
by clinical or imaging features in May 2020.
U.S. FDA APPROVED INDICATIONS
ZEPOSIA (ozanimod) is indicated for the treatment of:
1. Relapsing forms of multiple sclerosis (MS), to include
clinically isolated syndrome, relapsing-remitting disease, and
active secondary progressive disease, in adults.
2. Moderately to severely active ulcerative colitis (UC) 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 the presence of Mobitz type II
second-degree or third degree atrioventricular (AV) block, sick
sinus syndrome, or sino-atrial block, 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 or UC 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. PML has been reported in patients treated
with S1P receptor modulators and other MS and UC 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 the MS and UC 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 and UC.
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 sino-atrial 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 that occurred in the MS
clinical trials of ZEPOSIA-treated patients (≥ 4%): upper
respiratory infection, hepatic transaminase elevation, orthostatic
hypotension, urinary tract infection, back pain, and
hypertension
In the UC clinical trials, the most common adverse reactions
that occurred in ≥4% of ZEPOSIA-treated patients and greater than
in patients who received placebo were upper respiratory infection,
liver test increased, and headache
For additional safety information, please see the full
Prescribing Information and Medication Guide.
Bristol Myers Squibb: Pioneering Paths Forward in Immunology
to Transform Patients’ Lives
Bristol Myers Squibb is inspired by a single vision –
transforming patients’ lives through science. For people living
with immune-mediated diseases, the debilitating reality of enduring
chronic symptoms and disease progression can take a toll on their
physical, emotional and social well-being, making simple tasks and
daily life a challenge. Driven by our deep understanding of the
immune system that spans over 20 years of experience, and our
passion to help patients, the company continues to pursue
pathbreaking science with the goal of delivering meaningful
solutions that address unmet needs in rheumatology,
gastroenterology, dermatology and multiple sclerosis. We follow the
science, aiming to tailor therapies to individual needs, improve
outcomes and expand treatment options by working to identify
mechanisms with the potential to achieve long-term remission – and
perhaps even cures – in the future. By building partnerships with
researchers, patients and caregivers to deliver innovative
treatments, Bristol Myers Squibb strives to elevate patient care to
new standards and deliver what matters most – the promise of living
a better life.
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, any marketing approvals, if granted, may
have significant limitation on their use, that continued approval
of such product candidate for such 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 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, 2020, 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.
corporatefinancial-news
a
Clinical remission is defined as: rectal
bleeding subscore = 0, stool frequency subscore = 0 or 1 (and a
decrease from baseline in the stool frequency subscore of ≥ 1
point), and endoscopy subscore = 0 or 1 without friability.
b
Clinical response is defined as a
reduction from baseline in the 3-component Mayo score of ≥ 2 points
and ≥ 35%, and a reduction from baseline in the rectal bleeding
subscore of ≥ 1 point or an absolute rectal bleeding subscore of 0
or 1.
c
Endoscopic improvement is defined as a
Mayo endoscopy subscore of 0 or 1 without friability.
d
Endoscopic-histologic mucosal improvement
is defined as both Mayo endoscopic subscore of 0 or 1 without
friability and histologic improvement of colonic tissue (defined as
no neutrophils in the epithelial crypts or lamina propria and no
increase in eosinophils, no crypt destruction, and no erosions,
ulcerations, or granulation tissue, i.e., Geboes <2.0).
e
Corticosteroid-free remission is defined
as clinical remission at Week 52 while off corticosteroids for ≥ 12
weeks.
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