Data to be discussed with global health
authorities, including the U.S. Food and Drug Administration (FDA)
and European Medicines Agency (EMA)
Takeda Pharmaceutical Company Limited [TSE:4502] (“Takeda”)
today announced top-line results from the VISIBLE 1 clinical trial
evaluating the efficacy and safety of an investigational
subcutaneous (SC) formulation of vedolizumab for maintenance
therapy in adult patients with moderately to severely active
ulcerative colitis (UC) who achieved clinical response* at week 6
following two doses of open-label vedolizumab intravenous (IV)
induction therapy. In the primary endpoint of the trial, a
statistically significant proportion of patients receiving
vedolizumab SC beginning at week 6 and every two weeks following
achieved clinical remission** at week 52 compared to placebo. The
safety data were consistent with the known safety profile of
vedolizumab, and no new safety signals were identified. Further
data from the trial will be presented at a future scientific
congress.
“Meeting the primary endpoint of the VISIBLE 1 trial marks an
exciting milestone in our approach to developing new ways to meet
the needs of the ulcerative colitis patient community,” said Asit
Parikh, MD PhD, Head of Takeda’s Gastroenterology Therapeutic Area
Unit. “These results are encouraging and build on vedolizumab’s
robust clinical profile with more than 200,000 patient years of
exposure. We plan to discuss these data with health authorities
with the aim of bringing this innovative treatment option to
patients.”
VISIBLE 1 is a pivotal phase 3, randomized, double-dummy,
double-blind, placebo-controlled study, with a vedolizumab IV
reference arm, to evaluate the safety and efficacy of an
investigational SC formulation of vedolizumab as maintenance
therapy in adult patients with moderately to severely active UC who
have achieved clinical response at week 6 following two doses of
open-label vedolizumab IV therapy at weeks 0 and 2. The study
enrolled 384 patients, all of whom had inadequate response with,
loss of response to, or intolerance to corticosteroids,
immunomodulators, or tumor necrosis factor-alpha (TNFα)-antagonist
therapy prior to being enrolled. Patients who achieved clinical
response at week 6 were randomized into one of three treatment
groups, vedolizumab SC 108 mg and placebo IV, vedolizumab IV 300 mg
and placebo SC, or placebo SC and placebo IV. Subcutaneous doses
were administered every two weeks and intravenous doses were
administered every eight weeks.
Additional endpoints assessed in VISIBLE 1 include the
proportion of subjects achieving mucosal healing at week 52,***
durable clinical response,ǂ durable clinical remissionǂǂ and
corticosteroid-free clinical remission at week 52.ǂǂǂ
* Clinical response is defined as a reduction in Mayo score
of ≥3 points and ≥30% from baseline (week 0) with an accompanying
decrease in rectal bleeding subscore of ≥1 point or absolute rectal
bleeding subscore of ≤1 point. ** Clinical remission is defined as
a complete Mayo score of ≤2 points and no individual subscore
greater than >1 point. *** Mucosal healing is defined as a Mayo
endoscopic subscore of ≤1 point. ǂ Durable clinical response is
defined as clinical response at weeks 6 and 52, where clinical
response is defined as a reduction in complete Mayo score of ≥3
points and ≥30% from baseline (week 0) with an accompanying
decrease in rectal bleeding subscore of ≥1 point or absolute rectal
bleeding subscore of ≤1 point. ǂǂ Durable clinical remission is
defined as clinical remission at weeks 6 and 52. ǂǂǂ
Corticosteroid-free clinical remission is defined as participants
using oral corticosteroids at baseline (week 0) who have
discontinued oral corticosteroids and are in clinical remission at
week 52. Clinical remission is defined as a complete Mayo score of
≤2 points and no individual subscore greater than >1 point.
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About the VISIBLE clinical trial programThe VISIBLE
clinical trial program aims to assess the efficacy and safety of an
investigational subcutaneous (SC) formulation of vedolizumab as
maintenance therapy in adult patients with moderately to severely
active ulcerative colitis (UC) and Crohn’s disease (CD).
VISIBLE consists of three phase 3 studies involving over 1,000
patients which includes two randomized, double-blind,
placebo-controlled studies examining the percentage of participants
achieving clinical remission at week 52 in UC and CD respectively,
and an open-label extension study to determine the long-term safety
and efficacy of vedolizumab SC consisting of patients who have
completed one of the randomized clinical trials.
About Ulcerative Colitis and Crohn’s DiseaseUlcerative
colitis (UC) and Crohn’s disease (CD) are two of the most common
forms of inflammatory bowel disease (IBD). Both UC and CD are
chronic, relapsing, remitting, inflammatory conditions of the
gastrointestinal (GI) tract that are often progressive in nature.
UC only involves the large intestine as opposed to CD which can
affect any part of the GI tract from mouth to anus. CD can also
affect the entire thickness of the bowel wall, while UC only
involves the innermost lining of the large intestine. UC commonly
presents with symptoms of abdominal discomfort, loose bowel
movements, including blood or pus. CD commonly presents with
symptoms of abdominal pain, diarrhea, and weight loss. The cause of
UC or CD is not fully understood; however, recent research suggests
hereditary, genetics, environmental factors, and/or an abnormal
immune response to microbial antigens in genetically predisposed
individuals can lead to UC or CD.
About Entyvio® (vedolizumab)Vedolizumab is
a gut-selective biologic and is approved as an intravenous (IV)
formulation. It is a humanized monoclonal antibody designed to
specifically antagonize the alpha4beta7 integrin, inhibiting the
binding of alpha4beta7 integrin to intestinal mucosal addressin
cell adhesion molecule 1 (MAdCAM-1), but not vascular cell adhesion
molecule 1 (VCAM-1). MAdCAM-1 is preferentially expressed on blood
vessels and lymph nodes of the gastrointestinal tract. The
alpha4beta7 integrin is expressed on a subset of circulating white
blood cells. These cells have been shown to play a role in
mediating the inflammatory process in ulcerative colitis (UC) and
Crohn’s disease (CD). By inhibiting alpha4beta7 integrin,
vedolizumab may limit the ability of certain white blood cells to
infiltrate gut tissues.
Vedolizumab IV is approved for the treatment of adult patients
with moderately to severely active UC and CD, who have had an
inadequate response with, lost response to, or were intolerant to
either conventional therapy or a tumor necrosis factor-alpha (TNFα)
antagonist. Vedolizumab IV has been granted marketing authorization
in over 60 countries, including the United States and European
Union, with over 200,000 patient years of exposure to date.
Therapeutic Indications
Ulcerative colitisVedolizumab is indicated for the
treatment of adult patients with moderately to severely active
ulcerative colitis who have had an inadequate response with, lost
response to, or were intolerant to either conventional therapy or a
tumor necrosis factor-alpha (TNFα) antagonist.
Crohn’s diseaseVedolizumab is indicated for the treatment
of adult patients with moderately to severely active Crohn’s
disease who have had an inadequate response with, lost response to,
or were intolerant to either conventional therapy or a tumor
necrosis factor-alpha (TNFα) antagonist.
Important Safety Information
ContraindicationsHypersensitivity to the active substance
or to any of the excipients.
Special warnings and special precautions for
useVedolizumab should be administered by a healthcare
professional equipped to manage hypersensitivity reactions,
including anaphylaxis, if they occur. Appropriate monitoring and
medical support measures should be available for immediate use when
administering vedolizumab. Observe all patients during infusion and
until the infusion is complete.
Infusion-related reactionsIn clinical studies,
infusion-related reactions (IRR) and hypersensitivity reactions
have been reported, with the majority being mild to moderate in
severity. If a severe IRR, anaphylactic reaction, or other severe
reaction occurs, administration of vedolizumab must be discontinued
immediately and appropriate treatment initiated (e.g., epinephrine
and antihistamines). If a mild to moderate IRR occurs, the infusion
rate can be slowed or interrupted and appropriate treatment
initiated (e.g., epinephrine and antihistamines). Once the mild or
moderate IRR subsides, continue the infusion. Physicians should
consider pre-treatment (e.g., with antihistamine, hydrocortisone
and/or paracetamol) prior to the next infusion for patients with a
history of mild to moderate IRR to vedolizumab, in order to
minimize their risks.
InfectionsVedolizumab is a gut-selective integrin
antagonist with no identified systemic immunosuppressive activity.
Physicians should be aware of the potential increased risk of
opportunistic infections or infections for which the gut is a
defensive barrier. Vedolizumab treatment is not to be initiated in
patients with active, severe infections such as tuberculosis,
sepsis, cytomegalovirus, listeriosis, and opportunistic infections
until the infections are controlled, and physicians should consider
withholding treatment in patients who develop a severe infection
while on chronic treatment with vedolizumab. Caution should be
exercised when considering the use of vedolizumab in patients with
a controlled chronic severe infection or a history of recurring
severe infections. Patients should be monitored closely for
infections before, during and after treatment. Before starting
treatment with vedolizumab, screening for tuberculosis may be
considered according to local practice. Some integrin antagonists
and some systemic immunosuppressive agents have been associated
with progressive multifocal leukoencephalopathy (PML), which is a
rare and often fatal opportunistic infection caused by the John
Cunningham (JC) virus. By binding to the α4β7 integrin expressed on
gut-homing lymphocytes, vedolizumab exerts an immunosuppressive
effect on the gut. Although no systemic immunosuppressive effect
was noted in healthy subjects, the effects on systemic immune
system function in patients with inflammatory bowel disease are not
known. No cases of PML were reported in clinical studies of
vedolizumab however, healthcare professionals should monitor
patients on vedolizumab for any new onset or worsening of
neurological signs and symptoms, and consider neurological referral
if they occur. If PML is suspected, treatment with vedolizumab must
be withheld; if confirmed, treatment must be permanently
discontinued. Typical signs and symptoms associated with PML are
diverse, progress over days to weeks, and include progressive
weakness on one side of the body, clumsiness of limbs, disturbance
of vision, and changes in thinking, memory, and orientation leading
to confusion and personality changes. The progression of deficits
usually leads to death or severe disability over weeks or
months.
MalignanciesThe risk of malignancy is increased in
patients with ulcerative colitis and Crohn’s disease.
Immunomodulatory medicinal products may increase the risk of
malignancy.
Prior and concurrent use of biological productsNo
vedolizumab clinical trial data are available for patients
previously treated with natalizumab. Caution should be exercised
when considering the use of vedolizumab in these patients. No
clinical trial data for concomitant use of vedolizumab with
biologic immunosuppressants are available. Therefore, the use of
vedolizumab in such patients is not recommended.
VaccinationsPrior to initiating treatment with
vedolizumab all patients should be brought up to date with all
recommended immunizations. Patients receiving vedolizumab may
receive non-live vaccines (e.g., subunit or inactivated vaccines)
and may receive live vaccines only if the benefits outweigh the
risks.
Adverse reactions include: nasopharyngitis, headache,
arthralgia, upper respiratory tract infection, bronchitis,
influenza, sinusitis, cough, oropharyngeal pain, nausea, rash,
pruritus, back pain, pain in extremities, pyrexia, and fatigue.
Please consult with your local regulatory agency for approved
labeling in your country.
For U.S. audiences, please see the
full Prescribing
Information including Medication
Guide for ENTYVIO®.
For EU audiences, please see the Summary of Product
Characteristics (SmPC) for ENTYVIO®.
Takeda’s Commitment to GastroenterologyGastrointestinal
(GI) diseases can be complex, debilitating and life-changing.
Recognizing this unmet need, Takeda and our collaboration partners
have focused on improving the lives of patients through the
delivery of innovative medicines and dedicated patient disease
support programs for over 25 years. Takeda aspires to advance how
patients manage their disease. Additionally, Takeda is leading in
areas of gastroenterology associated with high unmet need, such as
inflammatory bowel disease, acid-related diseases and motility
disorders. Our GI Research & Development team is also exploring
solutions in celiac disease and liver diseases, as well as
scientific advancements through microbiome therapies.
About Takeda Pharmaceutical Company LimitedTakeda
Pharmaceutical Company Limited (TSE: 4502) is a global, research
and development-driven pharmaceutical company committed to bringing
better health and a brighter future to patients by translating
science into life-changing medicines. Takeda focuses its R&D
efforts on oncology, gastroenterology and neuroscience therapeutic
areas plus vaccines. Takeda conducts R&D both internally and
with partners to stay at the leading edge of innovation. Innovative
products, especially in oncology and gastroenterology, as well as
Takeda’s presence in emerging markets, are currently fueling the
growth of Takeda. Around 30,000 Takeda employees are committed to
improving quality of life for patients, working with Takeda’s
partners in health care in more than 70 countries.
For more information, visit
https://www.takeda.com/newsroom/.
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Takeda Pharmaceutical Company LimitedFor media outside
Japan:Luke WillatsTEL: +41-44-555-1145Luke.Willats@takeda.comorFor
Japanese media:Kazumi KobayashiTEL:
+81-3-3278-2095kazumi.kobayashi@takeda.com