Vedolizumab (Entyvio®) Achieves Superior Rates of Clinical Remission vs. Adalimumab (Humira®) in First Ever Head-to-Head Biologic Clinical Study in Ulcerative Colitis

Vedolizumab superior to adalimumab in achieving clinical remission
and mucosal healing at week 52 in patients with moderately to severely
active ulcerative colitis

OSAKA, Japan–(BUSINESS WIRE)–Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK)
(“Takeda”) today announced results from the Phase 3b head-to-head
VARSITY study which demonstrated that the gut-selective biologic
vedolizumab (Entyvio®) was superior to the anti-tumor
necrosis factor-alpha (anti-TNFα) biologic adalimumab (Humira®)
in achieving clinical remission* in patients with moderately to severely
active ulcerative colitis at week 52. Data showed that 31.3% (n=120/383)
of patients receiving vedolizumab intravenous (IV) achieved the primary
endpoint of clinical remission compared to 22.5% (n=87/386) of patients
treated with adalimumab subcutaneous (SC) at week 52, with the
difference being statistically significant (p=0.0061). These results
were announced as an oral presentation (OP34) on Saturday March 9, 2019
from 09:40-09:50, at the 14th Congress of the European Crohn’s and
Colitis Organisation (ECCO) in Copenhagen, Denmark.1

Furthermore, treatment with vedolizumab was associated with
significantly higher rates of mucosal healing** at week 52, with 39.7%
of patients receiving vedolizumab achieving mucosal healing compared to
27.7% treated with adalimumab (p=0.0005). A non-statistically
significant difference in favor of adalimumab was seen in the percentage
of patients using oral corticosteroids at baseline who discontinued
corticosteroids and were in clinical remission*** at week 52. While the
study was not powered to compare the safety of the two biologics,
patients treated with vedolizumab (62.7%) had a lower rate of overall
adverse events over 52 weeks than patients treated with adalimumab
(69.2%), with a lower rate of infections reported in patients treated
with vedolizumab (33.5%) as compared to adalimumab (43.5%). The rate of
serious adverse events was also lower in vedolizumab-treated patients
than adalimumab (11.0% vs. 13.7% respectively).1

“The VARSITY study addresses critical questions concerning the selection
of biologic therapy in ulcerative colitis,” said Dr. Bruce E. Sands,
primary investigator of the VARSITY study and Chief of the Dr. Henry D.
Janowitz Division of Gastroenterology at Mount Sinai Hospital and the
Icahn School of Medicine at Mount Sinai in New York. “The goal of
treatment in ulcerative colitis is to achieve clinical remission and
mucosal healing, and these results clearly highlight the benefits seen
with vedolizumab versus adalimumab on these important outcomes. The
results also showed lower rates of overall and serious adverse events
including infections in patients treated with vedolizumab than
adalimumab.”

“As the first clinical study to directly compare the efficacy and safety
of two commonly used biologic therapies in patients with ulcerative
colitis, VARSITY provides invaluable knowledge to help inform
physicians’ treatment decisions when initiating biologic therapy,” said
Jeff Bornstein, M.D., Executive Medical Director, Takeda. “This is also
the first time we have seen a direct comparison between two medicines
with distinct modes of action in ulcerative colitis, the gut-selective
anti-alpha4beta7 integrin vedolizumab and the anti-TNFα adalimumab. This
is an exciting time in the landscape of ulcerative colitis treatment, as
head-to-head clinical data has not previously been available to guide
treatment decisions around biologic therapies.”

VARSITY is a phase 3b, randomized, double-blind, double-dummy,
multi-center, active-controlled study to evaluate the efficacy and
safety of vedolizumab IV compared to adalimumab SC at week 52 in
patients with moderately to severely active ulcerative colitis. The
study randomized 769 patients (vedolizumab n=383 or adalimumab n=386),
all of whom had inadequate response with, loss of response to, or
intolerance to corticosteroids, immunomodulators, or one TNFα-antagonist
other than adalimumab prior to being enrolled. Patients were randomized
into one of two treatment groups, vedolizumab IV and placebo SC or
adalimumab SC and placebo IV. Patients in the vedolizumab group were
administered vedolizumab IV 300 mg at weeks 0, 2, 6 and every 8 weeks
thereafter until week 46, along with placebo SC at week 0 and every 2
weeks until week 50. The adalimumab group were administered adalimumab
SC 160 mg at week 0, 80 mg at week 2 and 40 mg every 2 weeks until week
50, along with placebo IV at weeks 0, 2, 6 and every 8 weeks thereafter
until week 46. Dose escalation was not permitted in either treatment arm
during the study.1,2

* Primary endpoint: Clinical remission is defined as a complete Mayo
score of ≤2 points and no individual subscore ˃1 point.2
** Secondary endpoint: Mucosal healing is defined as Mayo endoscopic
subscore of ≤1 point. Mayo score: instrument designed to measure
disease activity of ulcerative colitis.2
*** Secondary endpoint: Corticosteroid-free clinical remission is
defined as patients using oral corticosteroids at baseline (week 0)
who have discontinued oral corticosteroids and are in clinical
remission at week 52.2

About Ulcerative Colitis
Ulcerative colitis (UC) is one of
the most common forms of inflammatory bowel disease (IBD).3
UC is a chronic, relapsing, remitting, inflammatory condition of the
gastrointestinal tract that is often progressive in nature, and involves
the innermost lining of the large intestine.4,5 UC commonly
presents with symptoms of abdominal discomfort and loose bowel
movements, including blood or pus.5,6 The cause of UC 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
the condition.5,7,8

About Entyvio® (vedolizumab)
Vedolizumab
is a gut-selective biologic and is approved as an intravenous (IV)
formulation.9 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).10 MAdCAM-1 is preferentially expressed on blood
vessels and lymph nodes of the gastrointestinal tract.11 The
alpha4beta7 integrin is expressed on a subset of circulating white blood
cells.10 These cells have been shown to play a role in
mediating the inflammatory process in ulcerative colitis (UC) and
Crohn’s disease (CD).10,12,13 By inhibiting alpha4beta7
integrin, vedolizumab may limit the ability of certain white blood cells
to infiltrate gut tissues.10

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.9
Vedolizumab IV has been granted marketing authorization in over 60
countries, including the United States and European Union, with more
than 260,000 patient years of exposure to date.14

Therapeutic Indications

Ulcerative colitis
Vedolizumab 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 disease
Vedolizumab 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

Contraindications
Hypersensitivity to the active substance
or to any of the excipients.

Special warnings and special precautions for use
Vedolizumab
should be administered by a healthcare professional prepared 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 patients
during infusion and until the infusion is complete.

Infusion-related reactions
In 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.

Infections
Vedolizumab 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 specific to
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. 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.

Malignancies
The 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 products
No
vedolizumab clinical trial data are available for patients previously
treated with natalizumab. 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.

Vaccinations
Prior 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, fatigue and anaphylaxis.

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 Gastroenterology
Gastrointestinal
(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 Limited
Takeda
Pharmaceutical Company Limited (TSE:4502/NYSE:TAK)
is a global, values-based, R&D-driven biopharmaceutical leader
headquartered in Japan, committed to bringing Better Health and a
Brighter Future to patients by translating science into
highly-innovative medicines. Takeda focuses its R&D efforts on four
therapeutic areas: Oncology, Gastroenterology (GI), Neuroscience, and
Rare Diseases. We also make targeted R&D investments in Plasma-Derived
Therapies and Vaccines. We are focusing on developing highly innovative
medicines that contribute to making a difference in people’s lives by
advancing the frontier of new treatment options and leveraging our
enhanced collaborative R&D engine and capabilities to create a robust,
modality-diverse pipeline. Our employees are committed to improving
quality of life for patients and to working with our partners in health
care in approximately 80 countries and regions.

For more information, visit https://www.takeda.com

###

References

1 Schreiber S, Peyrin-Biroulet L, Loftus EV Jr, et al.
VARSITY: A double-blind, double-dummy, randomised, controlled trial of
vedolizumab versus adalimumab in patients with active ulcerative
colitis. Presented at the 14th Congress of the Crohn’s and
Colitis Organisation (ECCO), Copenhagen, Denmark. Oral presentation
#OP34 (Saturday March 9, 2019, 09:40-09:50).
2 An
efficacy and safety study of vedolizumab intravenous (IV) compared to
adalimumab subcutaneous (SC) in participants with ulcerative colitis.
ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT02497469.
Last updated: February 28, 2019. Last Accessed: February 2019.
3
Baumgart DC, Carding SR. Inflammatory bowel disease: cause and
immunobiology. Lancet. 2007;369:1627-1640.
4
Torres J, Billioud V, Sachar DB, et al. Ulcerative colitis as a
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Sands BE. From symptom to diagnosis: clinical distinctions among various
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7 Henckaerts L, Pierik M, Joossens
M, et al. Mutations in pattern recognition receptor genes modulate
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disease. Gut. 2007;56:1536-1542.
8 Kaser A,
Zeissig S, Blumberg RS. Genes and environment: How will our concepts on
the pathophysiology of IBD develop in the future? Dig Dis.
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9 European Medicines Agency. Entyvio
EPAR product information. EMEA/H/C/002782 – IB/0030 ANNEX 1 Summary of
Product Characteristics. Available at: https://www.ema.europa.eu/documents/product-information/entyvio-epar-product-information_en.pdf
Last updated: September 3, 2018. Last accessed: February 2019.
10
Soler D, Chapman T, Yang LL, et al. The binding specificity and
selective antagonism of vedolizumab, an anti-α4β7 integrin therapeutic
antibody in development for inflammatory bowel diseases. J Pharmacol
Exp Ther
. 2009;330:864-875.
11 Briskin M,
Winsor-Hines D, Shyjan A, et al. Human mucosal addressin cell adhesion
molecule-1 is preferentially expressed in intestinal tract and
associated lymphoid tissue. Am J Pathol. 1997;151:97-110.
12
Eksteen B, Liaskou E, Adams DH. Lymphocyte homing and its roles in the
pathogenesis of IBD. Inflamm Bowel Dis. 2008;14:1298-1312.
13
Wyant T, Fedyk E, Abhyankar B. An overview of the mechanism of action of
the monoclonal antibody vedolizumab. J Crohns Colitis.
2016;10:1437-1444.
14 Takeda Data on File. 2019.

Contacts

Media Contacts:
Media outside Japan
Luke Willats
luke.willats@takeda.com
+41-44-555-1145

Japanese Media
Kazumi Kobayashi
kazumi.kobayashi@takeda.com
+81
(0) 3-3278-2095