Entyvio® (vedolizumab) Shows Higher Rates of Mucosal Healing Versus TNFalpha-Antagonist Therapy in Ulcerative Colitis and Crohn's Disease Patients in Comparative Effectiveness Real-World Data Analysis

Osaka, Japan (ots/PRNewswire) - New clinical study also provides
data for Entyvio® in inducing complete mucosal healing and
endoscopic remission, particularly in bio-naïve patients

Takeda Pharmaceutical Company Limited (TSE: 4502) ("Takeda") today
announced new real-world data evaluating the comparative
effectiveness of Entyvio® (vedolizumab) and tumor necrosis
factor-alpha (TNF?)-antagonist therapy in patients with moderately to
severely active ulcerative colitis (UC) or Crohn's disease (CD).
These data were presented as oral presentations at the 13th Congress
of the European Crohn's and Colitis Organization (ECCO) from February
14 to 17, 2018 in Vienna, Austria. These analyses observed that
patients with UC treated with Entyvio compared to TNF?-antagonist
therapy had statistically significant higher 12-month cumulative
rates of mucosal healing (50% vs 42%, hazard ratio [HR] 1.73, 95%
confidence interval [CI] 1.10-2.73) and clinical remission (54% vs
37%; HR 1.54, 95% CI 1.08-2.18), and numerically higher steroid-free
clinical remission rates (49% vs 38%; HR 1.43, 95% CI 0.79-2.60). In
CD, results reported statistically significant higher 12-month
cumulative rates of mucosal healing (50% vs 41%; HR 1.67, 95% CI
1.13-2.47), and numerically higher rates of clinical remission (38%
vs 34%; HR 1.27, 95% CI 0.91-1.78) and steroid-free clinical
remission (26% vs 18%; HR 1.75, 95% CI 0.90-3.43) compared to
TNF?-antagonist therapy. These analyses were conducted by the VICTORY
(Vedolizumab Health OuTComes in InflammatORY Bowel Diseases)
Consortium.[1],[2]

"These data from the VICTORY Consortium highlight the effectiveness
of Entyvio in achieving mucosal healing and clinical remission in the
real-world, and support the use of Entyvio as a first-line biologic
therapy," said Professor William Sandborn, M.D., Chief, Division of
Gastroenterology, University of California San Diego. "While
additional research is needed to confirm these findings, these are
important comparative effectiveness analyses of real-world data
involving Entyvio and TNF?-antagonist therapy, which further aid our
understanding of biologic therapy in clinical practice."

Of the 646 UC and 1,122 CD VICTORY Consortium patients, data from 334
UC (n=167 Entyvio patients; 49% male; median age 36 years) and 538 CD
(n=269 Entyvio patients; 44% male; median age 35 years) were
analyzed. Entyvio patients were matched (1:1)* to patients on
anti-TNF? therapy using propensity scores to control for baseline
differences between groups. Researchers used Cox proportional hazard
models to compare cumulative rates of mucosal healing (absence of
ulcers or erosions for CD; Mayo endoscopic sub-score of 0 or 1 for
UC), clinical remission (complete resolution of symptoms based on
Physician Global Assessment) and steroid-free clinical remission (on
steroids at baseline, tapered off, no repeat steroid prescription for
4 weeks). Findings were reported after adjusting for concomitant
steroid or immunomodulator use, disease location (CD study only;
isolated small bowel, ileocolonic, isolated colonic), and number of
prior TNF?-antagonists used.[1],[2]

New clinical data also being presented at ECCO from the Phase 3b
open-label prospective multicenter study (VERSIFY) evaluating the
efficacy of Entyvio on complete mucosal healing (absence of
ulcerations), endoscopic remission (Simple endoscopic score for CD
[SES-CD] <=4) and endoscopic response (50% decrease in SES-CD from
baseline) provide insight into complete mucosal healing in CD.
Results at week 26 found Entyvio induced complete mucosal healing
(15%), endoscopic remission (12%) and endoscopic response (25%) in
the overall population of CD patients, particularly in an
anti-TNF?-naïve setting (complete mucosal healing 24%, endoscopic
remission 20%, and endoscopic response 28%). The trial included 101
patients with moderately to severely active CD who had previously
experienced treatment failure with corticosteroids, immunomodulators,
and/or at least one TNF?-antagonist therapy. In this study, 46% of
patients were categorized as having severe endoscopic activity at
entry (SES-CD score of >15). Patients received Entyvio 300 mg
intravenously at weeks 0, 2, 6, and then every 8 weeks for 26 weeks,
followed by a 26-week extension period. Dose escalation was not
permitted.[3]

"Endoscopic remission and mucosal healing are important targets in
the management of Crohn's disease and ulcerative colitis, as they
look beyond symptoms to show how disease activity could be impacting
underlying bowel damage. The VERSIFY clinical study generated
positive results in complete mucosal healing and endoscopic remission
rates in Crohn's disease, particularly in anti-TNF?-naïve patients.
Looking across the Entyvio data presented at ECCO, we're encouraged
by the large compendium of data for Entyvio regarding endoscopic
remission and mucosal healing in both clinical studies and the
real-world setting," said Mona Khalid, Senior Director, Head of
Evidence and Value Generation, Takeda Pharmaceuticals.

At this year's ECCO congress, Takeda sponsored 33 posters and
presentations on Entyvio, including real-world analyses and clinical
studies evaluating the impact of Entyvio on long-term remission,
comparative efficacy/effectiveness, mucosal healing, resource
utilization, and in special patient populations across CD and UC. For
a full list of poster titles and authors, visit https://www.ecco-ibd.eu/publications/congress-abstract-s/abstracts-2018.html.

*Propensity score matching (1:1) accounting for baseline differences
between groups including age, sex, prior UC/CD-related
hospitalization within the previous year, disease history, disease
extent, disease severity, steroid refractoriness or dependence and
prior TNF?-antagonist failure.

About Entyvio® (vedolizumab)

Vedolizumab is a gut-selective immunosuppressive biologic.[4] It is a
humanized monoclonal antibody that is designed to specifically
antagonize the alpha4beta7 integrin, inhibiting the binding of
alpha4beta7 integrin to intestinal mucosal addressin cell adhesion
molecule 1 (MAdCAM-1) and fibronectin, but not vascular cell adhesion
molecule 1 (VCAM-1).[5] MAdCAM-1 is preferentially expressed on blood
vessels and lymph nodes of the gastrointestinal tract.[6] The
alpha4beta7 integrin is expressed on a subset of circulating white
blood cells.[5] These cells have been shown to play a role in
mediating the inflammatory process in UC and CD.[5],[7],[8] By
inhibiting alpha4beta7 integrin, vedolizumab may limit the ability of
certain white blood cells to infiltrate gut tissues.[5]

About the VICTORY Consortium

The VICTORY (Vedolizumab Health OuTComes in InflammatORY Bowel
Diseases) Consortium is a collaboration of 12 leading inflammatory
bowel disease (IBD) centers from across the U.S. and represents the
first large, well-characterized cohort of patients taking Entyvio® in
a real-world setting in the U.S. Patients included in the consortium
were identified at each site through electronic medical record
searches, review of clinical records, and/or queries of infusion
center records. More than 1,700 UC and CD patients are now included
in the consortium database, which was started when Entyvio® was
launched in the U.S. in 2014.

About Ulcerative Colitis and Crohn's Disease

Ulcerative colitis (UC) and Crohn's disease (CD) are two of the most
common forms of inflammatory bowel disease (IBD).[9] Both UC and CD
are chronic, relapsing, remitting, inflammatory conditions of the
gastrointestinal (GI) tract that are often progressive in
nature.[10],[11] UC only involves the large intestine as opposed to
CD which can affect any part of the GI tract from mouth to
anus.[12],[13] CD can also affect the entire thickness of the bowel
wall, while UC only involves the innermost lining of the large
intestine.[12] UC commonly presents with symptoms of abdominal
discomfort, loose bowel movements, including blood or pus.[12],[14]
CD commonly presents with symptoms of abdominal pain, diarrhea, and
weight loss.[10] 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.[12],[15],[16]

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 (TNF?)
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 (TNF?)
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
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 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 ?4?7 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.

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. 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.

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, 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 (http://general.takedapharm.com/content/file.aspx?FileTypeCode=ENTYVIOPI&cacheRandomizer=16fe4788-e18e-4f60-bd42-ec16de9d5fc9) including

Medication Guide (http://general.takedapharm.com/content/file.aspx?filetypecode=ENTYVIOMG&CountryCode=US&LanguageCode=EN&cacheRandomizer=854644a6-db66-4a7b-8761-77c0a8f06456) for ENTYVIO®.[17]

For EU audiences, please see the Summary of Product Characteristics
(SmPC) (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002782/WC500168528.pdf) for ENTYVIO®.[4]

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)
(https://www.takeda.com/investors/) 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/.

References

1. Faleck D, Shashi P, Meserve J, et al. Comparative effectiveness of
vedolizumab and TNF-antagonist therapy in ulcerative colitis: A
multicentre consortium propensity score-matched analysis. Presented
at European Crohn's and Colitis Organisation (ECCO) Congress 2018,
Vienna, Austria. Oral presentation #36388 (Friday, February 16, 2018,
17:00-17:10).

2. Bohm M, Varma S, Fischer M, et al. Comparative effectiveness of
vedolizumab and tumour necrosis factor-antagonist therapy in Crohn's
disease: A multicentre consortium propensity score-matched analysis.
Presented at European Crohn's and Colitis Organisation (ECCO)
Congress 2018, Vienna, Austria. Oral presentation #36387 (Friday,
February 16, 2018, 16:50-17:00).

3. Danese S, Feagan BG, Sandborn WJ, et al. A phase 3b open-label
multicentre study (VERSIFY) of the efficacy of vedolizumab on
endoscopic healing in moderately to severely active Crohn's disease
(CD). Presented at European Crohn's and Colitis Organisation (ECCO)
Congress 2018, Vienna, Austria. Oral presentation #36350 (Friday,
February 16, 2018, 16:30-16:40).

4. Entyvio® Summary of Product Characteristics. September 2015.

5. 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.

6. 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.

7. Eksteen B, Liaskou E, Adams DH. Lymphocyte homing and its roles in
the pathogenesis of IBD. Inflamm Bowel Dis. 2008;14:1298-1312.

8. 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.

9. Baumgart DC, Carding SR. Inflammatory bowel disease: cause and
immunobiology. Lancet. 2007;369:1627-1640.

10. Baumgart DC, Sandborn WJ. Crohn's disease. Lancet.
2012;380:1590-1605.

11. Torres J, Billioud V, Sachar DB, et al. Ulcerative colitis as a
progressive disease: the forgotten evidence. Inflamm Bowel Dis.
2012;18:1356-1363.

12. Ordas I, Eckmann L, Talamini M, et al. Ulcerative colitis.
Lancet. 2012;380:1606-1619.

13. Feuerstein JD, Cheifetz AS. Crohn's disease: Epidemiology,
diagnosis and management. Mayo Clin Proc. 2017;92:1088-1103.

14. Sands BE. From symptom to diagnosis: clinical distinctions among
various forms of intestinal inflammation. Gastroenterology.
2004;126:1518-1532.

15. Henckaerts L, Pierik M, Joossens M, et al. Mutations in pattern
recognition receptor genes modulate seroreactivity to microbial
antigens in patients with inflammatory bowel disease. Gut.
2007;56:1536-1542.

16. Kaser A, Zeissig S, Blumberg RS. Genes and environment: How will
our concepts on the pathophysiology of IBD develop in the future? Dig
Dis. 2010;28:395-405.

17. Entyvio (vedolizumab) Prescribing Information. May 2014.

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