Entyvio(R) (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 TNFalpha-antagonist

PR72348

OSAKA, Japan, February 17, 2018 /PRNewswire=KYODO JBN/ --

       New clinical study also provides data for Entyvio(R) in inducing

complete mucosal healing and endoscopic remission, particularly in bio-naive

patients

    Takeda Pharmaceutical Company Limited (TSE: 4502) ("Takeda") today

announced new real-world data evaluating the comparative effectiveness of

Entyvio(R) (vedolizumab) and tumor necrosis factor-alpha (TNFalpha)-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 TNFalpha-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 TNFalpha-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 TNFalpha-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-TNFalpha 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 TNFalpha-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] less than or equal to4) 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-TNFalpha-naive 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

TNFalpha-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-TNFalpha-naive 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 TNFalpha-antagonist failure.

    About Entyvio(R) (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 (R) 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(R) 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 (TNFalpha) 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 (TNFalpha) 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 alpha4beta7 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(R).[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(R).[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(R) 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-alpha4beta7 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.

SOURCE: Takeda Pharmaceutical Company Limited