New Exploratory Data from VARSITY, First Head-to-Head Ulcerative Colitis Biologic Study Which Demonstrated Superiority of Vedolizumab to Adalimumab in Clinical Remission at Week 52, Presented at 2019 Digestive Disease Week®
May 20, 2019-
Exploratory data showed a greater proportion of patients
receiving vedolizumab achieved clinical response at week 14 than
adalimumab -
Additional exploratory data on absence of active histologic
disease showed vedolizumab was associated with a greater reduction of
microscopic inflammation in the gut compared to adalimumab -
Results provide additional information to the recent
presentation of primary endpoint data from the VARSITY study, which
demonstrated superiority of vedolizumab to adalimumab in achieving
clinical remission at week 52
OSAKA, Japan–(BUSINESS WIRE)–Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK)
(“Takeda”) today announced further 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* at week 52 in patients with moderately
to severely active ulcerative colitis (UC).1 New exploratory
data showed that a greater proportion of patients receiving vedolizumab
intravenous (IV) achieved clinical response** at week 14 compared to
those treated with adalimumab subcutaneous (SC), 67.1% vs. 45.9%
respectively. A separation between the treatment groups was seen as
early as week 6, favoring vedolizumab. These results were announced in a
Distinguished Abstract Plenary Lecture Presentation at the 2019
Digestive Disease Week® (DDW) annual scientific meeting (May
18-21 in San Diego, CA), one of 18 Takeda sponsored vedolizumab
abstracts accepted for presentation.2
Additional exploratory data on absence of active histologic disease were
also presented at the meeting. Histologic disease activity is an
endpoint assessing the degree of microscopic inflammation in the gut.
Absence of active histologic disease is achieved when inflammation is
less than a pre-defined severity threshold.2,3,4*** In the
VARSITY study, consistent results were seen with vedolizumab treatment
across both the Geboes Score (<3.2) and Robarts Histopathology Index
(<5), with absence of active histologic disease achieved in 33.4% and
42.3% of patients treated with vedolizumab, respectively, compared with
13.7% and 25.6% of patients treated with adalimumab, respectively.2
“Exploratory data from the VARSITY study suggest that more patients
experienced early symptomatic response and improvement of microscopic
intestinal inflammation with vedolizumab as compared to adalimumab,”
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. “In clinical practice there is a need to balance early symptomatic
improvement alongside the longer-term treatment goal of helping patients
to achieve clinical remission, making these findings important to
physicians.”
“Patients benefit from clinical trials that advance our understanding of
the disease. The VARSITY study, a first-of-its-kind comparison of two
biologics in ulcerative colitis, provides valuable information that can
help inform treatment decisions, while also increasing our understanding
of how these treatments are working at a microscopic level,” said Jeff
Bornstein, M.D., Executive Medical Director, Takeda. “Data from the
VARSITY study show consistent results for vedolizumab, supporting the
use of this treatment as a first-line biologic therapy in ulcerative
colitis.”
About VARSITY
VARSITY is a Phase 3b, randomized,
double-blind, double-dummy, multi-center, active-controlled study to
evaluate the efficacy and safety of vedolizumab intravenous (IV)
compared to adalimumab subcutaneous (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 tumor necrosis factor-alpha
(TNFα)-antagonist other than adalimumab prior to being enrolled.
Patients were randomized into one of two treatment groups, vedolizumab
IV 300 mg and placebo SC or adalimumab SC 160 mg and placebo IV. Dose
escalation was not permitted in either treatment arm during the study.1,5
At week 52, 31.3% (n=120/383) of patients receiving vedolizumab IV
achieved the primary endpoint of clinical remission* compared to 22.5%
(n=87/386) of patients treated with adalimumab SC, with the difference
being statistically significant (p=0.0061). In addition, 39.7% of
patients treated with vedolizumab achieved the secondary endpoint of
mucosal healing± at week 52, compared to 27.7% receiving
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 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
|
* Primary endpoint: Clinical remission is defined as a complete Mayo score of ≤2 points and no individual subscore ˃1 point.5 |
|
** Exploratory endpoint: Clinical response is defined as a reduction in partial Mayo score of ≥2 points and ≥25% from baseline, with an accompanying decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 point. Patients with missing clinical response status were considered non-responders.2 |
|
*** Exploratory endpoint: Absence of active histologic disease is defined as a Geboes Score (<3.2) or Robarts Histopathology Index (<5).2 |
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± Secondary endpoint: Mucosal healing is defined as Mayo endoscopic subscore of ≤1 point. Mayo score: instrument designed to measure disease activity of ulcerative colitis.5 |
|
† 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 52.5 |
About Digestive Disease Week® (DDW)
Digestive
Disease Week® (DDW) is the largest international gathering of
physicians, researchers and academics in the fields of gastroenterology,
hepatology, endoscopy and gastrointestinal surgery. Jointly sponsored by
the American Association for the Study of Liver Diseases (AASLD), the
American Gastroenterological Association (AGA) Institute, the American
Society for Gastrointestinal Endoscopy (ASGE) and the Society for
Surgery of the Alimentary Tract (SSAT), DDW takes place May 18-21, 2019,
at the San Diego Convention Center. The meeting showcases more than
5,000 abstracts and hundreds of lectures on the latest advances in GI
research, medicine and technology. More information can be found at www.ddw.org.
About Ulcerative Colitis
Ulcerative colitis (UC) is one of
the most common forms of inflammatory bowel disease (IBD).6
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.7,8 UC commonly
presents with symptoms of abdominal discomfort and loose bowel
movements, including blood or pus.8,9 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.8,10,11
About Entyvio® (vedolizumab)
Vedolizumab
is a gut-selective biologic and is approved as an intravenous (IV)
formulation.12 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).13 MAdCAM-1 is preferentially expressed on blood
vessels and lymph nodes of the gastrointestinal tract.14 The
alpha4beta7 integrin is expressed on a subset of circulating white blood
cells.13 These cells have been shown to play a role in
mediating the inflammatory process in ulcerative colitis (UC) and
Crohn’s disease (CD).13,15,16 By inhibiting alpha4beta7
integrin, vedolizumab may limit the ability of certain white blood cells
to infiltrate gut tissues.13
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.12
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.17
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. J CrohnsColitis. 2019;13(Supplement_1):S612–3. |
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2 Sands B, Peyrin-Biroulet, L, Loftus EV Jr, et al. Vedolizumab shows superior efficacy versus adalimumab: Results of VARSITY: The first head-to-head study of biologic therapy for moderate-to-severe ulcerative colitis. Presented at Digestive Disease Week (DDW) San Diego, California. Abstract #416a. (Oral presentation – Sunday, May 19, 2019, 17:16- 17:30 PDT). |
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3 Peyrin–Biroulet L, Bressenot A, Kampmank W, et al. Histologic remission: The ultimate therapeutic goal in ulcerative colitis? Clin Gastroenterol Hepatol. 2014;12:929–934. |
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4 Bessissow T, Lemmens B, Ferrante M, et al. Prognostic value of serologic and histologic markers on clinical relapse in ulcerative colitis patients with mucosal healing. Am J Gastroenterol. 2012 Nov;107(11):1684-92. |
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5 An efficacy and safety study of vedolizumab |
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6 Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet. 2007;369:1627-1640. |
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7 Torres J, Billioud V, Sachar DB, et al. Ulcerative colitis as a progressive disease: the forgotten evidence. Inflamm Bowel Dis. 2012;18:1356-1363. |
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8 Ordas I, Eckmann L, Talamini M, et al. Ulcerative colitis. Lancet. 2012;380:1606-1619. |
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9 Sands BE. From symptom to diagnosis: clinical distinctions among various forms of intestinal inflammation. Gastroenterology. 2004;126:1518-1532. |
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10 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. |
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11 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. |
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12 Entyvio Prescribing Information. Available at: https://general.takedapharm.com/ENTYVIOPI. |
|
13 Soler D, Chapman T, Yang LL, et al. The binding |
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14 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. |
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15 Eksteen B, Liaskou E, Adams DH. Lymphocyte homing and its roles in the pathogenesis of IBD. Inflamm Bowel Dis. 2008;14:1298-1312. |
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16 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. |
| 17 Takeda Data on File. 2019. |
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