U.S. Food & Drug Administration Accepts Takeda’s Biologics License Application for a Subcutaneous Formulation of Vedolizumab (Entyvio®) for Maintenance Therapy in Moderately to Severely Active Ulcerative Colitis
May 9, 2019-
An additional treatment modality would provide more flexibility
in how patients receive vedolizumab, a biologic with a gut-selective
mode of action -
Vedolizumab set to be the only maintenance therapy to offer the
option of intravenous or subcutaneous formulations for patients with
ulcerative colitis
OSAKA, Japan–(BUSINESS WIRE)–Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK)
(“Takeda”) today announced that the U.S. Food & Drug Administration
(FDA) has accepted for review a Biologics License Application (BLA) for
a subcutaneous (SC) formulation of vedolizumab for maintenance therapy
in adults with moderately to severely active ulcerative colitis (UC).
Takeda proposes to make vedolizumab SC available in both pre-filled
syringe and pen options.
“Acceptance of this regulatory submission for review brings us one step
closer to our goal of better meeting the diverse needs of patients with
ulcerative colitis in the U.S. The availability of a subcutaneous option
for maintenance therapy with vedolizumab, in addition to the currently
approved intravenous formulation, would provide physicians and patients
with greater flexibility on route of administration, if approved,” said
Uthra Sundaram, Senior Vice President, GI Business Unit, Takeda
Pharmaceuticals U.S.A., Inc.
The application is based on the pivotal VISIBLE 1 phase 3 study, which
assessed the safety and efficacy of a SC formulation of vedolizumab as
maintenance therapy in 216 adult patients with moderately to severely
active UC who achieved clinical response* at week 6 following two doses
of open-label vedolizumab intravenous (IV) therapy at weeks 0 and 2.1
The results of VISIBLE 1 were presented at the 2018 United European
Gastroenterology (UEG) Week Congress in Vienna, Austria.
In evaluating the primary endpoint of VISIBLE 1, a statistically
significant proportion of patients receiving vedolizumab SC 108 mg
maintenance therapy administered every two weeks achieved clinical
remission** compared to patients receiving placebo (46.2% vs. 14.3%;
p<0.001) at week 52. A similar rate of clinical remission was observed
in the vedolizumab IV 300 mg reference arm (42.6%) at week 52.
Furthermore, adverse event rates, including severe adverse events and
infections, were similar between the SC and IV groups at week 52.
Injection-site reactions were generally mild and experienced by 10.4% of
patients in the vedolizumab SC treatment arm (vs. 0% in the placebo
group), with none leading to treatment discontinuation.1,2
“The VISIBLE 1 study provides us with important knowledge on the
characterization of the efficacy and safety profile for the
investigational subcutaneous formulation of vedolizumab,” said Karen
Lasch, M.D., Medical Head, Specialty GI, U.S. Medical Office, Takeda.
“Takeda is deeply committed to bringing innovative medicines and
treatment modalities to patients living with gastrointestinal diseases.”
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* 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.3 |
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** Clinical remission is defined as a complete Mayo score of ≤2 points and no individual subscore >1 point.3 |
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About the VISIBLE clinical trial program
The 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 UC and CD
patients which includes two randomized, double-blind, placebo-controlled
studies examining the percentage of participants achieving clinical
remission at week 52, and an open-label extension study to determine the
long-term safety and efficacy of vedolizumab SC.3,4,5
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).6 Both UC and CD are
chronic, relapsing, remitting, inflammatory conditions of the
gastrointestinal tract that are often progressive in nature.7,8
UC only involves the large intestine as opposed to CD which can affect
any part of the GI tract from mouth to anus.9,10 CD can also
affect the entire thickness of the bowel wall, while UC only involves
the innermost lining of the large intestine.8,9 UC commonly
presents with symptoms of abdominal discomfort, loose bowel movements,
including blood or pus.9,11 CD commonly presents with
symptoms of abdominal pain, diarrhea, and weight loss.7 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. 9,12,13
About Entyvio® (vedolizumab)
Vedolizumab
is a gut-selective biologic and is approved as an intravenous (IV)
formulation.14 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).15 MAdCAM-1 is preferentially expressed on blood
vessels and lymph nodes of the gastrointestinal tract.16 The
alpha4beta7 integrin is expressed on a subset of circulating white blood
cells.15 These cells have been shown to play a role in
mediating the inflammatory process in ulcerative colitis (UC) and
Crohn’s disease (CD).15,17,18 By inhibiting alpha4beta7
integrin, vedolizumab may limit the ability of certain white blood cells
to infiltrate gut tissues.15
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.14
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.2
Therapeutic Indications (vedolizumab IV)
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
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References
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1 Sandborn WJ, Baert F, Danese S, et al. Efficacy and safety of a new vedolizumab subcutaneous formulation for ulcerative colitis: results of the VISIBLE 1 phase 3 trial. United European Gastroenterology J. 2018;6(Supplement 1). |
| 2 Takeda Data on File. 2019. |
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3 Efficacy and safety of vedolizumab subcutaneously |
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4 Efficacy and safety of vedolizumab subcutaneous (SC) |
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5 Vedolizumab subcutaneous long-term open-label |
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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 Baumgart DC, Sandborn WJ. Crohn’s disease. Lancet. 2012;380:1590-1605. |
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8 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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9 Ordas I, Eckmann L, Talamini M, et al. Ulcerative colitis. Lancet. 2012;380:1606-1619. |
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10 Feuerstein JD, Cheifetz AS. Crohn’s disease: Epidemiology, diagnosis and management. Mayo Clin Proc. 2017;92:1088-1103. |
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11 Sands BE. From symptom to diagnosis: clinical distinctions among various forms of intestinal inflammation. Gastroenterology. 2004;126:1518-1532. |
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12 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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13 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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14 Entyvio Prescribing Information. Available at: https://general.takedapharm.com/ENTYVIOPI. |
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15 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. |
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16 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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17 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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18 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. |
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