• Pivotal Phase 3 global KEPLER study of vedolizumab intravenous (IV) in pediatric patients ages 2 to 17, who had an inadequate response to either conventional treatment options or tumor necrosis factor (TNF) antagonists, found nearly half (47.3%) of randomized patients achieved primary endpoint of clinical remission at 54 weeks
• Vedolizumab’s safety profile was generally consistent with its known safety profile in adults
• Results were presented at the 21st Congress of the European Crohn’s and Colitis Organisation (ECCO)

OSAKA, Japan & CAMBRIDGE, Mass. -- (BUSINESS WIRE) --

Takeda (TSE:4502/NYSE:TAK) today announced positive data from the pivotal Phase 3 KEPLER trial, which demonstrated that ENTYVIO® (vedolizumab) can offer the possibility of clinical remission for patients ages 2 and older with moderately to severely active ulcerative colitis (UC), a chronic inflammatory disease of the gastrointestinal tract and one of the two most common types of inflammatory bowel disease.1,2 The results, presented at the 21st Congress of the European Crohn’s and Colitis Organisation (ECCO), show vedolizumab’s promising efficacy and safety profile in a patient population where therapy options remain limited. With KEPLER, Takeda is continuing to generate deeper scientific insights and identify additional patient populations who may benefit from vedolizumab, a cornerstone therapy for adults with ulcerative colitis. Vedolizumab is marketed under the trade name ENTYVIO®*.

“Ulcerative colitis is a life-altering diagnosis for young patients and their families, often leaving them searching for effective options. In the KEPLER study, we observed clinically meaningful improvements with vedolizumab in an especially difficult-to-treat patient population—children and adolescents who had failed on the current standard of care, including conventional therapies and/or tumor necrosis factor (TNF) antagonists,” said Ramalingam Arumugam, MD, study investigator and pediatric gastroenterologist at MNGI Digestive Health in Minnesota. “Study data showed nearly half of patients were in remission after one year and safety was generally consistent with vedolizumab’s profile in adults, suggesting that vedolizumab could become important in addressing pediatric UC in those 2 years of age and older.”

The KEPLER Phase 3 study included 120 children and adolescents 2 to 17 years-old with moderately to severely active UC who had an inadequate response to conventional treatments (such as steroids and immunomodulators) and/or tumor necrosis factor (TNF) antagonists. Study participants received open-label intravenous (IV) vedolizumab during a 14 week open-label induction period.1 Ninety-three (93) of 120 patients who achieved a clinical response at Week 14 were then randomized to low dose (n=47) or high dose (n=46) maintenance therapy with vedolizumab every 8 weeks. Of these 93 patients:

• Nearly half (47.3%) of participants achieved the primary endpoint of clinical remission at Week 54;
• More than one-third (34.7%) of patients achieved clinical remission at 14 weeks (secondary endpoint); and
• Greater than 1 in 4 (29%) participants attained the secondary endpoint of sustained clinical remission at both Weeks 14 and 54.
• Additionally, the safety profile of vedolizumab in trial participants was generally consistent with its established safety profile in adults, with no new safety signals identified.1 The most frequently occurring treatment-emergent adverse events (≥10%) reported with vedolizumab in the KEPLER study were upper respiratory infection (30%), ulcerative colitis (disease worsening) (17.5%), and pyrexia (12.5%).3

“For too long, families and clinicians caring for children and adolescents with ulcerative colitis have had limited therapeutic options,” said Awny Farajallah, MD, chief medical officer of Takeda. “The Phase 3 KEPLER results are encouraging and suggest that ENTYVIO, a therapy with a well-established role in the treatment of ulcerative colitis, may offer a meaningful benefit for patients as young as two years old. These findings build on more than a decade of scientific study demonstrating the safety and efficacy of ENTYVIO and reflect Takeda’s continued leadership in advancing evidence-based care across the full spectrum of inflammatory bowel disease. Importantly, this study underscores our commitment to supporting some of the most vulnerable patient populations in gastroenterology.”

Takeda plans to submit marketing applications in the United States, the European Union and other markets for intravenous ENTYVIO for the treatment of moderately to severely active ulcerative colitis in children and adolescents ages 2-17.

About the Phase 3 KEPLER Study  
KEPLER (NCT 04779307; EudraCT 2020-004300-34) is a Phase 3, global, randomized, double-blind, multi-center study to evaluate the efficacy and safety of vedolizumab IV in patients ages 2 to 17 with moderately to severely active ulcerative colitis (modified Mayo score of 5-9 with endoscopic subscore ≥2) with inadequate response to conventional therapy, such as steroids, immunomodulators, and/or tumor necrosis factor (TNF) antagonists.4,1 The study included a 14-week open-label induction period—all participants received IV vedolizumab—followed by a 40-week, randomized, double-blind maintenance period comparing two dose levels: low dose (LD) and high dose (HD). Ninety-three (93) participants were randomized to LD (n=47) or HD (n=46) arms, according to patient weight:

• Participants ≥30 kg: vedolizumab 300 mg (HD) or 150 mg (LD)
• Participants >15 to <30 kg: vedolizumab 200 mg (HD) or 100 mg (LD)
• Participants 10 to 15 kg: vedolizumab 150 mg (HD) or 100 mg (LD)

The primary endpoint was clinical remission at Week 54 in patients who achieved clinical response following open-label vedolizumab IV induction, defined here by symptomatic improvement and endoscopic evidence of no or minimal disease activity (modified Mayo Score).4 Secondary outcome measures included safety and tolerability across induction and maintenance, sustained clinical remission (clinical remission at Weeks 14 and 54), endoscopic outcomes, the impact of dose escalation for loss of response, and long-term safety and disease control assessed in follow-up periods.

About ENTYVIO® (vedolizumab)  
Vedolizumab is the only gut-selective biologic therapy available for ulcerative colitis and Crohn’s disease. It specifically binds to the alpha4beta7 integrin and blocks its interaction with MAdCAM-1, which is mainly expressed on the gut endothelial cells.5 Vedolizumab is approved for IV and subcutaneous (SC) administration in adults with moderately to severely active ulcerative colitis and 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 (approvals vary by market).6,7 Vedolizumab IV has been granted marketing authorization in more than 80 countries, including the United States and European Union. Vedolizumab SC has been granted marketing authorization in more than 50 countries, including the United States and European Union. Globally, vedolizumab IV and SC have more than one million patient years of exposure to date.3

*In most markets worldwide.

EUROPEAN UNION IMPORTANT SAFETY INFORMATION

Please consult the ENTYVIO (Vedolizumab) Summary of Product Characteristics (SmPC) before prescribing, particularly in relation to dosing and treatment monitoring.

GUIDANCE FOR USE: Entyvio should be initiated and supervised by a specialist healthcare professional experienced in diagnosis and treatment of ulcerative colitis, Crohn’s disease or pouchitis. Patients should be given the package leaflet.

CONTRAINDICATIONS: include Hypersensitivity to the active substance or to any of the excipients. Active severe infections such as tuberculosis (TB), sepsis, cytomegalovirus, listeriosis, and opportunistic infections such as Progressive Multifocal Leukoencephalopathy (PML).

UNDESIRABLE EFFECTS: The most commonly reported undesirable effects with ENTYVIO are nasopharyngitis, headache, arthralgia, pneumonia, Clostridium difficile infection, bronchitis, gastroenteritis, upper respiratory tract infection, influenza, sinusitis, pharyngitis, Herpes Zoster, paraesthesia, hypertension, oropharyngeal pain, nasal congestion, cough, anal abscess, anal fissure, nausea, dyspepsia, constipation, abdominal distension, flatulence, haemorrhoids, rectal haemorrhage, liver enzyme increased, rash, pruritus, eczema, erythema, night sweats, acne, muscle spasms, back pain, muscular weakness, fatigue, pain in the extremity, pyrexia, infusion related reaction, infusion site reaction and injection site reaction (subcutaneous administration only).

No clinically relevant differences in the overall safety profile and adverse reactions were observed in patients who received subcutaneous vedolizumab compared to the safety profile observed in clinical studies with intravenous vedolizumab with the exception of injection site reactions (with subcutaneous administration).

Please click for the full EU SmPC.

U.S. IMPORTANT SAFETY INFORMATION 

CONTRAINDICATIONS  
ENTYVIO is contraindicated in patients who have had a known serious or severe hypersensitivity reaction to ENTYVIO or any of its excipients. 

WARNINGS AND PRECAUTIONS 

• Infusion-Related and Hypersensitivity Reactions: Infusion-related reactions and hypersensitivity reactions including anaphylaxis, dyspnea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate have been reported. These reactions may occur with the first or subsequent infusions and may vary in their time of onset from during infusion or up to several hours post-infusion. If anaphylaxis or other serious infusion-related or hypersensitivity reactions occur, discontinue administration of ENTYVIO immediately and initiate appropriate treatment.
• Infections: Patients treated with ENTYVIO are at increased risk for developing infections. Serious infections have been reported in patients treated with ENTYVIO, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis, and cytomegaloviral colitis. ENTYVIO is not recommended in patients with active, severe infections until the infections are controlled. Consider withholding ENTYVIO in patients who develop a severe infection while on treatment with ENTYVIO. Exercise caution in patients with a history of recurring severe infections. Consider screening for tuberculosis (TB) according to the local practice.
• Progressive Multifocal Leukoencephalopathy (PML): PML, a rare and often fatal opportunistic infection of the central nervous system (CNS), has been reported with systemic immunosuppressants, including another integrin receptor antagonist. PML typically only occurs in patients who are immunocompromised. One case of PML in an ENTYVIO-treated patient with multiple contributory factors has been reported. Although unlikely, a risk of PML cannot be ruled out. Monitor patients for any new or worsening neurological signs or symptoms that may include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. If PML is suspected, withhold dosing with ENTYVIO and refer to neurologist; if confirmed, discontinue ENTYVIO dosing permanently.
• Liver Injury: There have been reports of elevations of transaminase and/or bilirubin in patients receiving ENTYVIO. ENTYVIO should be discontinued in patients with jaundice or other evidence of significant liver injury.
• Live and Oral Vaccines: Prior to initiating treatment with ENTYVIO, all patients should be brought up to date with all immunizations according to current immunization guidelines. Patients receiving ENTYVIO may receive non-live vaccines and may receive live vaccines if the benefits outweigh the risks.

ADVERSE REACTIONS  
The most common adverse reactions (incidence ≥3% and ≥1% higher than placebo) were: nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain, pain in extremities, and injection site reactions with subcutaneous administration.

DRUG INTERACTIONS  
Because of the potential for increased risk of PML and other infections, avoid the concomitant use of ENTYVIO with natalizumab products and with TNF blockers. Upon initiation or discontinuation of ENTYVIO in patients treated with CYP450 substrates, monitor drug concentrations or other therapeutic parameters, and adjust the dosage of the CYP substrate as needed. 

INDICATIONS  
Adult Ulcerative Colitis (UC):  
ENTYVIO is indicated in adults for the treatment of moderately to severely active UC. 

Adult Crohn’s Disease (CD):  
ENTYVIO is indicated in adults for the treatment of moderately to severely active CD. 

DOSAGE FORMS & STRENGTHS: 

• ENTYVIO Intravenous (IV) Infusion: 300 mg vedolizumab 
• ENTYVIO Subcutaneous (SC) Injection: 108 mg vedolizumab

Please click for Full U.S. Prescribing Information.

About Takeda  
Takeda is focused on creating better health for people and a brighter future for the world. We aim to discover and deliver life-transforming treatments in our core therapeutic and business areas, including gastrointestinal and inflammation, rare diseases, plasma-derived therapies, oncology, neuroscience and vaccines. Together with our partners, we aim to improve the patient experience and advance a new frontier of treatment options through our dynamic and diverse pipeline. As a leading values-based, R&D-driven biopharmaceutical company headquartered in Japan, we are guided by our commitment to patients, our people and the planet. Our employees in approximately 80 countries and regions are driven by our purpose and are grounded in the values that have defined us for more than two centuries. For more information, visit www.takeda.com.

Important Notice  
For the purposes of this notice, “press release” means this document, any oral presentation, any question and answer session and any written or oral material discussed or distributed by Takeda Pharmaceutical Company Limited (“Takeda”) regarding this release. This press release (including any oral briefing and any question-and-answer in connection with it) is not intended to, and does not constitute, represent or form part of any offer, invitation or solicitation of any offer to purchase, otherwise acquire, subscribe for, exchange, sell or otherwise dispose of, any securities or the solicitation of any vote or approval in any jurisdiction. No shares or other securities are being offered to the public by means of this press release. No offering of securities shall be made in the United States except pursuant to registration under the U.S. Securities Act of 1933, as amended, or an exemption therefrom. This press release is being given (together with any further information which may be provided to the recipient) on the condition that it is for use by the recipient for information purposes only (and not for the evaluation of any investment, acquisition, disposal or any other transaction). Any failure to comply with these restrictions may constitute a violation of applicable securities laws.

The companies in which Takeda directly and indirectly owns investments are separate entities. In this press release, “Takeda” is sometimes used for convenience where references are made to Takeda and its subsidiaries in general. Likewise, the words “we”, “us” and “our” are also used to refer to subsidiaries in general or to those who work for them. These expressions are also used where no useful purpose is served by identifying the particular company or companies.

Forward-Looking Statements  
This press release and any materials distributed in connection with this press release may contain forward-looking statements, beliefs or opinions regarding Takeda’s future business, future position and results of operations, including estimates, forecasts, targets and plans for Takeda. Without limitation, forward-looking statements often include words such as “targets”, “plans”, “believes”, “hopes”, “continues”, “expects”, “aims”, “intends”, “ensures”, “will”, “may”, “should”, “would”, “could”, “anticipates”, “estimates”, “projects” or similar expressions or the negative thereof. These forward-looking statements are based on assumptions about many important factors, including the following, which could cause actual results to differ materially from those expressed or implied by the forward-looking statements: the economic circumstances surrounding Takeda’s global business, including general economic conditions in Japan and the United States; competitive pressures and developments; changes to applicable laws and regulations, including global health care reforms; challenges inherent in new product development, including uncertainty of clinical success and decisions of regulatory authorities and the timing thereof; uncertainty of commercial success for new and existing products; manufacturing difficulties or delays; fluctuations in interest and currency exchange rates; claims or concerns regarding the safety or efficacy of marketed products or product candidates; the impact of health crises, like the novel coronavirus pandemic, on Takeda and its customers and suppliers, including foreign governments in countries in which Takeda operates, or on other facets of its business; the timing and impact of post-merger integration efforts with acquired companies; the ability to divest assets that are not core to Takeda’s operations and the timing of any such divestment(s); and other factors identified in Takeda’s most recent Annual Report on Form 20-F and Takeda’s other reports filed with the U.S. Securities and Exchange Commission, available on Takeda’s website at: https://www.takeda.com/investors/sec-filings-and-security-reports/ or at www.sec.gov. Takeda does not undertake to update any of the forward-looking statements contained in this press release or any other forward-looking statements it may make, except as required by law or stock exchange rule. Past performance is not an indicator of future results and the results or statements of Takeda in this press release may not be indicative of, and are not an estimate, forecast, guarantee or projection of Takeda’s future results.

Medical Information  
This press release contains information about products that may not be available in all countries, or may be available under different trademarks, for different indications, in different dosages, or in different strengths. Nothing contained herein should be considered a solicitation, promotion or advertisement for any prescription drugs including the ones under development.