This analysis examining treatment with vedolizumab in patients with moderately to severely active ulcerative colitis or Crohn's disease observed no significant safety concerns
ZURICH, May 12, 2016 /PRNewswire/ -- Takeda Pharmaceutical Company Limited [TSE: 4502], ("Takeda") announced that an integrated summary of long-term safety data results from six clinical studies of vedolizumab, including two Phase 2 and four Phase 3 studies, in adult patients with moderately to severely active ulcerative colitis (UC) or Crohn's disease (CD), was published as an online first in the journal Gut. The analysis, examining vedolizumab exposure for up to five years in a population of more than 2,800 patients, did not report significant safety concerns associated with vedolizumab treatment.
"For healthcare professionals and patients, symptom remission and avoidance of surgery is the ultimate goal of ulcerative colitis and Crohn's disease treatment, however there are few durable options available for the community," said Professor Jean-Frederic Colombel, MD, Division of Gastroenterology, Icahn School of Medicine at Mount Sinai Hospital in New York City. "These safety findings underscore the viability of vedolizumab as an important and generally well-tolerated treatment option over the long-term, with the clinical data collected to-date showing a low risk of common or serious complications that can be seen when otherwise treating these chronic diseases."
Investigators examined data from six previously published vedolizumab clinical trials, looking specifically at safety and tolerability data and end points, including adverse events (AEs) and serious AEs, infusion-related reactions (IRRs), serious infections and predictors of serious infections, malignancies, immunogenicity, hepatobiliary events, gastrointestinal (GI) events, and risk for progressive multifocal leukoencephalopathy (PML). The analysis reported that vedolizumab exposure over the long-term has a favorable benefit-risk profile, without significant safety concerns or risk of serious and opportunistic infections reported up to today.
"Ulcerative colitis and Crohn's disease require life-long management, and symptoms can cause patients a significant burden when not properly treated," explained Asit Parikh, MD, PhD, senior vice president, Head Gastroenterology Therapeutic Area, Takeda. "Since the early stages of development, and further underscored by the data analyzed in this publication, we are encouraged by the favorable benefit-risk profile of vedolizumab over an extended period. These data indicate that patients with either ulcerative colitis or Crohn's disease seeking to achieve long-term remission can receive treatment with minimal increased risk for other complications."
About the integrated analysis
Safety data were integrated from the six clinical trials (two Phase 2 and four Phase 3 GEMINI trials) of vedolizumab conducted to-date examining treatment of vedolizumab in patients with moderately to severely active UC or CD. These trials took place between May 2007 and June 2013. The overall safety population was defined as all patients (N=2932) who received one or more doses of study drug (vedolizumab or placebo) in at least one of the six studies. Analyses were performed separately based on indication (UC or CD). For patients who participated in multiple studies, all safety data during vedolizumab exposure were combined. For the GEMINI Long-Term Safety (LTS) study, which is still ongoing, an interim data cut through June 27, 2013 was used.
Safety and tolerability were evaluated in all patients in the safety population according to their exposure to study drug (vedolizumab or placebo), which was calculated using the number of days the patient received study drug, based on first and last dose dates. For patients who received only placebo, exposure to vedolizumab was calculated as 0 days. Placebo-exposed patients were similar to the overall population with respect to age, sex, disease duration, concomitant medication use, narcotic analgesic use, smoking status and prior anti-TNF failure history.
AEs were defined as any untoward medical occurrence in a patient administered a pharmaceutical product, and serious AEs (SAEs) were defined as any diagnosis of PML or any AE that was considered an important medical event, a congenital anomaly or life-threatening, or resulted in significant disability, hospitalization or death. IRRs were defined as AEs occurring on the day of or one calendar day after the infusion that were assessed by the investigator as infusion-related. A Cox proportional hazards model with time-dependent covariates was used to determine the relative contribution (HRs and 95% CIs) of different factors to the occurrence of serious infections in the Phase 3 safety population, which included patients in both treatment arms.
AEs were reported as exposure-adjusted incidence rates as the number of patients experiencing the event per 100 person-years (PYs) of exposure. Of the 2,932 total patients enrolled, 2,830 patients were exposed to one or more doses of vedolizumab, contributing a total of 4,811 PYs of vedolizumab exposure.
Investigators found that exposure-adjusted incidence rates for all AEs and all SAEs were lower with vedolizumab exposure than with placebo. In the overall safety population, 247.8 (95% CI 229.8 to 265.8) and 20.0 (95% CI 18.5 to 21.5) vedolizumab-exposed patients experienced an AE or SAE, respectively, per 100 PYs of follow-up compared with 419.4 (95% CI 359.3 to 479.5) and 28.3 (95% CI 20.6 to 35.9) patients receiving placebo. The majority of SAEs were GI events and infections. Prolonged exposure to vedolizumab did not increase the frequency of AEs or SAEs, including GI SAEs or serious infections.
In the overall safety population studied, the exposure-adjusted incidence rates of any infection were lower among patients receiving vedolizumab. Most infections were mild to moderate in severity and responded to standard treatment while patients had continued exposure to vedolizumab. The exposure-adjusted incidence rates of serious infections were similar for vedolizumab and placebo; serious clostridial infections, sepsis and tuberculosis were reported infrequently (≤0.6% of patients). Few patients (<1%) discontinued treatment because of infection.
In addition, no cases of PML were observed during vedolizumab clinical development in the context of a rigorous risk monitoring program.
Overall, the majority of IRRs were mild or moderate in intensity, and rarely resulted in discontinuation of study drug.
While some treatments for inflammatory bowel disease (IBD) increase the risk of cancer, including non-melanoma skin cancer, investigators did not observe vedolizumab-exposed patients to be at a greater risk than patients receiving placebo.
Overall, the integrated safety data for >4,000 PYs of vedolizumab exposure in the six clinical trials examined indicate that extended treatment with vedolizumab is well-tolerated with an acceptable safety profile in patients with moderately to severely active UC or CD. The safety profile of vedolizumab in the integrated safety analysis over an extended treatment period was similar to that reported in the individual clinical studies.
Vedolizumab was approved as a gut-selective humanized monoclonal antibody, available in the European Union under the trade name Entyvio® (vedolizumab). Entyvio was also approved in the United States in 2014. Entyvio is now approved in 48 countries, across five continents. It is the first and only biologic therapy to be approved simultaneously for the treatment of adults with moderately to severely active UC or CD who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a tumor necrosis factor-alpha antagonist.
About ulcerative colitis and Crohn's disease
Ulcerative colitis (UC) and Crohn's disease (CD) are marked by inflammation in the GI tract. UC impacts the large intestine only, which includes the colon and the rectum. The most common symptoms of UC include abdominal discomfort and blood or pus in diarrhea. CD can impact any part of the digestive tract and common symptoms may include abdominal pain, diarrhea, rectal bleeding, weight loss, and fever. There is no known cause for UC or CD, although many researchers believe that the interaction between genes, the body's immune system, and environmental factors play a role. The aim of UC and CD treatments is to induce and maintain remission, or achieve extended periods of time when patients do not experience symptoms.
About Entyvio® (vedolizumab)
Vedolizumab, developed for the treatment of UC and CD, is a humanized monoclonal antibody that is designed to specifically antagonize the alpha4beta7 integrin, inhibiting the binding of alpha4beta7 to intestinal mucosal addressin cell adhesion molecule 1 (MAdCAM-1) and fibronectin, but not vascular cell adhesion molecule 1 (VCAM-1). MAdCAM-1 is preferentially expressed on blood vessels and lymph nodes of the gastrointestinal tract. The alpha4beta7 integrin is expressed on a subset of circulating white blood cells. These cells have been shown to play a role in mediating the inflammatory process in UC and CD. By inhibiting alpha4beta7, vedolizumab may limit the ability of certain white blood cells to infiltrate gut tissues.
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.
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
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.
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.
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 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 patients is 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.
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.
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, Bronchitis, Upper respiratory tract infection, Influenza, Sinusitis, Headache, Oropharyngeal pain, Cough, Nausea, Rash, Pruritus, Arthralgia, Back pain, Pain in extremities, and Pyrexia.
Please consult with your local regulatory agency for approved labeling in your country.
For EU audiences, please see the Summary of Product Characteristics (SmPC) for ENTYVIO.
About Takeda Pharmaceutical Company
Takeda Pharmaceutical Company Limited is a global, R&D-driven pharmaceutical company committed to bringing better health and a brighter future to patients by translating science into life-changing medicines. Takeda focuses its research efforts on oncology, gastroenterology and central nervous system therapeutic areas. It also has specific development programs in specialty cardiovascular diseases as well as late-stage candidates for vaccines. Takeda conducts R&D both internally and with partners to stay at the leading edge of innovation. New innovative products, especially in oncology and gastroenterology, as well as its presence in emerging markets, fuel the growth of Takeda. More than 30,000 Takeda employees are committed to improving quality of life for patients, working with our partners in health care in more than 70 countries. For more information, visit http://www.takeda.com/news.
SOURCE Takeda Pharmaceutical Company Limited