The US Food and Drug Administration (FDA) today approved vedolizumab (Entyvio, Takeda Pharmaceuticals USA, Inc) injection for treatment of adults with moderate to severe ulcerative colitis and adults with moderate to severe Crohn's disease.
Vedolizumab is approved to treat those conditions when 1 or more standard therapies (corticosteroids, immunomodulators, or tumor necrosis factor [TNF] blocker medications) have been inadequate.
The approvals follow a joint meeting of the FDA's Gastrointestinal Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee on December 9, 2013, during which the drug was recommended by wide margins.
Vedolizumab is a humanized immunoglobulin G1 monoclonal antibody that is given intravenously. Vedolizumab binds exclusively to the α4β7 integrin, a primary mediator of gastrointestinal inflammation. It lessens inflammation in the gastrointestinal tract by selectively inhibiting the entry of inflammation-stimulating lymphocytes into the gastrointestinal tract without blocking systemic adaptive immunity.
Researchers established the safety and effectiveness of vedolizumab for ulcerative colitis in 2 clinical trials in approximately 900 patients who had failed to respond adequately to corticosteroids, immunomodulators, or TNF blocker medications. Patient evaluations included measures of stool frequency, rectal bleeding, endoscopic findings, and a physician's overall assessment.
Results show that a greater percentage of those treated with vedolizumab compared with a placebo "achieved and maintained clinical response, achieved and maintained clinical remission, achieved corticosteroid-free clinical remission, and as seen during endoscopy, had improved appearance of the colon," according to the FDA statement.
Vedolizumab's safety and effectiveness for Crohn's disease were established in 3 clinical trials in approximately 1500 patients who had failed to respond adequately to corticosteroids, immunomodulators, or TNF blocker medications. A greater percentage of participants treated with vedolizumab compared with a placebo achieved clinical response, clinical remission, and corticosteroid-free clinical remission.
"Revolutionary First-Line Treatment"
Matthew A. Ciorba MD, assistant professor of medicine, Division of Gastroenterology, Inflammatory Bowel Diseases Program, Washington University in Saint Louis, Missouri, told Medscape Medical News that vedolizumab for ulcerative colitis could be a potentially revolutionary first-line treatment. (Dr. Ciorba's institution participated in the clinical trial, but he was not directly involved with the research.)
Patients with ongoing intestinal problems, either ulcerative colitis or Crohn's disease, need drugs with new mechanisms of action, Edward V. Loftus, Jr, MD, professor of medicine and director, Inflammatory Bowel Disease Interest Group, Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota, told Medscape Medical News. (Dr. Loftus's institution participated in the clinical trial, but he was not directly involved with the research.)
"There's a big unmet need in the field, because there are many patients with inflammatory bowel disease who have difficult-to-control disease, and they've already been on other biologics, like the anti-TNF agents. They've either not tolerated them or they've lost response to them," Dr. Loftus explained.
"The nice thing about this drug is that the molecule that the drug targets is expressed in the vascular cells that line the gut, and maybe to a lesser extent the upper respiratory tract, so it seems to be more gut-selective. It seems to have...high efficacy," Dr. Loftus added.
Medication Adherence Was a Problem
"[The clinical trials suggest that vedolizumab] is going to be better at inducing remission than azathioprine, which is our other main non-TNFα...inhibitor option at this time. Its long-term maintenance may be better as well. It may be better than TNFα inhibitors as well," Dr. Ciorba said.
"[A recent study showed that] only about 30% of people who start on a TNFα inhibitor are still on it at 12 months. That means that 70% of people stop their medication, either because of inefficacy, intolerance, or for other unknown reasons, [suggesting that] they weren't doing well enough," he said.
"There's still something to be learned on how we might use and how we're going to position vedolizumab for Crohn's disease. Are people going to be on concomitant therapies like we've started to do with Remicade [Janssen]? Are people going to use a steroid for induction of remission?" Dr. Ciorba said.
No Cases of PML
Another type of integrin receptor antagonist has been associated with progressive multifocal leukoencephalopathy (PML), a rare and often deadly opportunistic infection of the central nervous system. PML is caused by a virus and usually only occurs in those whose immune systems are compromised. There were no identified cases of PML among research participants.
"It's a very exciting development, [because] we have basically had its sister drug, [natalizumab], which worked remarkably well in maintaining long-term remission in particularly challenging or refractory Crohn's disease patients," Dr. Ciorba said.
"Unfortunately, the potential side effect risk of PML is basically unacceptable, because it was occurring in about 1 [in] 1000 patients...anybody with refractory Crohn's disease has inevitably been on several therapies before. Those seemed to increase the risk that somebody would develop PML," he said.
"Now we have a drug that has been tried in over 3000 patients, and there hasn't been a single case of PML reported. More importantly, the specific mechanism of this α4β7 blockade, rather than the general α4, which is what [natalizumab] was, suggests that it isn't going to affect the brain," Dr. Ciorba explained.
"[PML] shouldn't be an issue anyway, because the molecular target of the drug is not expressed in the blood–brain barrier," Dr. Loftus said.
He explained that it is early and that it sometimes takes a year or 2 after a new drug comes out before some safety issues are recognized.
In clinical trials, patients are actively monitored for PML with frequent and regular screenings and evaluations of any new, unexplained neurological symptoms, as necessary. "Because clinical trials are conducted under tightly controlled conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates that might be observed in practice," the FDA news release notes.
"Health care professionals should monitor patients on Entyvio for any new onset, or worsening, of neurological signs and symptoms. The FDA will continue to work with the sponsor to further investigate the risk of PML through a required post-marketing study and enhanced, expedited adverse event reporting," the release states.
"I think there's going to be a more tempered or calculated approach on which patients [with Crohn's disease] to use it in. At the same time, it could be a major advance to our current armamentarium," Dr. Ciorba said.
Vedolizumab may be a major option for patients with colonic Crohn's disease, which is particularly difficult to treat, he said.
"Many of us who work in inflammatory bowel disease centers are looking forward to the commercial availability of this drug because there is such an unmet need," Dr. Loftus said.
Dr. Ciorba's institution participated in the clinical trial, but he was not directly involved with the research. His institution received research support, but he has received no compensation from Takeda Pharmaceuticals. Dr. Loftus's institution participated in the clinical trial, but he was not directly involved with the research. He reports consulting for Takeda Pharmaceuticals on advisory boards related to vedolizumab, and his institution received research support, but he has received no compensation from Takeda Pharmaceuticals.
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Cite this: FDA OKs Vedolizumab (Entyvio) for Ulcerative Colitis, Crohn’s - Medscape - May 20, 2014.