Vedolizumab Recommended for Ulcerative Colitis, Crohn's

Troy Brown

December 10, 2013

Vedolizumab (VDZ; Entyvio, Takeda Pharmaceuticals USA, Inc) was recommended by wide margins for the treatment of adults with ulcerative colitis (UC) and Crohn's disease (CD) at a joint meeting of the US Food and Drug Administration's (FDA's) Gastrointestinal Drugs Advisory Committee (GIDAC) and the Drug Safety and Risk Management Advisory Committee (DSaRMAC), held December 9.

The vote follows a discussion of data from 5 phase 3 trials: 2 in UC and 3 in CD. The 2 major types of inflammatory bowel disease, UC and CD are autoimmune diseases with similar clinical presentation and course but differences in histology, extraintestinal involvement, and complications.

VDZ is a humanized immunoglobulin G1 monoclonal antibody that binds exclusively to the α4β7 integrin, a primary mediator of gastrointestinal inflammation. VDZ alleviates inflammation in the gastrointestinal tract by selectively inhibiting the entry of inflammation-promoting lymphocytes into the gastrointestinal tract without blocking systemic adaptive immunity, according to a company briefing. VDZ is given intravenously.

For each indication, the committee was asked to vote on whether the benefits outweigh the risks for VDZ (in particular, progressive multifocal leukoencephalopathy [PML]) to support approval for the proposed population that has failed steroids or immunosuppressants or TNFα-antagonists, for patients who have failed immunosuppressants or TNFα-antagonists, or for neither.

Ulcerative Colitis

The committee recommended VDZ for the indication of reducing signs and symptoms, inducing and maintaining clinical response and remission, and mucosal healing, and for achieving corticosteroid-free remission in adults with moderately to severely active UC who have responded inadequately to, lost response to, or were intolerant to either conventional therapy (including steroids and immunosuppressants) or a tumor necrosis factor-alpha (TNFα) antagonist.

Both the induction trial (C13006) and the maintenance trial (C13006) in patients with UC demonstrated VDZ's efficacy.

The committee voted 13 (patients who have failed steroids or immunosuppressants or TNFα-antagonists) to 8 (patients who have failed immunosuppressants or TNFα-antagonists) to recommend VDZ for patients with UC who have failed any of the 3 treatments.

"Given that the risks are at this point fairly minor in context of the disease benefits, the flexibility probably outweighs the concerns of limiting the indication [to those who have failed immunosuppressants or TNFα but not steroids]," DSaRMAC voting member Tobias Gerhard, PhD, RPh, assistant professor, Rutgers University, Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, New Brunswick, New Jersey, said.

Crohn's Disease

The panel recommended VDZ for reducing signs and symptoms, inducing and maintaining clinical response and remission, and mucosal healing, as well as for achieving corticosteroid-free remission in adults with moderately to severely active CD who have responded inadequately to, lost response to, or were intolerant to either conventional therapy or a TNFα antagonist.

Only 1 (C13007) of 2 induction trials in patients with CD met its primary endpoint of clinical remission at week 52. The FDA questioned whether the evidence in that trial was strong enough to support using only a single trial for approval.

In the second induction trial (C13011), the primary endpoint was clinical remission at week 6. The primary endpoint was not achieved in this study.

Expecting a clinical response at 6 weeks after only 2 doses of VDZ is too stringent a requirement, and it would be unjustifiable to ask the company to do additional studies in this population, said DSaRMAC voting member Maria Suarez-Almazor, MD, PhD, Barnts Family Distinguished Professor, University of Texas, MD Anderson Cancer Center in Houston.

"It would be many years, and it would probably delay the approval of this drug...by 10 years," she said.

The committee voted 14 (patients who have failed steroids or immunosuppressants or TNFα-antagonists) to 6 (patients who have failed immunosuppressants or TNFα-antagonists) to recommend VDZ for patients with CD who have failed any of the 3 treatments, with 1 abstention.

Safety

A total of 12 deaths occurred in patients who received VDZ; the FDA reviewer concluded that none of those deaths were related to VDZ.

In the comparative safety data, infections were higher overall in the VDZ group than the placebo (PBO) group (43% vs 35%), but serious infections were about the same across groups (4% in VDZ, 3% in PBO, and 3% in VDZ/PBO).

Upper respiratory tract infections were the most frequently reported infections (high-level term; 24% VDZ vs 17% PBO) and appear to have driven the difference in frequency of overall infections between the VDZ and PBO groups.

Herpes viral infections (none serious) were reported by 51 patients; most were oral herpes. Herpes infection rates were similar between the treatment groups (3% VDZ/PBO, 2% PBO, and 3% VDZ).

Low Risk for PML

None of the patients developed PML, a serious infection that has been associated with a similar drug, natalizumab. On the basis of the "rule of 3," the company estimates that the true rate of PML will be lower than 2.99 in 1000 with 95% confidence in patients who received at least 24 infusions.

The committee agreed unanimously that the company had adequately characterized the potential risk for PML with VDZ to support approval.

"The applicant made a good case for describing the mechanism, and the clinical studies gave enough information to go on for recommendation of approval," GIDAC committee voting member Marc Wishingrad, MD, an assistant clinical professor of medicine, Division of Digestive Disease, Department of Medicine at David Geffen School of Medicine/University of California, Los Angeles, and private practitioner at Santa Monica Digestive Specialists in Santa Monica, California, said.

The committee voted 19 to 1 (1 abstention) against limiting concomitant immunosuppressants to a specific duration (eg, during induction only).

The committee members have disclosed no relevant financial relationships.

Joint meeting of the Gastrointestinal Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee, December 9, 2013.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....