Ulcerative Colitis, also related closely to Crohn’s disease, is not considered an autoimmune disease. However, because the disease involves the body’s immune system attacking the gastrointestinal tract, treatments for the disease are often shared with those to treat autoimmune diseases that involve chronic inflammation, such as rheumatoid arthritis. Unfortunately, many of the treatments for autoimmune diseases offer mixed results in term of managing symptoms.
A new drug called Vedolizumab (VDZ, trade name Entyvio) made by Takeda Pharmaceuticals USA, Inc., however, has been recommended for treatment of adults with ulcerative colitis (UC) and Crohn’s disease (CD) by the FDA’s Gastrointestinal Drugs Advisory Committee (GIDAC) and the Drug Safety and Risk Management Advisory Committee (DsaRMAC). The new FDA approval will give sufferers of this disease a possible new treatment option.
Although often combined, UC and CD, which are the two major types of inflammatory bowel disease and behave like autoimmune diseases and present similar clinical symptoms and course, do have differences in histology, extra intestinal involvement, and complications. In the new study involving Vedolizumab, data was presented from 5 phase 3 trials of which two were in UC and three were in CD in order to cover both diseases effectively.
Read more about Crohn’s Disease.
Vedolizumab is a humanized immunoglobulin G1 monoclonal antibody which has the capacity to bind specifically to α4β7 integrin which is a primary mediator of gastrointestinal inflammation. The monoclonal antibody alleviates gastrointestinal inflammation by selectively inhibiting the entry of inflammation-promoting lymphocytes into the gastrointestinal tract without blocking systemic adaptive immunity. VDZ is administered intravenously.
The committee voted on whether the benefits outweigh the risks for VDZ. In particular, they looked at 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.
In terms of UC, VDZ was recommended 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.
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, noted, “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]”.
VDZ has been recommended for patients with UC who have failed any of the 3 therapies. The committee voted 13 for patients who have failed steroids or immunosuppressants or TNFα-antagonists to 8 for patients who have failed immunosuppressants or TNFα-antagonists.
For Crohn’s disease, the committee 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. This is for 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.
At week 52, only 1 (C13007) of the two induction trials in patients with CD met its primary endpoint of clinical remission. Since there was only one trial with useful data, the FDA questioned whether the evidence provided by that trial was strong enough to support the use of VDZ. In the second induction trial (C13011), the primary endpoint was clinical remission at week 6. The primary endpoint was not achieved in this study.
According to DSaRMAC voting member Maria Suarez-Almazor, MD, PhD, Barnts Family Distinguished Professor, University of Texas, MD Anderson Cancer Center in Houston, 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. “It would be many years, and it would probably delay the approval of this drug…by 10 years”.
The committee voted 14 for patients who have failed steroids or immunosuppressants or TNFα-antagonists to 6 for 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.
Twelve deaths where reported in patients who received VDZ, however the FDA concluded that none of those deaths were related to VDZ. It was also reported that infections were higher in the VDZ group than placebo (PBO) group (43 percent vs 35 percent), however serious infections were about the same across groups. Four percent were reported in the VDZ group, 3 percent in the PBO group and 3 percent in VDZ/PBO. Upper respiratory tract infections were reported (high-level term; 24 percent for VDZ vs 17 percent for PBO). This appears to have driven the difference in frequency of overall infections between the VDZ and PBO groups. Herpes viral infections, mostly in the mouth, were reported by 51 patients however none were serious (3% VDZ/PBO, 2% PBO, and 3% VDZ).
None of the patients developed PML, a serious infection that has been associated with a similar drug known as 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. They voted unanimously that the company adequately characterized the potential risk for PML with VDZ.
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, noted, “The applicant made a good case for describing the mechanism, and the clinical studies gave enough information to go on for recommendation of approval.”