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Anti-MAdCAM antibody induces remission in moderate-to-severe UC
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An investigational anti-MAdCAM antibody was safe, well tolerated and superior to placebo for inducing remission in patients with moderate-to-severe ulcerative colitis in the phase 2 TURANDOT trial.
Preliminary results from this trial were previously shared at ECCO 2015 and DDW 2015, and have now been published in full in The Lancet.
SHP647 (Shire; formerly PF-00547659, Pfizer) is a fully human monoclonal antibody that directly targets a GI endothelial adhesion molecule called mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and blocks its interaction with the alpha-4/beta-7 integrin. Shire licensed global rights to the agent from Pfizer in June of last year, and said it hopes to launch a pivotal phase 3 trial in the second half of 2017.
Séverine Vermeire
“The TURANDOT trial is the first study to investigate a new biologic, an anti-MAdCAM antibody, as a potential treatment for ulcerative colitis, a chronic intestinal disease with high unmet need,” Séverine Vermeire, MD, of the department of gastroenterology at University Hospital Leuven, Belgium, said in a press release. “These statistically significant results demonstrate the role that cell adhesion plays in ulcerative colitis and suggest that inhibition of cell adhesion mediated by MAdCAM may result in a potential treatment for patients suffering with this disease.”
Between November 2012 and February 2016, Vermeire and colleagues performed a double blind trial involving 357 adults with moderate-to-severe active ulcerative colitis recruited from 105 sites spanning 21 countries. All patients failed or were intolerant to at least one conventional therapy.
The investigators randomly assigned patients to receive placebo or one of four doses of SHP647 via subcutaneous injection at baseline and every 4 weeks for 12 weeks. Rates of remission (defined as a total Mayo score 2 with no individual subscore >1 and rectal bleeding subscore 1) at week 12 served as the primary endpoint, which was achieved by three of the four treatment groups.
Remission rates were highest in the 22.5- and 75-mg groups, with 11.3% of patients in the 7.5-mg group, 16.7% in the 22.5-mg group, 15.5% in the 75-mg group and 5.7% of the 225-mg group achieving remission at week 12 compared with 2.7% of the placebo group. Remission rates were substantially higher in patients who had not received prior treatment with anti-TNF therapy (10% to 25.8%) compared with those who had (2.5% to 9.8%).
Greater proportions of patients in the treatment groups also achieved clinical response and mucosal healing at 12 weeks compared with placebo.
The drug appeared to be well tolerated, and adverse events were comparable across groups, with headache being the most common reported by about 10% of patients, followed by ulcerative colitis and abdominal pain. Fewer than 5% of patients stopped treatment due to treatment-emergent adverse events, and serious adverse events occurred in 5.5% of the placebo group vs. 14.1% of the 7.5-mg group, 1.4% of the 22.5-mg group, 4.1% of the 75-mg group and 4.3% of the 225-mg group. There was one death in the 7.5-mg group due to adenocarcinoma of the colon, which was deemed “unlikely to be associated with the study drug.” The investigators noted that the safety data should be interpreted with caution as a larger patient population treated for a longer duration is required to fully assess the agent’s safety.
In a related editorial, David Laharie, MD, of the Centre Hospitalier Universitaire de Bordeaux, France, emphasized the importance of choice resulting from several emerging treatment options for IBD, including this anti-MAdCAM antibody.
David Laharie
“In the coming years, physicians treating patients with refractory ulcerative colitis will have several therapeutic options with multiple modes of action,” he wrote. “In parallel with Crohn’s disease, the choice of the first line biological agents in ulcerative colitis seems crucial. This choice is currently driven by indirect comparisons of efficacy and safety profiles, routes of administration and costs.”
He concluded that head-to-head comparative trials and strategic studies are currently needed to guide therapeutic sequencing and combinations. – by Adam Leitenberger
Disclosures: This study was funded by Pfizer. Vermeire reports she has received research support from AbbVie, MSD and Takeda, consulting fees from AbbVie, Celgene, Ferring, Galapagos, Genentech/Roche, Hospira, Janssen, MSD, Mundipharma, Pfizer, Second Genome, Shire and Takeda, and speaker fees from AbbVie, Falk Pharma, Ferring, Hospira, MSD, Takeda and Tillotts. Please see the full study for a list of all other researchers’ relevant financial disclosures. Laharie reports he has received consulting fees from AbbVie, Janssen, MSD, Pfizer and Takeda, and lecture fees and travel accommodations from AbbVie, Ferring, Janssen, MSD, Pfizer, Takeda and Tillotts.
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