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detected and its mechanism of action should not increase the risk of PML, this was
a short-term induction study, thus requiring a larger and longer-term trial to more
appropriately assess this outcome.
One milestone of this study was the finding of a 0% remission rate in the placebo
group, thought to be in part to the use of central readers and entry criteria [ 11 ].
Another interesting post hoc exploratory analysis from the phase II study suggested
a possible heterogeneity in treatment benefit or patients with varying αE concentra-
tion. The finding that baseline colonic αE expression could improve response to
etrolizumab and that treatment reduced αE+ lymphocytes in the epithelium suggests
that αEβ7+ lymphocytes contribute to the pathogenesis of UC and that specific
blockade of these lymphocytes could provide a novel dual therapeutic approach to
treatment [ 12 ]. These hypotheses, of course, will need further study and testing in
the longer-term phase III trials.
The phase III trial program for etrolizumab includes at least eight studies, includ-
ing one in Crohn’s disease, and is novel for several reasons. Besides using standard-
ized centralized endoscopic scoring, it will also be the first phase III trials to perform
head-to-head biologic comparison to anti-TNF therapy (infliximab in one trial,
adalimumab in another).
PF-00547659 (Anti-MAdCAM-1, Monoclonal Ab, SC Route,
UC/CD)
PF-00547659 is a monoclonal IgG2 antibody directed against mucosal vascular
addressin cell adhesion molecule 1 (MAdCAM-1) [ 14 ]. MAdCAM-1, found in the
endothelium of venules, preferentially binds leukocytes expressing α 4 β7 receptor
integrins in the gut and results in migration of lymphocytes from the bloodstream
into the intestine and promotion of the inflammatory cascade locally [ 15 ]. Thus,
while PF-00547659 is similar to vedolizumab and etrolizumab in that it prevents
migration of α 4 β7-expressing lymphocytes from migrating to the gut, it works quite
differently by blocking the effector receptor in the intestinal vasculature
(MAdCAM-1) as opposed to its α 4 β7 integrin ligand on the lymphocytes [ 1 ].
Phase III clinical trials using this molecule are reportedly planned. TURANDOT,
a phase II randomized controlled trial, enrolled patients with moderate to severe
ulcerative colitis [ 14 ]. This induction study achieved its primary endpoint, clinical
remission at week 12. There was no increased incidence of infection, including in
MAdCAM-1 bearing tissues (gastrointestinal tract, nasal tissue, spleen, bladder,
uterus, and lung). There were no cases of PML in this short-term induction study.
Even though mechanistically there is low concern for PML, nonetheless this
question is best addressed in longer-term studies. TURNADOT II is the open-label
long- term treatment study which is ongoing but no longer recruiting. The estimated
completion date is December 2017.
OPERA I, a phase II randomized controlled clinical trial, enrolled patients with
moderate to severe Crohn’s disease [ 16 ]. This induction study missed its primary
F. Velayos