294
PF-00547659 (Anti-MAdCAM-1)
PF-00547659 is a monoclonal IgG2 antibody directed against MAdCAM-1.
MAdCAM-1 is expressed on vascular endothelium of the intestinal lamina propria
and through its binding to α 4 β7, it regulates intestinal homeostasis of lymphocytes
[ 8 , 11 ]. In a multicentre, double-blind, placebo-controlled first-in-human study
designed to explore the safety and efficacy of PF-00547659 in 80 patients with active
UC, subjects received single or multiple (three doses at 4 weeks interval) doses of
PF-00547659, 0.03–10 mg/kg, IV/SC or placebo [ 67 ]. Overall response and remis-
sion rates at 4 and 12 weeks were 52%, 42% and 22%, respectively, with combined
PF-00547659 doses as compared to 32% and 21%, respectively, with placebo [ 67 ].
Equivalent endoscopic response rates were 50% and 42% vs. 26% and 29%, respec-
tively. The study was not powered to detect statistically significant differences in
clinical/endoscopic response or remission rates and biomarkers (secondary outcome
measures). PF-00547659 was noted to be safe, well tolerated and devoid of immuno-
genicity. Although no statistically significant differences were noted, between drug
and placebo, some benefits over clinical and endoscopic endpoints were seen. Of
note, faecal calprotectin levels were significantly reduced in patients treated with
PF-00547659 relative to placebo, lending support to the anti- inflammatory effect of
the drug in the colon [ 67 ]. Phase II trials on induction (OPERA) and maintenance
(OPERA II) in CD and phase II trials on induction (TURANDOT) and maintenance
(TURANDOT II) in UC are in progress (http://www.clinicaltrials.gov).
Etrolizumab
Etrolizumab (rhuMAb β7) is a humanised monoclonal antibody against the β7 sub-
unit of the heterodimeric integrins α 4 β7 and αEβ7. A phase I trial in subjects with
moderate-severe UC (Mayo clinic score ≥ 5) suggested it to be safe and well toler-
ated [ 68 ]. The most common adverse effect was headache, followed by fatigue,
abdominal pain and nasopharyngitis. Neither enteric nor respiratory infections were
increased in the etrolizumab-treated group [ 68 ]. In a subsequent double-blind ran-
domised placebo-controlled phase II trial (EUCALYPTUS) that studied the effects
of etrolizumab on the induction of remission in patients moderate to severe UC, 124
patients were randomised to receive monthly SC injections, of either etrolizumab at
100 mg or 300 mg plus a loading dose (420 mg SC between weeks 0 and 2) or pla-
cebo [ 12 ]. After three doses, both dosing levels of etrolizumab were associated with
higher rates of clinical remission compared with placebo at 10 weeks. In the 100-
mg treatment group, 20.5% achieved clinical remission (P = 0.004), and in the
300 mg plus loading dose, 10.3% (P = 0.049) achieved clinical remission. None of
the subjects (0%) receiving placebo achieved clinical remission. In subgroup analy-
sis, the clinical efficacy of etrolizumab was demonstrated in anti-TNF-naive patients
(43.8% and 25% at 100 and 300 mg + loading dose, respectively). Those with an
inadequate response to prior anti-TNF therapy (n = 47) did not meet the primary
J.K. Limdi and F.A. Farraye