307endpoint, a reduction of 70 points in the CDAI at week 12, and this was attributed
to a high placebo response rate. A statistically significant difference in response to
those with an elevated CRP (above 18) suggested that perhaps better identifying
those with true inflammation would help in trial design. There were no cases of
PML in this short-term induction study. OPERA II is a phase II open-label long-
term treatment study that completed in July 2016.
The central nervous system is constitutively devoid of MAdCAM-1; thus the
strategy of blocking MAdCAM-1 should not result in cases of PML. As corroborat-
ing data that this strategy should not be associated with PML, the TOSCA study
performed up to two lumbar punctures in 24 patients with Crohn’s who received
PF-00547659 after failing TNF therapy [ 17 ]. The results showed no change in the
CSF lymphocytes, supporting a CNS-sparing mechanism with this drug.
Ozanimod (SIP Receptor 1 and 5 Agonist, Small Molecule, po
Route, UC/CD)
Ozanimod is a small molecule inhibitor with a different strategy than other leuko-
cyte anti-trafficking strategies discussed above. Instead of inhibiting circulating
lymphocytes from entering injured/inflamed tissue through blockade of the α 4 β 7
integrin or its counter-receptor, MAdCAM-1, ozanimod effectively traps lympho-
cytes at the earliest phase of trafficking [ 1 ]. Besides the novel mechanism of action,
this drug is also novel in that it is an oral medication.
Ozanimod traps lymphocytes through internalization and degradation of the
sphingosine-1-phosphate receptor (S1P) found on the lymphocytes [ 18 ]. Without
the S1P receptor, the lymphocyte is unable to respond to S1P expressed along the
lymphatic endothelium, a necessary step for activated lymphocytes to leave the
lymph nodes. The arrest of lymphocytes in the lymph nodes leads to a reversible
reduction of circulating lymphocytes in the blood.
There are five S1P subtypes (S1P1 through S1P5), responsible for regulating
multiple immunologic and cardiovascular effects [ 18 ]. S1P1–3 are expressed ubiq-
uitously, S1P4 is generally confirmed to lymphoid cells and tissues, and S1P5 is
predominantly located in the central nervous system [ 19 , 20 ]. Ozanimod blocks two
of these subtypes, primarily subtype 1 but also subtype 5. Blockade of subtypes 2,
3, and 4 is associated with cardiovascular issues (bradycardia, second-degree AV
block), elevated aminotransferases, and macular edema. Blockade of subtypes 1 and
5 in patients with multiple sclerosis showed reduction in brain lesions with minimal
effect on heart rate and liver enzymes [ 18 ].
A phase III randomized controlled trial is underway in UC. TOUCHSTONE, a
phase II randomized controlled trial, recruited patients with moderate to severe UC
[ 18 ]. This study achieved its primary induction primary endpoint, clinical remission
at 8 weeks over placebo. It also achieved its primary maintenance endpoint, clinical
remission at week 32 [ 18 ]. Treatment with ozanimod at the highest-dose group
reduced circulating lymphocytes by 49% with no significant side effects. Even so,
17 Novel Agents in Inflammatory Bowel Disease