309specifically seek this group as a population of interest. A phase III randomized
clinical trial in ulcerative colitis is recruiting patients with an estimated primary
completion date of April 2018.
Risankizumab (Anti-IL23, Monoclonal Ab, IV Route, CD)
Unlike ustekinumab, which blocks both IL12 and IL23 through a shared p40 sub-
unit, risankizumab, a monoclonal antibody, more selectively blocks IL23 by tar-
geting its p19 subunit. Although no phase III studies are currently registered, a
recently completed phase II randomized clinical trial in Crohn’s disease showed it
met its induction efficacy endpoint, clinical remission at week 12 for its higher
dose arm [ 26 ]. An open-label, long-term extension safety study is ongoing but not
recruiting participants. Its estimated completion date is October 2019. The FDA
has granted the drug orphan status for the investigational treatment of pediatric
Crohn’s disease [ 27 ].
Tofacitinib (Anti-JAK1-3, Small Molecule, po Route, UC)
There are four known Janus kinase subtypes, JAk1, JAK2, JAk3, and TYK2.
Tofacitinib inhibits three of the subtypes, primarily JAK1 and JAK3 and to a lesser
extent JAK2 [ 28 ]. When cell-surface receptors for various cytokines interact with
JAKs, signal transduction pathways are activated (JAK-STAT pathway), resulting in
the selective production of messenger RNA and synthesis of critical proinflamma-
tory cytokines, primarily interleukins [ 28 , 29 ]. Inhibition of the JAK-STAT pathway
through the use of JAK inhibitors such as tofacitinib downregulates these various
inflammatory mediators.
Phase III randomized controlled trials provide the evidence base demonstrating
the efficacy of tofacitinib. The OCTAVE phase III clinical trial program enrolled
patients with moderate-severe ulcerative colitis [ 30 ]. OCTAVE 1 and 2 were 8-week
induction studies and met the endpoint of clinical remission at week 8. Increased
levels of serum lipids and creatinine kinase were observed in patients treated with
tofacitinib. In the maintenance trial, OCTAVE Sustain, the primary endpoint, remis-
sion at week 52, was met [ 31 ]. There were no new adverse events. There were more
frequent infections in the tofacitinib group, a dose-dependent increase in herpes
infections, and no intestinal perforations, and there were changes in lipid and creati-
nine kinase profiles, consistent with results from prior studies. The drug is currently
under FDA review. Two phase IIb randomized control trials in Crohn’s disease were
negative for both induction and maintenance [ 32 ].
The novel aspects of these trials and this agent are that central readers were used
to assess mucosal inflammation and that this therapy is oral, a significant advance in
ease of administration compared to infusions and subcutaneous injections.
17 Novel Agents in Inflammatory Bowel Disease