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the study was deemed as preliminary by the authors [ 18 ]. The reasons were size of
the study (around 65 patients per group) and insufficient duration to establish clini-
cal efficacy or assess safety. A phase II study in Crohn’s disease is ongoing but not
recruiting patients. Estimated completion date is September 2018.
Inflammatory Cascade Antagonists
Ustekinumab (Anti-IL12 and Anti-IL23, Monoclonal Ab, IV
then SC Route, UC/CD)
Activated lymphocytes, if allowed to leave the lymph node and enter the gut, will
participate in the local and dysregulated inflammatory cascade that includes various
cytokines [ 1 ]. The traditional anti-cytokine strategy in IBD had been to target tumor
necrosis factor α. New data show this is not the only potentially successful target.
Ustekinumab, a monoclonal antibody that targets interleukins IL12 and IL23,
was approved by the FDA in September 2016 for use in moderate to severe Crohn’s
disease. Genome-wide association studies have shown an association between the
IL12/IL23 pathway and CD, and the IL12/IL23 pathway is an important driver of
inflammation in adaptive immune responses [ 21 , 22 ]. Ustekinumab, an interleukin
inhibitor, blocks the p40 subunit of IL12 and IL23 and prevents their interaction
with the IL12Rb1 receptor on the surface of T cells, natural killer cells, and antigen-
presenting cells. The result is inhibition of IL12- and IL23-mediated cell signaling,
activation, and cytokine production [ 22 , 23 ].
Phase III randomized controlled trials provide the evidence base demonstrating
the efficacy of ustekinumab in additional to a large phase IIb clinical trial. CERTIFI,
a phase IIb randomized controlled trial, enrolled patients with moderate to severe
Crohn’s disease resistant to TNF antagonists [ 24 ]. Patients were enrolled in an
8-week intravenous induction and then a 28-week subcutaneous maintenance trial.
The study met its primary endpoint response at week 6. There was no difference in
remission at week 6; however rates of remission and response were superior at the
end of maintenance.
The phase III randomized controlled trials (UNITI) enrolled patients who failed
TNF (UNITI-1) or who were biologic naïve (UNITI-2) to receive a single intrave-
nous induction dose of ustekinumab followed by subcutaneous maintenance for
44 weeks (IM-UNITI) [ 25 ]. The induction studies met their primary endpoint, clini-
cal response at week 6. The maintenance study also met its primary endpoint,
remission at week 52 of the trial (week 44 of maintenance). Adverse effects were
similar among the groups.
The formulation and trial are novel in that it involves an intravenous formulation
for induction and then a subcutaneous formulation for maintenance and that the
trial specifically enrolled and demonstrated efficacy in TNF failures. Previous stud-
ies have used the same formulation (intravenous or subcutaneous injection) for
both the induction and maintenance phases and permitted TNF failures, but did not
F. Velayos