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Filgotinib (Anti-JAK1, Small Molecule, po Route, UC/CD)
Similar to tofacitinib, filgotinib is an oral small molecule directed against the
JAK- STAT pathway. Unlike tofacitinib, which is a pan JAK kinase inhibitor, fil-
gotinib is a JAK1 selective inhibitor, with 30–50x greater affinity to JAK1 than
JAK2 or JAK3 [ 33 ].
A phase III randomized controlled trial is underway in CD and UC. FITZROY,
a phase II randomized controlled trial, recruited patients with moderate to severe
CD [ 33 ]. This study achieved its primary induction endpoint, clinical remission at
week 10 over placebo. Patients were then followed for an additional 10 weeks to
assess safety. At 20 weeks, filgotinib-treated patients had higher rates of serious
infections. Filgotinib-treated patients also had some elevations in lipids (both LDL
and HDL), similar to what was observed with tofacitinib. Longer-term safety data
are needed to more accurately determine if more selective JAK inhibition reduces
the risk of infection.
This study and molecule is novel and important in suggesting that selective Janus
kinase inhibition may not completely protect against infection. Also notable and
perplexing is that this study showed filgotinib was effective for treating Crohn’s
while another JAK kinase inhibitor, tofacitinib, was not.
Mongerson (Anti-SMAD7, Small Molecule, Oral Route,
UC/CD)
Mongerson is an oral Smad7 antisense oligonucleotide that normalizes activity of
transforming factor (TGF-β1), an immunosuppressive cytokine [ 34 , 35 ]. Gut
inflammation reduces TGF-β1 activity, thereby suppressing an important counter-
regulatory cytokine. This is due to increased levels of SMAD7, an intracellular
protein that binds the TGF-β receptor and prevents TGF-β1-associated anti-
inflammatory signaling. Mongerson hybridizes to SMAD7 messenger RNA,
mediating degradation and downregulation of SMAD7 and normalizing TGF-β 1
activity [ 36 ].
A phase III randomized clinical trial in Crohn’s disease is underway based on a
very promising phase II randomized clinical trial. In a phase II induction trial, the
primary outcome was met, clinical remission at day 15 with maintenance of remis-
sion for at least 2 weeks. The novelty of this study and this compound goes beyond
the simple novelty of not being an anti-TNF [ 37 ]. For one, it is an oral compound,
which is quite attractive as a treatment delivery system. Second, it targets the
counter- regulatory processes of Crohn’s by restoring the body’s natural anti-
inflammatory cytokine, TGF-β1. In contrast, anti-TNF strategies and the other
cytokine- based targets presented in this chapter target the proinflammatory cytokine
pathways. The third is the unprecedented rate of remission after only 2 weeks of
therapy, between 55 and 65%, for the two highest-dosing groups. Fourth is that the
F. Velayos