Table 1.

Findings From Clinical Trials of Patients With IBD

	Key Outcomes and Observations	Insights and Lessons Learned
IL23/Th17 pathway
Mannon44, 2004 Phase 2A, briakinumab Crohn’s disease	- Significant increase in response rates with weekly SQ weight-based dosing - Accompanied by improvement in histologic activity and cytokine response - Higher rate of injection site reaction with intervention vs placebo - Presence of ADA prior to initiation of therapy	- Dose response: weekly SQ treatment at higher dose associated with best response and efficacy - Possibly related to immunogenicity and improved drug concentration with higher dose
Panaccione48, 2015 Phase 2B, briakinumab Crohn’s disease	- Failed to meet primary end-point (clinical remission at week 6) - Week 12 rates of remission and response higher in some active intervention groups but no consistent demonstrable efficacy and considered a negative study - Higher rate of infusion reactions with intervention (switched to different formulation compared to phase 2A trial)	- Immunogenicity may have impacted outcomes - Clinical remission too strict as primary outcome for phase 2 if used early (i.e. week 6) - May have time dependency efficacy which impacts optimal time point of assessment and re-randomization design
Sandborn45, 2008 Phase 2A, ustekinumab Crohn’s disease	- Failed to meet primary end-point (clinical response at week 8), although there was a significant increase in week 4 and 6 response rates and there was a measurable reduction in inflammation for intervention arm but not placebo - Efficacy influenced by prior anti-TNF therapy with improved efficacy demonstrated in anti-TNF failures - Efficacy influenced by use of 100-point CDAI response as end-point - Enhanced efficacy with IV vs SQ formulation of drug	- 100-point CDAI response and shorter follow-up interval to assess primary end-point - Enrich future trials with anti-TNF failures - Switch to IV weight-based dosing regimens
Sandborn46, 2012 Phase 2B, ustekinumb Crohn’s disease	- Met its primary end-point (clinical response at week 6) for highest weight-based dose (6 mg/kg) - Among responders, use of SQ maintenance therapy associated with higher response, remission, and steroid-free remission rates - Efficacy again influenced by prior anti-TNF therapy with improved efficacy demonstrated in anti-TNF failures	- Study anti-TNF failures and non-failures or those naïve to anti-TNF therapy separately - IV weight-based induction with SQ fixed-dose maintenance feasible and associated with treatment efficacy
Feagan47, 2016 Phase 3, ustekinumab Crohn’s disease	- Met its primary end-point (clinical response at week 6) for fixed-dose and weight-based IV induction regimen - Association between drug concentrations and treatment outcomes, with weight-based regimen achieving therapeutic concentrations more often - Difference between intervention and placebo similar for both anti-TNF naïve and anti-TNF failure, with trend towards improved outcomes for anti-TNF naive - Demonstrable efficacy for IV induction with SQ maintenance	- Pharmacokinetics likely similar to that of anti-TNF therapy with regards to drug concentration and treatment efficacy association and dosing - Rapid treatment onset and effect - Prior signals for enhanced efficacy in anti-TNF failures not clearly shown
Sands56, 2015 Phase 2, MEDI2070 Crohn’s disease	- Higher rate of clinical effect (clinical remission OR clinical response) and clinical effect + > 50% reduction in CRP or FC, but rates of remission specifically not significantly higher in active treatment arm vs placebo at week 8	- IL23p19 inhibition at least equally efficacious as compared IL12p40 inhibition - Week 12 may be ideal assessment point - Consider enrichment with biomarkers or endoscopic evaluation of inflammation
Feagan55, 2016 Phase 2, Risankizumab Crohn’s disease	- Higher rate of clinical remission, endoscopic response, and endoscopic remission at week 12 as compared to placebo
Hueber57, 2012 Phase 2A, Secukinumab Crohn’s disease	- Study stopped due to futility given higher response rate in placebo group vs active treatment group - Genetic polymorphisms identified to be associated with response and/or worsening of disease activity with drug exposure - Increased frequency of infectious complications, with specific increase in fungal infections	- These class of agents have been abandoned in IBD - Potential for genetic enrichment of trials
Th1 Pathway
Reinisch52, 2006 Phase 2, fontolizumab Crohn’s disease	- No clear dose-dependent safety signal or intolerability - Dose-dependent signal of efficacy and response to therapy. However, the placebo group had high rates of response and no statistical significance - Treatment effect more prominent when stratifying by CRP	- anti-IFNG biologics are tolerable and there may be a signal of efficacy at higher doses - High placebo rates possibly driven by lack of active inflammation and improved treatment effect size when stratifying by CRP
Hommes51, 2006 Phase 2, fontolizumab Crohn’s disease	- Failed to meet primary end-point (response on day 28 after single dose) - Statistically significant rates of response with follow-up dosing at day 56 with trend towards significance for clinical remission - Treatment effect again more prominent when stratifying by CRP with accompanying reduction in placebo response rates - Pharmacodynamic effects were observed by immunohistochemistry	- Multiple doses are needed to demonstrate the potential efficacy of this agent - Placebo rates and CRP again impacted results and consideration for baseline assessment of inflammation
Reinisch53, 2010 Phase 2, fontolizumab Crohn’s disease	- Failed to meet its primary end-point (response on day 29) - Again observed increased response over time - Higher rate of adverse events and ADA antibodies (study switched to using SQ formulation of drug after first IV based dose)	- Primary end-point should be beyond 28 days - Unclear pharmacokinetics of SQ formulation
Th2 Pathway
Danese102, 2015 Phase 2, Tralokinumab UC	- Higher rate of clinical remission but not clinical response or mucosal healing at week 8 as compared to placebo	- Add on therapy with anti-cytokine agents targeting IL-13 in UC is not efficacious
Reinisch103, 2015 Phase 2, Anrukinzumab UC	- Failed to meet its primary end-point with a high dropout rate due to lack of efficacy
Other Cytokines
Ito105, 2004 Phase 2, MRA (anti-L6R) Crohn’s disease	- Higher rates of response and clinical remission at week 8 and 12 as compared to placebo, but no difference in endoscopic or histologic response	- Targeting IL-6 may be a therapeutic option
Danese106, 2016 Phase 2, anti-IL6 Crohn’s disease	- Met its primary end-point for clinical response (CDAI score of 70) at weeks 8 and 12 - Higher rate of clinical remission with 50mg dosing regimen - Concerns surrounding safety, with majority of events with high dose (200mg)	- Anti-IL6 therapies are efficacious but may be associated with increased rates of adverse events
JAK Pathway
Sandborn110, 2012 Phase 2A, Tofacitinib UC	- Met its primary end-point (clinical response) along with key secondary outcomes (clinical and endoscopic remission) - Dose dependent increase in cholesterol and potentially neutropenia	- Efficacious treatment option for UC - 10mg twice daily optimal dosing strategy - Rapid onset of treatment efficacy - Equally efficacious in anti-TNF naïve and exposed individuals
Sandborn111, 2016 Phase 3, Tofacitinib UC	- Again demonstrated a significant increase in response, remission, and mucosal healing outcomes with active treatment arm as compared to placebo - Rapid treatment onset (within 2 weeks of therapy) and outcomes similar in anti-TNF naïve and anti-TNF exposed
Sandborn112, 2014 Phase 2A, Tofacitinib Crohn’s disease	- No improvement in clinical efficacy for any of the dosing regimens at week 4, although highest dose did result in reductions in systemic inflammation - Dose dependent increase in cholesterol	- High placebo rates may be due to lack of disease activity assessment prior to enrollment - May have slower onset of action in CD as compared to UC, and may require longer follow-up to assess treatment efficacy
Panes113, 2016 Phase 2B, Tofacitinib Crohn’s disease	- Again failed to meet primary end-point now at week 8, but did demonstrate reduction in systemic inflammation (CRP and FC)	- Non-selective inhibition of JAK pathway may not be an efficacious treatment option in CD
Vermeire114, 2016 Phase 2, Filgotinib Crohn’s disease	- Significantly higher rate of response and remission at week 4	- Selective JAK1 inhibition may be a more effective approach for targeting the JAK pathway in CD

ADA: antidrug antibodies; IV: intravenous; SQ: subcutaneous; CRP: C-reactive protein, FC: fecal calprotectin; CD: Crohn’s disease