Morris, Nathan

Abstract Background The primary objective of the VIVID-1 trial (NCT03926130) was to demonstrate efficacy and safety of mirikizumab (miri), a p19-directed anti-IL-23 antibody, compared to placebo (PBO) in patients (pts) with moderate-to-severe Crohn’s disease. Miri demonstrated statistically significant improvements in co-primary and all key secondary endpoints versus (vs) PBO1. Here we present the results of secondary endpoints on the comparisons of miri to ustekinumab (uste), a p40 directed anti-IL-12/IL-23 inhibitor from the Phase 3, randomised, double-blind, double-dummy, active- and PBO-controlled, treat-through (TT) study, VIVID-1 (NCT03926130). Methods Adult pts (N=1065) were randomised 6:3:2 to miri (N=579) 900mg intravenously (IV) every 4 weeks (Q4W) to W12, then 300mg subcutaneously (SC) Q4W to W52, uste (N=287) one ~6 mg/kg IV dose, then 90mg SC Q8W to W52 or PBO (N=199). At W12 PBO responders continued PBO to W52; PBO non-responders received the same blinded miri regimen as described above (IV then SC). Efficacy of miri vs uste was assessed by the proportion of pts achieving endoscopic response and by the proportion of pts achieving clinical remission by Crohn’s Disease Activity Index (CDAI) at W52 (both gated). Additional non-multiplicity-adjusted endpoints included endoscopic remission, corticosteroid-free clinical remission by CDAI, and the composite of CDAI clinical remission and endoscopic response at W52. (Figure 1 for definitions). Results Baseline characteristics were overall balanced across the three treatment groups (table 1). Pts treated with miri achieved all key major secondary endpoints (p<.000001) compared to PBO (Figure 1). Miri achieved non-inferiority to uste for clinical remission by CDAI (p=0.113117) (Figure 1C). Although superiority to uste in endoscopic response was not achieved (p=0.51) (Figure 1A), in biologic failed pts miri demonstrated a numerical trend towards greater response rates compared to uste for endoscopic response and clinical remission by CDAI (Figure 1 B & D). The overall safety profile was consistent with the known safety profile of miri. The proportion of treatment emergent adverse events (TEAE) were similar for miri (78.6%) and uste (77.3%); most common TEAEs were COVID-19, anaemia, arthralgia, headache, upper respiratory tract infection, nasopharyngitis and injection site reaction. Instances of serious adverse events were comparable for miri (10.3%) and uste (10.7%). Conclusion In this phase 3 TT design study, miri achieved non-inferiority to uste for clinical remission by CDAI. In biologic failed pts miri had a numerical trend towards greater response compared to uste in clinical and endoscopic endpoints, with an acceptable safety profile. 1Ferrante et al., submitted to ECCO 2024

Abstract Background and Aims To evaluate the effect of mirikizumab, a p19-targeted anti-interleukin-23, on histological and/or endoscopic outcomes in moderately-to-severely active ulcerative colitis [UC]. Methods Endoscopic remission [ER], histological improvement [HI], histological remission [HR], histological-endoscopic mucosal improvement [HEMI], and histological-endoscopic mucosal remission [HEMR] were assessed at Week [W]12 [LUCENT-1: N = 1162, induction] and W40 [LUCENT-2: N = 544, maintenance] for patients randomised to mirikizumab or placebo. Analyses were performed to evaluate predictors of: HEMI at W12 with mirikizumab and HEMR at W40 in patients re-randomised to subcutaneous [SC] mirikizumab; associations between W12 histological/endoscopic endpoints and W40 outcomes in mirikizumab responders re-randomised to mirikizumab SC; and associations between W40 endoscopic normalisation [EN] with/without HR. Results Significantly more patients treated with mirikizumab achieved HI, HR, ER, HEMI, and HEMR vs placebo [p <0.001], irrespective of prior biologic/tofacitinib failure [p <0.05]. Lower clinical baseline disease activity, female sex, no baseline immunomodulator use, and no prior biologic/tofacitinib failure were predictors of HEMI at W12 [p <0.05]. Corticosteroid use and longer disease duration were negative predictors of achieving HEMR at W40 [p <0.05]. W12 HI, HR, or ER was associated with W40 HEMI or HEMR [p <0.05]; ER at W12 was associated with clinical remission [CR] [p <0.05] and corticosteroid-free remission [CSFR] at W40 [p = 0.052]. HR and HEMR at W12 were associated with CSFR, CR, and symptomatic remission at W40. Alternate HEMR [EN + HR] at W40 was associated with bowel urgency remission at W40 [p <0.05]. Conclusions Early resolution of endoscopic and histological inflammation with mirikizumab is associated with better UC outcomes. Clinicaltrials.gov: LUCENT-1, NCT03518086; LUCENT-2, NCT03524092.

Current genome‐wide association studies still heavily rely on a single‐marker strategy, in which each single nucleotide polymorphism (SNP) is tested individually for association with a phenotype. Although methods and software packages that consider multimarker models have become available, they have been slow to become widely adopted and their efficacy in real data analysis is often questioned. Based on conducting extensive simulations, here we endeavor to provide more insights into the performance of simple multimarker association tests as compared to single‐marker tests. The results reveal the power advantage as well as disadvantage of the two‐ vs. the single‐marker test. Power differentials depend on the correlation structure among tag SNPs, as well as that between tag SNPs and causal variants. A two‐marker test has relatively better performance than single‐marker tests when the correlation of the two adjacent markers is high. However, using HapMap data, two‐marker tests tended to have a greater chance of being less powerful than single‐marker tests, due to constraints on the number of actual possible haplotypes in the HapMap data. Yet, the average power difference was small whenever the one‐marker test is more powerful, while there were many situations where the two‐marker test can be much more powerful. These findings can be useful to guide analyses of future studies. Genet. Epidemiol. 36:480‐487, 2012. © 2012 Wiley Periodicals, Inc.