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Randomized Controlled Trial
. 2023 Oct 20;17(9):1457-1470.
doi: 10.1093/ecco-jcc/jjad050.

Resolving Histological Inflammation in Ulcerative Colitis With Mirikizumab in the LUCENT Induction and Maintenance Trial Programmes

Fernando Magro  1   2 , Rish K Pai  3 , Taku Kobayashi  4 , Vipul Jairath  5   6   7 , Florian Rieder  8   9 , Isabel Redondo  10 , Trevor Lissoos  11 , Nathan Morris  11 , Mingyang Shan  11 , Meekyong Park  12 , Laurent Peyrin-Biroulet  13
Affiliations
Randomized Controlled Trial

Resolving Histological Inflammation in Ulcerative Colitis With Mirikizumab in the LUCENT Induction and Maintenance Trial Programmes

Fernando Magro et al. J Crohns Colitis. .

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.

Keywords: Histological remission; mirikizumab; ulcerative colitis.

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Conflict of interest statement

FM has served as a speaker and received honoraria from: AbbVie, Biogen, Falk, Ferring, Hospira, Laboratórios Vitória, Merck Sharp & Dohme, and Vifor. RKP has receiving consulting fees from: AbbVie, Alimentiv, Allergan, Eli Lilly, Genentech, and PathAI. TK has received grants and/or contracts from: AbbVie, Activaid, Alfresa Pharma, Bristol-Myers Squibb, EA Pharma, Eli Lilly Japan, Gilead Sciences, Google Asia Pacific, Janssen Japan, JIMRO, JMDC, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Otsuka Holdings, Pfizer Japan, Takeda, and Zeria Pharmaceutical; has received lecture payments or honoraria from: AbbVie, Activaid, Alfresa Pharma, Galapagos, Janssen Japan, JIMRO, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Nippon Kayaku, Pfizer Japan, Takeda, ThermoFisher Diagnostics, Zeria Pharmaceutical; has received payment for expert testimony from: AbbVie, Activaid, Alfresa Pharma, EA Pharma, Janssen Japan, KISSEI Pharmaceutical, Kyorin Pharmaceutical, Mitsubishi Tanabe, Mochida Pharmaceutical, Nippon Kayaku, Pfizer Japan, and Takeda; and has participated on data safety monitoring boards or advisory boards for: Bristol-Myers Squibb, EA Pharma, Eli Lilly, and Janssen. VJ has received grants or contracts from: AbbVie, Adare, Atlantic, Boehringer Ingelheim, Celgene/Bristol-Myers Squibb, Eli Lilly, Janssen, Seres, Takeda, UCB Pharma, and VH Squared; has received consulting fees from: AbbVie, Alimentiv, Arena, Asahi, Asieris, Bristol-Myers Squibb, Celltrion, Eli Lilly, Ferring, Fresenius, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Kabi, Kasei Pharma, Landos Biopharma, Merck, Mylan, Organon Pandion, Pendopharm, Pfizer, Prometheus Biosciences, Protagonist Therapeutics, Reistone Biopharma, Roche, Sandoz, Second Genome, Takeda, Teva, Ventyx Biosciences, and Vividion Therapeutics; has received payments or honoraria from: AbbVie, Ferring, Galapagos, Janssen, Pfizer, and Takeda; and has participated on data safety monitoring or advisory boards for: AbbVie, Arena, Bristol-Myers Squibb, Fresenius, Gilead Sciences, Janssen, Kabi, Mylan, Roche, and Takeda. FR has received consulting or advisory board fees from: AbbVie, Adnovate, Agomab, Allergan, Arena, Boehringer-Ingelheim, Celgene/BMS, CDISC, Celsius, Cowen, Ferring, Galapagos, Galmed, Genentech, Gilead Sciences, Gossamer, Guidepoint, Helmsley, Horizon Therapeutics, Image Analysis, Index Pharma, Jannsen, Koutif, Mestag, Metacrine, Mopac, Morphic, Organovo, Origo, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Surmodics, Surrozen, Takeda, Techlab, Theravance, Thetis, UCB Pharma, Ysios, and 89Bio. IR, TL, NM, and MS are employees and shareholders of Eli Lilly and Company. MP has nothing to disclose. LPB has received consulting fees from: AbbVie, Abivax, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, Bristol-Myers Squibb, Celltrion, Connect Biopharma, Cytoki Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, H.A.C. Pharma, IAG, InDex Pharmaceuticals, Inotrem, Janssen, Medac, Mopac, Morphic, Merck Sharp & Dohme, Norgine, Novartis, OM Pharma, Ono Pharmaceutical, OSE Immunotherapeutics, Pandion Therapeutics, Pfizer, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Takeda, Theravance, ThermoFisher Diagnostics, TiGenix, Tillotts Pharma, Viatris, Vifor, and YSOPIA Bioscience; has received grants from: Celltrion, Fresenius Kabi, and Takeda; and has received lecture fees from: AbbVie, Amgen, Arena, Biogen, Celltrion, Eli Lilly, Ferring Pharmaceuticals, Galapagos, Genentech, Gilead Sciences, Janssen, Medac, Merck Sharp & Dohme, Pfizer, Sandoz, Takeda, Tillotts Pharma, Viatris, and Vifor.

Figures

Figure 1.
Figure 1.
Proportion of patients with histological improvement [HI], histological remission [HR], endoscopic remission [ER], histological-endoscopic mucosal improvement [HEMI], and histological-endoscopic mucosal remission [HEMR] at Week 12 in LUCENT-1 induction [A] and at Week 40 in LUCENT-2 mirikizumab [MIRI] induction responders [B]. HI was defined using the Geboes scoring system: neutrophil infiltration of <5% of crypts; no crypt destruction; and no erosions, ulcerations, or granulation tissue [Geboes score ≤3.1]. HR was defined using the Geboes scoring system, with no lamina propria neutrophils; no neutrophils in the surface or crypt epithelium; no crypt destruction; and no erosions, ulcerations, or granulation tissue [Geboes score ≤2B.0]. ER was defined as endoscopic subscore = 0 or 1 [excluding friability]. HEMI was defined as achieving both HI and ER [defined above]. ***p <0.001 vs placebo [PBO]. CI, confidence interval; IV, intravenous; Q4W, every 4 weeks; SC, subcutaneous.
Figure 2.
Figure 2.
Proportion of patients with or without prior biologic or tofacitinib failure who achieved histological improvement [HI], histological remission [HR], endoscopic remission [ER], histological-endoscopic mucosal improvement [HEMI], and histological-endoscopic mucosal remission [HEMR] at Week 12 in LUCENT-1 induction [A] and at Week 40 in LUCENT-2 mirikizumab [MIRI] induction responders [B]. HI was defined using the Geboes scoring system: neutrophil infiltration of <5% of crypts; no crypt destruction; and no erosions, ulcerations, or granulation tissue [Geboes score ≤3.1]. HR was defined using the Geboes scoring system, with no lamina propria neutrophils; no neutrophils in the surface or crypt epithelium; no crypt destruction; and no erosions, ulcerations, or granulation tissue [Geboes score ≤2B.0]. ER was defined as endoscopic subscore = 0 or 1 [excluding friability]. HEMI was defined as achieving HI and ER [defined above]. HEMR was defined as achieving HR and ER [defined above]. *p <0.05, **p <0.01; ***p <0.001 vs placebo [PBO]. CI, confidence interval; IV, intravenous; ns, not significant; Q4W, every 4 weeks; SC, subcutaneous.
Figure 3.
Figure 3.
Association between histological or endoscopic outcomes at Week 12 in LUCENT-1 and histological-endoscopic mucosal improvement [HEMI] or histological-endoscopic mucosal remission [HEMR] at Week 40 in mirikizumab induction responders re-randomised to mirikizumab 200 mg SC. Histological improvement was defined using the Geboes scoring system: neutrophil infiltration of <5% of crypts; no crypt destruction; and no erosions, ulcerations, or granulation tissue [Geboes score ≤3.1]. Histological remission was defined using the Geboes scoring system, with no lamina propria neutrophils; no neutrophils in the surface or crypt epithelium; no crypt destruction; and no erosions, ulcerations, or granulation tissue [Geboes score ≤2B.0]. Endoscopic remission was defined as Mayo endoscopic subscore = 0 or 1 [excluding friability]. HEMI was defined as achieving histological improvement and endoscopic remission. HEMR was defined as achieving histological remission and endoscopic remission. p-value for the OR of the binary outcomes was calculated by chi square test. CI, confidence interval; Ny, number of patients achieving the histological-endoscopic endpoint among mirikizumab induction responders re-randomised to mirikizumab 200 mg SC at Week 40 in LUCENT-2; OR, odds ratio; SC, subcutaneous.
Figure 4.
Figure 4.
Proportion of patients achieving clinical or symptomatic outcomes at Week 40 based on Week 12 histological-endoscopic outcomes. Histological-endoscopic mucosal improvement [HEMI] was defined as histological improvement [HI, neutrophil infiltration of <5% of crypts; no crypt destruction; and no erosions, ulcerations, or granulation tissue [Geboes score ≤3.1]] and endoscopic remission (ER, Mayo endoscopic subscore = 0 or 1 [excluding friability]). ER only was defined as ER without HI. HI only was defined as HI without ER. IBDQ remission was defined as IBDQ score ≥170. Pairwise comparisons by Fisher’s exact test. *p <0.05, **p <0.01 vs neither HI nor ER; #p <0.05 vs HI only. IBDQ, Inflammatory Bowel Disease Questionnaire; IV, intravenous; NRS, numerical rating scale; Nx, number of patients achieving the histological-endoscopic endpoint among patients randomised to mirikizumab 300 mg IV at Week 12 in LUCENT-1.
Figure 5.
Figure 5.
Proportion of patients achieving clinical or symptomatic outcomes at Week 40 based on Week 40 histological-endoscopic outcomes. Alternate histological-endoscopic mucosal remission [HEMR] was defined as histological remission [HR, Geboes score ≤2B] and endoscopic normalisation [EN, Mayo endoscopic subscore = 0]. EN only was defined as EN without HR, and HR only was defined as HR without EN. IBDQ remission was defined as IBDQ score ≥170. Pairwise comparisons by Fisher’s exact test. *p <0.05, **p <0.01, ***p <0.001 vs neither HR nor EN; #p <0.05 vs HR only. IBDQ, Inflammatory Bowel Disease Questionnaire; NRS, numerical rating scale; Ny, number of patients achieving the histological-endoscopic endpoint among mirikizumab induction responders randomised to mirikizumab 200 mg SC at Week 40 in LUCENT-2; SC, subcutaneous.
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