Association of Histologic-Endoscopic Response and Long-Term Clinical Outcomes: Results From Phase 2 Mirikizumab Trial in Patients With Moderately-to-Severely Active Crohn's Disease

Introduction: We explored the potential relationship between early histologic and endoscopic responses on long term clinical outcomes after 2 years of mirikizumab (miri) treatment in a Phase 2 trial in patients with moderately-to-severely active Crohn’s disease (CD). Methods: Patients were randomized 2:1:1:2 to 4 treatment arms: miri 1000mg, 600mg, 200mg, and PBO administered intravenously (IV) at W0, W4, and W8. Patients who received miri and achieved ≥1 point improvement at W12 in Simple Endoscopic Score for Crohn’s disease score were re-randomized to either continue their induction IV dose or receive miri 300mg subcutaneously every 4 weeks up to W52. Subjects reported to experience clinical benefit received 300mg SC from W52 to W104. Biopsies were obtained during endoscopy at W0, W12 and W52 from the edges of any ulcers or from the most inflamed mucosa in the terminal ileum and 4 colonic segments and were scored by blinded central readers. Endpoints were defined post-hoc and prior to analyses (see Table 1). Among patients receiving miri with active histological disease at baseline, we determined the relationship between histologic and/or endoscopic response or remission at W12 and W52 with clinical remission based on the Crohn’s Disease Activity Index (CDAI), patient-reported outcomes (PRO), and hospitalization rates at W104. Results: W104, 56.9% patients (N=137) achieved CDAI remission vs 41.5% of 176 patients at W52. We observed no association between early (W12) histologic, endoscopic, or combined (histo-endo) response and clinical remission (CDAI & PRO) at 2 years. After 2 years, the percentage of patients achieving remission based on CDAI varied according to their response at W52 by histology (60%), endoscopy (25.9%), both histo-endo (56.3%), or neither (10.5%, P=0.006; Table 1). Similarly, the proportion of patients who achieved 2-year clinical remission (by CDAI) varied according to W52 remission by histology (72.7%), endoscopy (40%), both histo-endo (40%) or neither (19.5%, P=0.007). Hospitalization rates during this period were low and varied according to W52 response by histology (16.7%), endoscopy (0%), both (0%) or neither (3.9%, P=0.021). Conclusion: In CD patients treated with miri for 2 years, long term clinical remission (CDAI, PRO) was significantly correlated with histologic response alone as well as combined histologic-endoscopic response at W52, but not at W12. The small sample size was likely a limitation. This data will be further studied in Phase 3 trials. Table 1. - Week 104 clinical remission and hospitalization rates by histologic and endoscopic response at Week 12 and Week 52, and by histologic and endoscopic remission at Week 52 Week 104 Without Histologic or Endoscopic Response Histologic Without Endoscopic Response Endoscopic response Without Histologic Histologic and Endoscopic Response P value Without Histologic or Endoscopic Remission Histologic Without Endoscopic Remission Endoscopic Without Histologic Remission Histologic and Endoscopic Remission P value Week 12a Week 12 CDAI remission 60 (12/20) 57.9 (11/19) 50 (2/4) 61.3 (19/31) >0.999 Due to the low number of patients with endoscopic or histologic remission at Week 12, no data are shown in this quadrant PRO remission 55 (11/20) 31.6 (6/19) 50 (2/4) 61.3 (19/31) 0.237 Hospitalizations due to CDb 0 (0/42) 3.9 (1/26) 0 (0/8) 3.2 (1/31) 0.426 Week 52c Week 52c CDAI remission 10.5 (2/19) 60 (6/10) 25.9 (7/27) 56.3 (9/16) 0.006 19.5 (8/41) 72.7 (8/11) 40 (6/15) 40 (2/5) 0.007 PRO remission 10.5 (2/19) 30 (3/10) 11.1 (3/27) 68.8 (11/16) <0.001 12.2 (5/41) 63.6 (7/11) 33.3 (5/15) 40 (2/5) 0.003 Hospitalizations due to CDb 3.9 (1/26) 16.7 (2/12) 0 (0/39) 0 (0/24) 0.021 3.9 (2/52) 5 (1/20) 0 (0/24) 0 (0/5) 0.809 Note: Data displayed as % (n/N). For categorical outcomes, P-values are based on Fisher’s exact test. Histologic response was defined as: a) absence of neutrophils in epithelium, and absence of epithelial damage, erosions and ulceration or b) decrease of either RHI or modified GHAS ≥50% from baseline. Endoscopic response is defined as a 50% reduction from baseline in SES-CD. Histologic remission was defined as absence of mucosal neutrophils, epithelial damage, erosions, and ulceration. Endoscopic remission is defined as SES-CD of < 4 ileal-colonic or < 2 for isolated ileal disease, and no subscore of >1. CDAI remission is defined as CDAI Total Score < 150; PRO remission is defined as (7-day average of SF ≤2.5 and no worse than baseline) + (7-day average of AP≤1 and no worse than baseline). SF captures number of liquid or very soft stools; AP score is classified as 0=none, 1=mild, 2=moderate, 3=severe.AP= abdominal pain; CDAI= Crohn’s Disease Activity Index; GHAS= Global Histologic Disease Activity Score; PRO= patient-reported outcomes; N=number of patients in the histologic/endoscopic response group; n = number of patients in the specified category; RHI= Robarts Histologic Index; SES-CD=Simple Endoscopic Score for Crohn’s Disease; SF= stool frequency.aPatients with Active histologic disease at Baseline and with both Endoscopic and Histologic measures at Week 12.bDefined as serious adverse event due to hospitalization. Week 12 columns depict hospitalizations from Weeks 12-52. Week 52 columns depict hospitalizations from Weeks 52-104.cPatients with Active histologic disease at Baseline and with both Endoscopic and Histologic measures at Week 52.