Introduction

MAESTRO-NASH (NCT03900429) is an ongoing 54-month, randomized, double-blind, placebo-controlled Phase 3 trial evaluating the efficacy of resmetirom in patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH/MASH) and fibrosis. 966 patients with biopsy confirmed NASH were randomized 1:1:1 to resmetirom 80 mg, resmetirom 100 mg, or placebo administered once daily. Dual primary endpoints at Week 52 were achieved with both resmetirom 80 mg and 100 mg: NASH resolution with no worsening of fibrosis (NR) or ≥1-stage improvement in fibrosis with no worsening of NAS (FI). We evaluated the baseline and effect of resmetirom compared with placebo on fibrosis biomarkers PRO-C3 and P3NP/ELF.

Aims & Methods

Pearson’s correlation was used to examine the association between 2 PRO-C3 ELISA assay methods (ELISA GEN1 and ELISA GEN2, NORDIC BIOSCIENCE) using PRO-C3 baseline data (N=919). The rest of the analyses used the ELISA GEN2 assay. Mean SD or SE and median [Q1, Q3] were calculated to summarize PRO-C3 data. ANCOVA was used for comparisons between resmetirom 80 or 100 mg vs. placebo in PRO-C3 change from baseline at week 52 (wk52CHG), while controlling for baseline PRO-C3 level. Mean difference with 95% CI and nominal P-values were obtained from the ANCOVA. Scatterplots and Spearman’s correlations with 95% CIs were used to assess the associations between P3NP/ELF and PRO-C3 both at baseline and wk52CHG.

Results

The two PRO-C3 assays ELISA GEN1 and ELISA GEN2 data were positively associated with a Pearson’s correlation of 0.78 (P-value <0.0001). At baseline, PRO-C3 was mean (SD)=137 (71.7) ng/ml. At week 52, PRO-C3 wk52CHG for 100 mg resmetirom= -23.05 (4.76), 80 mg= -17.93 (4.61) and placebo= -0.19, 4.07 with mean difference (95% CI) in PRO-C3 wk52CHG between 80 mg and placebo= -16.9 (-27.0, -6.76; p= 0.0011); 100 mg and placebo= -22.1 (-32.3, -11.84; p < 0.0001). Larger reductions in PRO-C3 mean (SD) on the resmetirom arms were observed in F3 patients: 80 mg= -22.42 (6.38) and 100 mg= -27.42 (6.72) compared with placebo= -0.50 (5.46). Baseline P3NP and ELF were correlated with PRO-C3 (0.563 and 0.458, respectively). The wk52CHG in P3NP was positively associated with wk52CHG in PRO-C3 (0.557, 0.548 and 0.524 for 100 mg, 80 mg and placebo; respectively). A weaker positive correlation between wk52CHG for ELF and PRO-C3 (0.483, 0.484 and 0.487 for 100 mg, 80 mg and placebo, respectively) were also observed.

Conclusion

Two Pro-C3 assays (ELISA GEN1 and ELISA GEN2, NORDIC BIOSCIENCE) were correlated at baseline, indicating ELISA GEN2 assay was reasonable for measuring PRO-C3 levels. For PRO-C3 ELISA GEN2, drug effects were statistically significant for both doses of resmetirom vs. placebo. The assay was more sensitive in detecting resmetirom effect in F3 patients. ELF and PRO-C3 was less strongly correlated than P3NP and PRO-C3.

Disclosure

Authors are investigators in the MAESTRO-NASH trial or employees of Madrigal Pharmaceuticals.

Introduction

Fistulating peri-anal Crohn’s disease can affect approximately 20% of patients and have a major impact on quality of life. Despite being an important area of unmet clinical need, there is a paucity of evidence for most medical treatments and a lack of dedicated clinical trials for perianal Crohn’s disease. Current studies also report a high level of heterogeneity for outcomes with both treatments and placebo - making interpretation of the available data challenging for both clinical practice and design of clinical trials. Use of Bayesian methodology offers an attractive solution to help address some of these challenges. We sought to conduct a Bayesian prior elicitation exercise to determine the efficacy of licensed medical therapies for fistulating perianal Crohn’s disease.

Aims & Methods

A formal Bayesian prior elicitation meeting was convened. This was composed of a group of 11 gastroenterologists and 5 statisticians. Consensus priors were developed leveraging both published data and expertise of the gastroenterologists, to determine one-year fistula remission rates for seven options of licensed medical treatments based on five different mechanisms of action (anti-TNF, anti-integrin, anti-IL12/23, anti-IL-23, and JAK inhibitor). Consensus priors on the efficacy of each of seven treatment options was determined relative to an elicited consensus prior for placebo control. The log-odds ratio for efficacy for each of the seven therapy options versus placebo control was also established.

Results

Consensus priors were obtained for seven medical treatments for likelihood of fistula remission at one year. The prior mean, together with a 90% prior credible interval, of the one-year fistula remission rate was 0.22 (0.05, 0.46) for placebo, 0.58 (0.09, 0.96) for intravenous infliximab, 0.39 (0.06, 0.82) for adalimumab, 0.53 (0.09, 0.93) for subcutaneous infliximab, 0.24 (0.03, 0.60) for intravenous vedolizumab, 0.44 (0.05, 0.90) for upadacitinib, 0.34 (0.04, 0.77) for ustekinumab, and 0.36 (0.04, 0.82) for risankizumab. When assessing treatment effect on the log-odds ratio scale, oral upadacitinib and subcutaneous infliximab had the strongest “priors”, with the highest probability for likely efficacy, alongside intravenous infliximab.

Conclusion

We have conducted, to the best of our knowledge, the first formal Bayesian prior elicitation exercise for efficacy of medical therapies in perianal Crohn’s disease. These priors developed for the efficacy of licensed medical therapies can be internationally validated and potentially taken forward for planning of dedicated clinical trials. Importantly, these results could be used to enhance the design and analysis of clinical trials for fistulating perianal Crohn’s disease. Notable potential benefits from these findings include: improved estimation of treatment efficacy, reduction in the required sample sizes, and with minimisation or even avoidance of placebo control arms for future dedicated fistulating perianal Crohn’s disease clinical trials.

Disclosure

NMN declares educational/travel grants and/or speaker fees from AbbVie, Bristol Myers Squibb, Celltrion, Dr Falk Pharma, Ferring, Galapagos, J&J, Lilly, Pfizer, Pharmacosmos, Takeda and Tillotts Pharma AG. RC reports personal fees from AbbVie, Galapagos, Lilly outside the submitted work, and grants from Celltrion, Ferring, Tillotts Pharma outside the submitted work; and fees from advisory board membership of AbbVie, Bristol Myers Squibb outside the submitted work. SD reports personal fees from AbbVie, Ferring, Janssen, Takeda outside the submitted work; and grants from AbbVie, Dr Falk, Janssen, outside the submitted work; and fees from advisory board membership of AbbVie outside the submitted work. HG has received speaker fees from: Janssen, Ferring, Takeda, and AbbVie, and consultancy fees from. AbbVie, Galapagos. KBK reports serving as a speaker, a consultant, and/or an advisory board member for Abbvie, Falk, Galapagos, Janssen, and Takeda. JOL reports personal fees from AbbVie, Atlantic Healthcare, Bristol Meyer Squibb, Celgene, Celltrion, Engytix, Eli Lilly, Ferring, Galapagos, Gilead, GSK, Janssen, MSD, Norgine, Pfizer, Shire, and Takeda outside the submitted work; and grants from AbbVie, Ferring, Gilead, Takeda, and Shire outside the submitted work. GWM declares consultancy fees/grant funding from AbbVie, AstraZeneca and Janssen; all outside the submitted work. KVP reports personal fees from AbbVie, DrFalk, Galapagos, Janssen, PredictImmune, Pfizer, Takeda outside the submitted work; and grants from AbbVie, Celltrion, Dr Falk, Ferring, Janssen, Takeda, Tillotts Pharma outside the submitted work; and fees from advisory board membership of AbbVie, Galapagos, Janssen, Pfizer outside the submitted work. SS reports consulting fees from Takeda, AbbVie, Merck, Ferring, Pharmacosmos, Warner Chilcott, J&J Innovative Medicine, Dr Falk Pharma, Biohit, TriGenix, Celgene, and Tillots Pharma outside the submitted work; payment or honoraria from AbbVie, Takeda, Celltrion, Pfizer, Biogen, AbbVie, J&J Innovative Medicine, Merck, Warner Chilcott, Dr Falk Pharma, outside the submitted work; and is co-director of research for the South Asian IBD Alliance. TR has received research/educational grants and/or speaker/consultation fees from Abbvie, Arena, Aslan, AstraZeneca, Boehringer-Ingelheim, BMS, Celgene, Eli Lilly, Ferring, Galapagos, Gilead, GSK, Heptares, LabGenius, Janssen, MonteRosa, Mylan, MSD, Novartis, Numab, Pfizer, Roche, Sandoz, Takeda, UCB, and XAP Therapeutics. SS reports person fees from Abbvie, Celltrion, Dr. Falk, Ipsen, Janssen, Takeda outside the submitted work. ALH has received consultancy fees from AbbVie, Bristol Myers Squibb, Celltrion, Galapagos, Johnson & Johnson, Takeda, Pfizer, and Lilly; has received honoraria from AbbVie, Bristol Myers Squibb, Celltrion, Galapogos, Johnson & Johnson, Takeda, Pfizer, Lilly; and has received support for attending meetings or travel from AbbVie, Bristol Myers Squibb, Celltrion, Galapagos, Johnson & Johnson, Takeda, Pfizer, and Lilly; all outside of the submitted work. MP reports personal fees from Janssen and Takeda outside the submitted work; and grants from AstraZeneca, Galapagos, Gilead, Pfizer outside the submitted work. All other authors declare no conflicts of interest.

Introduction

Interleukin (IL)-23 is a key driver in the pathogenesis of Crohn’s disease (CD). IL-23 is a heterodimer, consisting of p19 and p40 subunits encoded by IL-23A and -23R, respectively. Signaling through the IL-23 receptor complex leads to the transcription of effector cytokine genes, including IL-17A, -17F and -22. Risankizumab (RZB), a monoclonal antibody with specificity for IL-23p19 has demonstrated safety and efficacy for the treatment of CD.^1,2 Here we investigate if baseline (BL) IL-23 pathway gene expression (IL-17A, -17F, -22, -23R, and -23A) in CD patients (pts) is associated with clinical remission and endoscopic response at week (wk) 12 of induction in patients treated with RZB (see Table footnote for endpoint definitions).

Aims & Methods

RNA-sequencing was performed to examine IL-23 pathway gene expression at BL in intestinal biopsy samples (n=280) obtained from pts (n=160) in the 600 mg intravenous (IV) RZB arms of the ADVANCE and MOTIVATE induction studies.¹ Biopsies were taken from the site of active disease (colon [n=146] and/or ileum [n=134]). A linear model based differential expression was conducted between response and non-response using the co-primary endpoints of SF/APS clinical remission and endoscopic response at induction wk 12. Data were normalized using trimmed mean of M-values and log2 counts per million. P-values were adjusted using Benjamini-Hochberg method of multiple testing correction. Comparisons were performed between endoscopic responders or clinical remitters (R) and endoscopic non-responders or clinical non-remitters (NR) in all pts. Analyses were stratified by disease location and/or prior biologic response status.

Results

In the total cohort, IL-23A gene expression was higher at BL in clinical R versus (vs) NR (p=0.03) (see Table for results). However, this difference was only significant in patients with prior bio-failure (p=0.03). Additionally, no difference was observed in IL-23 pathway gene expression between endoscopic R vs NR. When stratifying by disease location, higher BL expression of IL-17A, -17F, -22 and -23A were observed in patients with colonic disease in clinical R vs NR with (p<0.05). This difference was observed in both bio-failure and non-bio-failure patients (p<0.05). No difference was observed between endoscopic R vs NR. In pts with ileal disease, no differences in IL-23 pathway gene expression were observed between clinical R versus NR. Higher BL expression of IL-17A and -17F, and lower BL expression of IL-23R, were demonstrated in endoscopic R vs NR at wk 12 (p<0.05). However this difference was only significant in bio-failure patients.

Conclusion

Endpoint	Patient Subgr​oups​​​​​	Baseline Gene Expression NR vs R Adjusted P-value (p<0.05 denoted in bold)
		IL-17A	IL-17F	IL-22	IL-23R	IL-23A
Clinical Remission at Week 12a	All Patients N=160 (62 R, 98 NR) Colonic Disease N=146 (56 R, 90 NR) Ileal Disease N=134 (47 R, 87 NR) Prior Bio-Failure N=113 (37 R, 76 NR) Without Prior Bio-Failure N=47 (25 R, 22 NR) Colonic Disease + Prior Bio-Failure N=101 (33 R, 68 NR) Colonic Disease + Without Prior Bio-Failure N=45 (23 R, 22 NR) Ileal Disease + Prior Bio-Failure N=94 (26 R, 68 NR) Ileal Disease + Without Prior Bio-Failure N=40 (21 R, 19 NR)	0.40 0.04 0.21 0.11 0.79 0.048 0.51 0.99 0.26	0.5 0.04 0.94 0.10 0.82 0.06 0.50 0.70 0.73	0.17 0.03 0.78 0.26 0.30 0.04 0.41 0.68 0.52	0.95 0.84 0.65 0.23 0.30 0.25 0.45 0.77 0.44	0.03 0.002 0.92 0.03 0.73 0.005 0.44 0.71 0.65
Endoscopic Response At Week 12b	All Patients N=160 (69 R, 91 NR) Colonic Disease N=146 (37 R, 109 NR) Ileal Disease N=134 (35 R, 99 NR) Prior Bio-Failure N=113 (23 R, 90 NR) Without Prior Bio-Failure N=47 (19 R, 28 NR) Colonic Disease + Prior Bio-Failure N=101 (20 R, 81 NR) Colonic Disease + Without Prior Bio-Failure N=45 (17 R, 28 NR) Ileal Disease + Prior Bio-Failure N=94 (18 R, 76 NR) Ileal Disease + Without Prior Bio-Failure, N=40 (17 R, 23 NR)	0.83 0.08 0.01 0.77 0.65 0.10 0.57 0.049 0.19	0.45 0.44 0.049 0.35 0.98 0.49 0.85 0.02 0.9	0.44 0.06 0.42 0.48 0.53 0.09 0.43 0.49 0.90	0.44 0.06 0.42 0.48 0.53 0.09 0.43 0.49 0.90	0.79 0.07 0.10 0.84 1.00 0.09 0.71 0.14 0.63
aAverage daily SF ≤ 2.8 and not worse than BL AND average daily AP score ≤ 1 and not worse than BL; bDecrease in SES-CD > 50% from BL (or for subjects with isolated ileal disease and a BL SES-CD of 4, at least a 2 point reduction from BL), as scored by central reviewer

Minimal differences in BL expression of IL-23 pathway genes were detected in the total cohort between clinical R vs NR and endoscopic R vs NR. Significant differences in BL expression of several IL-23 pathway genes were identified between clinical R and NR in pts with colonic disease. Shared and unique IL-23 pathway genes were significantly altered in pts with ileal disease between endoscopic R vs NR. However, these differences are unlikely to be clinically meaningful or predictive of response to RZB.

References

1. D’Haens G, Panaccione R, Baert F, Bossuyt P, Colombel JF, Danese S, et al. Risankizumab as induction therapy for Crohn’s disease: results from the phase 3 ADVANCE and MOTIVATE induction trials. The Lancet. 2022 May;399(10340):2015–30.
2. Ferrante M, Panaccione R, Baert F, Bossuyt P, Colombel JF, Danese S, et al. Risankizumab as maintenance therapy for moderately to severely active Crohn’s disease: results from the multicentre, randomised, double-blind, placebo-controlled, withdrawal phase 3 FORTIFY maintenance trial. The Lancet. 2022 May;399(10340):2031–46.

Disclosure

James Lindsay: Consultant and an advisory board participant for AbbVie, Atlantic Healthcare, Bristol-Myers Squibb, Celgene, Celltrion, Eli Lilly, Ferring Pharmaceuticals, Galapagos, Gilead, GSK, Janssen, MSD, Napp, Pfizer, Shire, Takeda, and Vifor Pharma; has received speaker fees and sponsorship for academic meetings from AbbVie, Ferring Pharmaceuticals, Janssen, MSD, Napp, Norgine, Pfizer, Shire, Tillotts Pharma, and Takeda; and has received investigator-led research grants from AbbVie, Gilead, Pfizer, Shire and Takeda.
Bram Verstockt: Research support from AbbVie, Biora Therapeutics, Landos, Pfizer, Sossei Heptares and Takeda. -Speaker’s fees from Abbvie, Biogen, Bristol Myers Squibb, Celltrion, Chiesi, Falk, Ferring, Galapagos, Janssen, MSD, Pfizer, R-Biopharm, Takeda, Truvion and Viatris. Consultancy fees from Abbvie, Alimentiv, Applied Strategic, Atheneum, Biora Therapeutics, Bristol Myers Squibb, Galapagos, Guidepont, Mylan, Inotrem, Ipsos, Janssen, Pfizer, Progenity, Sandoz, Sosei Heptares, Takeda, Tillots Pharma and Viatris.
Jean Frederic Colombel: Research grants from AbbVie, Janssen Pharmaceuticals and Takeda; receiving payment for lectures from AbbVie, Amgen, Allergan, Inc. Ferring Pharmaceuticals, Shire, and Takeda; consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, BMS, Celgene Corporation, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, Genentech, Glaxo Smith Kline, Janssen Pharmaceuticals, Kaleido Biosciences, Imedex, Immunic, Iterative Scopes, Merck, Microbia, Novartis, PBM Capital, Pfizer, Protagonist Therapeutics, Sanofi,Takeda, TiGenix, Vifor; and hold stock options in Intestinal Biotech Development
Valerie Pivorunas, Naim Al Mahi, Nizar Smaoui, F. Stephen Laroux, Kristina Kligys Kori Wallace, and Heath Guay are AbbVie employees and may own AbbVie stock and/or options.

Introduction

Emerging evidence indicates an immunomodulatory role of the appendix in ulcerative colitis (UC). Previous studies suggest a beneficiary effect for appendectomy in inducing and maintaining remission. Therefore, appendectomy might be considered as an alternative treatment in these patients.

Aims & Methods

Aim: To evaluate the efficacy of appendectomy in maintaining remission in UC patients.
Methods: Adult patients with established UC in complete clinical and endoscopic remission (defined as Mayo score <3 with endoscopic subscore of 0 or 1) after being medically treated for disease relapse within 12 months prior to randomization were enrolled in the Netherlands and United Kingdom. Patients were randomized (1:1) to undergo additional appendectomy (intervention group) or continue current medical therapy (control group). The primary outcome was the one-year UC relapse rate, defined as a total Mayo-score score ≥5 with endoscopic subscore of 2 or 3. To detect a clinically relevant decrease in relapse rate from 40% to 20%, 82 patients per study arm were needed. Trial progress and safety reports with accumulated number of (serious) adverse events in both groups were presented to the Data Safety Monitoring Board (DSMB) annually, and therefore data are available. Last patient was included in August 2022, so the final analyses will commence in September 2023.

Results

Between September 2012 and September 2022, 198 patients were randomized. A total of 99 patients were included in the intervention group and 99 patients in the control group. The one-year follow-up data were complete for 183 patients in April 2023.
There were 86 males and 112 females, with a median age of 41 years (IQR 33-52). Baseline characteristics were comparable in both groups, with the majority of patients having been treated for either proctitis (38.9%) or left sided colitis (35.9%) (Table 1). A total of three serious adverse events (SAE) were reported in the appendectomy group, of which two were related to the surgical procedure (reintervention for mechanical ileus and postoperative hematoma) and one hospitalisation for clostridium infection. One SAE was reported within the first year in the control group (appendicitis). During follow up there were no colectomies in the appendectomy group, whereas three patients underwent colectomy for therapy-refractory disease in the control group. In addition, the one-year reported colitis-associated adverse event rate was significantly lower in the appendectomy group when compared to the control group (43.4% vs. 62.7%, P=0.01).

Table 1. Baseline characteristics of the patients included in the ACCURE-trial
Characteristic	Appendectomy (N=99)	Control (N=99)
Sex (female), n (% n/N)	57 (57.6)	55 (55.6)
Age (years), median (IQR)	41 (32-49)	42 (34-53)
Extent of disease Proctitis, n (% n/N) Left-sided colitis, n (% n/N) Pancolitis, n (% n/N)	38 (38.4) 35 (35.4) 26 (26.4)	39 (39.4) 36 (36.4) 24 (24.2)

Conclusion

Appendectomy in patients with UC has the possibility to decrease the rate of colitis-associated (serious) adverse events significantly. This suggests that the final analysis of the primary outcome parameter (relapse rate) in September 2023 could demonstrate that appendectomy is superior to standard medical therapy alone in maintaining remission in these patients.