Introduction

Histologic inflammation persists in up to 1/4 of patients (pts) with Crohn’s Disease (CD) despite endoscopic mucosal healing. Responsiveness of histologic inflammation and of combined endoscopic-histologic endpoints to treatment are evolving measures of disease activity in CD. Mirikizumab (MIRI) increased histologic response (H-Res) and remission (H-Rem) relative to placebo (PBO) in the Phase 2 SERENITY trial.¹

Aims & Methods

To evaluate the impact of MIRI and ustekinumab (UST) on H-Res and H-Rem and combined endoscopic-histologic response (EH-Res) and remission (EH-Rem) in all pts, pts with prior biologic failure (BF), pts without prior BF in moderately to severely active CD, in the randomized, double-blind, double-dummy, treat-through Phase 3 VIVID-1 trial (NCT03926130). Two biopsy specimens from each of 5 intestinal segments (1 ileal and 4 colonic) were obtained from the edge of the ulcers, or the most inflamed mucosa from randomized pts at screening, and weeks (W)12, and 52. Criteria for H-Res were the absence of epithelial neutrophils and epithelial damage, erosions and ulceration or ≥50% decrease in either the active Robarts Histopathology Index or the active Global Histologic Disease Activity Score. H-Rem was defined as complete absence of mucosal neutrophils (in epithelium and lamina propria), and no epithelial damage, erosions and ulcers; these criteria had to be met in all biopsy specimens. Endoscopic response was defined as ≥50% improvement from baseline in Simple Endoscopic Score for CD (SES-CD). Endoscopic remission was defined as SES-CD total score ≤4 and ≥2-point reduction from baseline and no subscore >1 in any individual variable.

Results

At W52, nominally significant differences between MIRI and UST were observed in achieving H-Res in all pts (58.2% vs 48.8%; p=.007 and in BF pts (56.5% vs 41.3%; p=.006). For EH-Res, differences of MIRI vs UST were numerically greater but not statistically significant in all pts (41.1% vs 34.4%; p=.063) but were nominally significant among BF pts (39.6% vs 27.8%; p=.023). While numerical differences between MIRI and UST were observed in H-Rem and EH-Rem in all pts (H-Rem: 30.2% vs 28.9%; p=.685; EH-Rem: 17.2% vs 14.8%; p=.363) and in BF pts (H-Rem: 24.3% vs 19.8%; p=.365; EH-Rem: 13.3% vs 8.7%; p=.237), no significant differences were observed in these endpoints(Table).

Conclusion

Using strict definitions, all histology-based endpoints were achieved by MIRI versus PBO. For comparison versus UST, MIRI also showed nominal statistical difference for H-Res, which was prespecified and is considered the most sensitive to change, particularly driven by BF pts. The implication of these results on clinical endpoints and long-term outcomes, including hospitalization rates and surgeries, requires further evaluation.

References

1. Magro F, et al. Clin Gastroenterol Hepatol. 2023:S1542-3565(23)00948-5.

Disclosure

• V. Jairath received consulting/advisory board fees: AbbVie, Alimentiv, Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris Pharmaceuticals, AstraZeneca, Avoro Capital, Bristol Myers Squibb, Celltrion, Eli Lilly and Company, Endpoint Health, Enthera, Ferring Pharmaceuticals, Flagship Pioneering, Fresenius Kabi, Galapagos NV, Gilde Healthcare, GlaxoSmithKline, Genentech, Gilead Sciences, Innomar, JAMP, Janssen, Merck, Metacrine, Mylan, Pandion Therapeutics, Pendopharm, Pfizer, Prometheus Biosciences, Protagonist Therapeutics, Reistone Biopharma, Roche, Roivant Sciences, Sandoz, SCOPE, Second Genome, Sorriso Pharmaceuticals, Takeda, TD Securities, Teva, Topivert, Ventyx Biosciences, and Vividion Therapeutics; and speaker’s fees: AbbVie, Bristol Myers Squibb, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos NV, Janssen, Pfizer, Shire, and Takeda
• F. Magro speaker: AbbVie, Arena, Biogen, Bristol Myers Squibb, Eli Lilly and Company, Falk, Ferring Pharmaceuticals, Hospira, Janssen, Laboratórios Vitoria, Merck Sharp & Dohme, Pfizer, Sandoz, Takeda, UCB, and Vifor
• G. De Hertogh received fees for clinical trial activities with Centocor Inc; and received consultancy fees: Eli Lilly and Company and MRM Health
• B. Feagan was a consultant: AbbVie, AbolerIS Pharma, Agomab Therapeutics, Allianthera, Amgen, AnaptysBio, Applied Molecular Transport, Arena Pharmaceuticals, Avoro Capital Advisors, Atomwise, BioJamp, Biora Therapeutics, Boehringer Ingelheim, Boxer, Celgene/BMS, Celsius Therapeutics, Connect BioPharma, Cytoki Pharma, Disc Medicine, Duality, EcoR1, Eli Lilly and Company, Equillium, Ermium Therapeutics, First Wave BioPharma, First Word Group, Galapagos NV, Galen Atlantica, Genentech/Roche, Gilead Sciences, Gossamer Pharma, GlaxoSmithKline, Hinge Bio, Hot Spot Therapeutics, InDex Pharma, Imhotex, Immunic Therapeutics, JAKAcademy, Janssen, Japan Tobacco, Kaleido Biosciences, Landos Biopharma, Leadiant, L.E.K. Consulting, Lenczner Slaght, LifeSci Capital, Lument AB, Millennium Pharmaceuticals, MiroBio, Morgan Lewis, Morphic Therapeutics, Mylan, OM Pharma, Origo BioPharma, Orphagen, Pandion Therapeutics, Pendopharm, Pfizer, Prometheus Therapeutics and Diagnostics, Play to Know AG, Progenity, Protagonist Therapeutics, PTM Therapeutics, Q32 Bio, Rebiotix, Redx Pharma, Roche, Sandoz, Sanofi, Seres Therapeutics, Silverback Therapeutics, Surrozen Inc., Takeda, Teva, Thelium, Tigenix, Tillotts, Ventyx Biosciences, VHsquared, Viatris, Ysios, YSOPIA Bioscience, and Zealand Pharma; was on the speaker’s bureau: AbbVie, Janssen, and Takeda; member of the Scientific Advisory Board, DSMB for: AbbVie, Amgen, AMT, AnaptysBio, Axio Research, Boehringer Ingelheim, Celgene/BMS, Ecor1Capital, Eli Lilly and Company, Genentech/Roche, GlaxoSmithKline, InDex Pharma, Janssen, MiroBio, Morphic, Origo BioPharma, Pfizer, Progenity, Prometheus, Redx Pharma, Sanofi, Takeda, Tillotts Pharma, and Teva; stock shareholder of: Gossamer Pharma; and employee as Senior Scientific Director of: Western University and Alimentiv
• N. Harpaz advisory board member and/or consultant: AbbVie, Bristol Meyers Squibb, Eli Lilly and Company, and PathAI Inc
• T. Hisamatsu received lecture fees: AbbVie, EA Pharma, Gilead Sciences, Janssen Pharmaceutical K.K., JIMRO, Kyorin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer, and Takeda; received honoraria as an advisory board member or consultant: AbbVie, EA Pharma, Eli Lilly and Company, Gilead Sciences, Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma, Pfizer, and Takeda; and received pharmaceutical/research grants from: AbbVie, Alfresa Pharma, Daiichi Sankyo, EA Pharma, JIMRO, Kyorin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nichi-lko Pharmaceutical, Nippon Kayaku, Pfizer, Takeda, and Zeria Pharmaceutical
• G. D’Haens advisor: AbbVie, Agomab Therapeutics, Alimentiv, AstraZeneca, Biora, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Eli Lilly and Company, Exeliom Biosciences, Galapagos NV, Genentech/Hoffmann-La Roche, GlaxoSmithKline, Immunic Therapeutics, Johnson & Johnson, Merck Sharp & Dohme, Pfizer, Protagonist Therapeutics, Samsung Bioepis, Sandoz, Seres Therapeutics/Nestec/Nestlé, Takeda, Tillotts Pharma AG, Ventyx; received speaker fees: AbbVie, Johnson & Johnson, Takeda, Pfizer, Tillotts Pharma AG
• R. Pai received consulting fees: Alimentiv Inc, Allergan, and BRACCO
• Z. Lin, N. Morris, M. Protic, E. Hon, C. Owen, R. Escobar are employees and shareholders: Eli Lilly and Company
• W. Reinisch received lecture and consulting fees from and/or served as an advisory board member: AbbVie, Actelion, Alpha Wasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring Pharmaceuticals, Genentech, Grunenthal, Johnson & Johnson, Millennium, Merck, Novo Nordisk, Nycomed, Pfizer, Pharmacosmos, Schering-Plough, Salix Pharmaceuticals, Takeda, UCB Pharma, and Vifor Pharma

Introduction

The safety and efficacy of mirikizumab (miri), an anti-IL-23p19 antibody, for moderately-to-severely active ulcerative colitis (UC) have been shown in Phase 3 trials (LUCENT-1 and -2; NCT03518086, NCT03524092). Extended induction with 3 additional intravenous (IV) doses of miri induced clinical response at Week (W)24 in more than 50% of patients who did not initially achieve clinical response to induction with miri at W12. Among the clinical non-responders, some had achieved partial response at W12 (Table 1). We assessed response over time in clinical non-responders at the end of induction who received extended induction with miri for an additional 12W.

Aims & Methods

In LUCENT-1, patients (N=1281) were randomly assigned 3:1 to receive miri 300mg or placebo IV at W0, W4, and W8. Patients not achieving clinical response with miri 300mg IV at W12 of LUCENT-1 (n=272) received extended induction treatment with open-label miri 300mg IV at W12, W16, and W20 (LUCENT-2). Symptomatic remission, symptomatic response, bowel urgency (BU) remission, and BU change from baseline at W16 and W20 are reported (definitions in Table 1) in addition to the previously disclosed outcomes at W24. For categorical variables, number and percentage of patients who are responders/remitters were presented. For continuous variables, mean change from baseline with standard deviation (SD) was used. Missing data were imputed as non-response.

Results

Among patients who were clinical non-responders to 12W of initial induction treatment (n=272), 53 (19.5%); 73 (26.8%); 101 (37.1%) achieved symptomatic remission and 144 (52.9%); 169 (62.1%); 197 (72.4%) patients achieved symptomatic response at W16, W20, and W24, respectively. Among miri induction non-responders with Urgency Numeric Rating Scale (NRS) score ≥3 at induction baseline (n=256), 10.9% achieved BU remission at W16, 14.8% at W20, and 19.9% at W24. There was a 1.8±2.4 (mean±SD) point reduction in Urgency NRS scores at W16, 2.1±2.5 reduction at W20, and 2.5±2.7 reduction at W24 (Table 1).

Conclusion

Among patients who were clinical non-responders to induction at W12, more than 50% achieved clinical response after 3 additional induction doses with miri. A proportion of patients benefited earlier from extended induction at W16 and W20, respectively, regarding symptomatic response and remission, and BU outcomes. The results demonstrate continued symptomatic improvement and further support the potential benefit of extended induction treatment.

Disclosure

DR receives grants or contracts from Takeda, and discloses consultancy fees with Abbvie, Altrubio, Allergan, Inc., American College of Gastroenterology, Arena Pharmaceuticals, Athos Therapeutics, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Ltd., Bristol-Myers Squibb, Celgene Corp/Syneos, Cornerstones Health, Inc. (non-profit), GalenPharma/Atlantica, Genentech/Roche, Gilead Sciences, GoDuRn, LLC, InDex Pharmaceuticals, Ironwood Pharmaceuticals, Iterative Scopes, Janssen Pharmaceuticals, Eli Lilly and Company, Materia Prima, Pfizer, Prometheus Biosciences, Reistone, Takeda and Techlab, Inc.
AC is on the advisory board of and/or a consultant for and/or receives educational grants from Abbvie, Eli Lilly and Company, Janssen, Pfizer, and Takeda.
VJ has received consulting/advisory board fees from AbbVie, Alimentiv Inc. (formerly Robarts Clinical Trials), Arena Pharmaceuticals, Asieris, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Mylan, Pandion, Pendopharm, Pfizer, Reistone Biopharma, Roche, Sandoz, Takeda and TopiVert, and speaker’s fees from AbbVie, Ferring, Galapagos, Janssen, Pfizer, Shire and Takeda.
JW has received consultancy or advisory board fees from Medtronic and Eli Lilly and Company.
KM, RM,SM, RE, SB are employees and minor shareholders of Eli Lilly and Company
LZ-P is an employee of HaaPACS GmbH and contractor for Eli Lilly and Company
TK has received lecture fees from Abbie GK, Activaid, Alfresa Pharma, Janssen Pharmaceutical, JIMRO, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Nippon Kayaku, Pfizer Japan, Takeda Pharmaceutical, Thermo Fisher Diagnostics and Zeria Pharmaceutical; research grants from Abbvie GK, Activaid, Alfresa Pharma, Bristol Myers Squibb, Eli Lilly Japan, Ferring Pharmaceuticals, Gilead Sciences, Janssen Pharmaceutical, JMDC, Mochida Pharmaceutical, Nippon Kayaku, Pfizer Japan and Takeda Pharmaceutical; scholarship contributions from Mitsubishi Tanabe Pharma, Nippon Kayaku and Zeria Pharmaceutical; study group sponsorship by Abbvie GK, EA Pharma, JIMRO, Kyorin Pharmaceutical, Mochida Pharmaceutical, Otsuka Holdings and Zeria Pharmaceutical; and advisory or consultancy fees from Abbie GK, Activaid, Alfresa Pharma, EA Pharma, Janssen Pharmaceutical, KISSEI Pharmaceutical, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Pfizer Japan and Takeda Pharmaceutical.

Introduction

A dysfunctional intestinal mucosal barrier is a key pathophysiological hallmark and driver of a broad range of gastrointestinal diseases including celiac disease and inflammatory bowel disease. To date, there are no adequate treatment strategies to ameliorate impaired barrier function.
IMU-856 is an orally available and systemically acting small molecule modulator of sirtuin 6 (SIRT6), a histone/non-histone protein deacetylase which serves as a transcriptional regulator of intestinal barrier function and regeneration of bowel epithelium. IMU-856 may represent a new approach to treat gastrointestinal diseases with compromised barrier function.

Aims & Methods

This was a first-in-human, double-blind, randomized, placebo-controlled clinical trial of IMU-856 in healthy volunteers and patients with celiac disease. In the multiple ascending dose part, healthy human subjects were dosed once-daily for 14 consecutive days with IMU-856 at three different dose levels or placebo. Additionally, the Phase 1/1b study was designed to assess safety and tolerability of IMU-856 at two different dose levels in patients with celiac disease during periods of gluten-free diet and a 15-day gluten challenge. Further objectives included pharmacokinetics and the assessment of histological changes. Biomarkers reflecting intestinal enterocyte mass and function, nutrient absorption, and enteroendocrine hormones like GLP-1 were analyzed to assess potential effects on gut health.

Results

IMU-856 was safe and well-tolerated with a benign adverse event profile and pharmacokinetics that allow once-daily dosing. Treatment with IMU-856 protected against gluten-induced histologic deterioration, improved the health and metabolic function of intestinal enterocytes as measured by nutrient uptake and citrulline [1], and had positive effects on enteroendocrine cells increasing endogenous GLP-1 levels in a dose-dependent manner.

Conclusion

IMU-856 is a safe, highly selective and potent epigenetic modulator, improving the intestinal barrier function in patients with celiac disease undergoing a gluten challenge.
Positive effects of IMU-856 on gut hormones and various biomarkers for overall gut health including intestinal function and integrity were observed. Therefore, IMU-856 may offer extensive potential for treatment of gastrointestinal diseases with compromised intestinal barrier function and metabolic diseases.

References

1. Daveson AJM, Stubbs R, Polasek TM, Isola J, Anderson R, Tye-Din JA, et al. Safety, clinical activity, pharmacodynamics, and pharmacokinetics of IMU-856, a SIRT6 modulator, in coeliac disease: a first-in-human, randomised, double-blind, placebo-controlled, phase 1 trial.

Disclosure

AS, MW, EP: employees of Immunic AG, option and shareholders of Immunic, Inc.
IPO, JF, IK, SE: employees of Immunic AG, option and/or shareholders of Immunic, Inc.
HK: employee of Immunic AG, shareholder of Immunic, Inc., co-inventor of patents for the drug in investigation
DP: option holder of Immunic, Inc.
DV, AM: employees of Immunic AG and Immunic, Inc., shareholders of Immunic, Inc., co-inventors of patents for the drug in investigation