Introduction
Risankizumab (RZB), a humanised monoclonal antibody targeting the p19 subunit of interleukin-23 (IL-23), demonstrated substantial improvements in clinical and endoscopic outcomes in patients (pts) with active Crohn’s disease (CD) in the phase 3 studies (ADVANCE [NCT03104413], MOTIVATE [NCT03105128], and FORTIFY [NCT03105102]).1-2 In the FORTIFY study, clinical remission rates at week 52 were higher than expected in responders to induction RZB who were randomized to placebo (WD PBO) for maintenance, suggesting a durable effect of RZB. In this study, we investigated the molecular mechanisms associated with sustained clinical effects of RZB in CD pts in the phase 3 studies.
Aims & Methods
Bulk RNA sequencing was performed on colon biopsies collected longitudinally from a subset of pts in the phase 3 studies (True PBO, n=23; WD PBO, n=29; pooled RZB 180 and 360 mg, n=77) with matched samples at baseline (BL), wk12 (induction), and wk52 (maintenance). Differentially expressed genes (DEGs) from BL to wk52 were identified with linear mixed-effect models (false discovery rate ≤0.05) in all pts as well as in pts who achieved clinical remission (average daily stool frequency ≤2.8 and not worse than BL and average daily abdominal pain score ≤1 and not worse than BL) at wk52 and those who achieved maintenance of clinical remission from wk12 to wk52. Pathway enrichment analyses were performed with Ingenuity Pathway Analysis (IPA). Cell type enrichment analyses based on gut cell signatures from Buckley et al3 was conducted using Gene Set Variation Analysis (GSVA).
Results
Analysis of DEGs in colon biopsies from all pts yielded a highly significant subset of genes modulated from BL to wk52 in the WD PBO and RZB treatment arms. Shared upregulated DEGs across the WD PBO and RZB groups (MT-ND6, MT-ND4, MT-ND5, MT-ATP6, MT-ND4L, MT-ND1, MT-ND2, MT-CYB, MT-ND3, MT-CO2, MT-CO3, MT-CO2 and EIF3C) are associated with reduced mitochondrial dysfunction and upregulation of mitochondrial oxidative phosphorylation. Modulation of these genes were also enriched in pts who achieved wk52 clinical remission as well as pts who achieved maintenance of clinical remission from wk12 to wk52. Next, we validated the enrichment of the MT genes (based on the top 13 upregulated genes) at the patient level and found that all 13 shared MT gene signatures were significantly enriched at wk52 compared to BL and wk12 in both the WD PBO and RZB treatment arms. Additionally, the MT signature scores were comparable between the WD PBO and RZB arms at wk52. Cell type enrichment analyses further revealed that all 13 MT genes were expressed at higher levels in epithelial cells compared to other immune cell subsets, highlighting their potential role in epithelial cell function. These MT genes were also enriched in colonocytes, enterocytes, and LRG+ stem cells of pts who achieved wk52 clinical remission in both WD PBO and RZB groups, with significantly higher expression at wk52 compared to BL and wk12.
Conclusion
In this study, we identified molecular mechanisms indicating an immunometabolic shift, characterized by downregulation of canonical inflammatory pathways (such as neutrophil degranulation) and an enrichment of oxidative phosphorylation and enhanced mitochondrial activity in RZB-treated pts who demonstrated sustained clinical remission through 52 weeks of drug withdrawal. Durable clinical effects observed with RZB could be due to the enrichment of MT genes in colonic epithelial cells in the gut, which may signify RZB’s ability to restore mitochondrial function and energy metabolism.
References
- Schreiber SW, et al. J Crohn's Colitis. 2021;15(S1).
- Ferrante M, et al. The Lancet. 2022;399(10340):2031-2046.
- Thomas T, et al. Nat Immunol. 2024;25:2152–2165.
Disclosure
Author Disclosures
Nick Powell has received research grants from AstraZeneca, Bristol Myers Squibb, CCUK, Celltrion Healthcare, Helmsley Charitable Trust, Pfizer, and Takeda; received personal fees from AbbVie, Allergan, AstraZeneca, Bristol Myers Squibb, Celgene, Eli Lilly, Galapagos, GlaxoSmithKline, Janssen, Pfizer, Takeda, and Roche; served as a speaker or on the advisory board for AbbVie, Allergan, AstraZeneca, Bristol Myers Squibb, Celgene, Dr Falk, Galapagos, and Vifor; and serves on the data safety monitoring board for AstraZeneca and Bristol Myers Squibb.
Bram Verstockt has received 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, Landos, Mylan, Inotrem, Ipsos, Janssen, Progenity, Sandoz, Sosei Heptares, Takeda, Tillots Pharma, and Viatris; and stock options from Vagustim.
Geert D’Haens has received consulting and/or lecture fees from AbbVie, ActoGeniX, AIM, Boehringer Ingelheim, Centocor, ChemoCentryx, Cosmo Technologies, Dr Falk Pharma, Elan Pharmaceuticals, enGene, Ferring, Galapagos, Giuliani SpA, Given Imaging, GlaxoSmithKline, Janssen, MSD, Neovacs, Novo Nordisk, Otsuka, PDL BioPharma, Pfizer, Receptos, Salix, SetPoint, Shire, Schering-Plough, Takeda, Tillotts, UCB Pharma, Versant and Vifor Pharma; research grants from AbbVie, Dr Falk Pharma, Given Imaging, Janssen, MSD and PhotoPill; and speaking honoraria from AbbVie, Ferring, MSD, Norgine, Shire, Tillotts, Tramedico and UCB Pharma.
Naim Al Mahi, Stephen Laroux, Ari Stromberg, Heath Guay, and Buvana Ravishankar are full-time employees of AbbVie and may own AbbVie stock or stock options.
James Lindsay has served as a 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.
Funding
AbbVie funded this trial and participated in the trial design, research, analysis, data collection, interpretation of data, and the review and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. AbbVie and the authors thank the patients, study sites, and investigators who participated in this clinical trial.
