Browsing by Author "D’Haens, Geert"

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    Concomitant Administration of Ozanimod and Serotonergic Antidepressants in Patients With Ulcerative Colitis or Relapsing Multiple Sclerosis
    (Oxford University Press, 2025) Regueiro, Miguel; Siegmund, Britta; Horst, Sara; Moslin, Ryan; Charles, Lorna; Petersen, AnnKatrin; Tatosian, Daniel; Wu, Hsiuanlin; Lawlor, Garrett; Fischer, Monika; D’Haens, Geert; Colombel, Jean-Frederic; Medicine, School of Medicine
    Background: Ozanimod, approved for the treatment of moderately to severely active ulcerative colitis (UC) and relapsing multiple sclerosis (RMS), is a weak in vitro monoamine oxidase B (MAO-B) inhibitor. MAO-B inhibitors can cause serotonin accumulation with concomitant use of selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs). We evaluated the incidence of treatment-emergent adverse events (TEAEs) potentially associated with serotonin accumulation during ozanimod and concomitant SSRI/SNRI use in this post hoc analysis of pooled UC studies and the open-label extension RMS DAYBREAK. Methods: Data for ozanimod 0.92 mg from pooled UC studies (n = 1158; cutoff: January 10, 2022) and RMS DAYBREAK (n = 2257; cutoff: February 1, 2022) were analyzed. Concomitant SSRI/SNRI use was allowed in the UC (n = 67) and RMS (n = 274) studies. A narrow Medical Dictionary for Regulatory Activities search ("serotonin syndrome," "neuroleptic malignant syndrome," and "malignant hyperthermia") and a broad search including terms potentially associated with serotonin accumulation were conducted. The percentages of patients with TEAEs in both searches were analyzed by concomitant SSRI/SNRI use when the TEAE occurred. Results: No patients had TEAEs matching the narrow search criteria. No differences were observed in the percentages of patients with ≥1 TEAE matching the broad search regardless of SSRI/SNRI use in UC (with: 25.4% [n = 17 of 67]; without: 15.0% [n = 164 of 1091]) and RMS (with: 12.4% [n = 34 of 274]; without: 15.6% [n = 310 of 1982]) studies. Conclusions: No evidence of increased TEAEs potentially associated with serotonin accumulation was observed with concurrent use of ozanimod and SSRIs/SNRIs.
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    Efficacy and Safety of Mirikizumab in a Randomized Phase 2 Study of Patients With Crohn’s Disease
    (Elsevier, 2022-02) Sands, Bruce E.; Peyrin-Biroulet, Laurent; Kierkus, Jaroslaw; Higgins, Peter D.R.; Fischer, Monika; Jairath, Vipul; Hirai, Fumihito; D’Haens, Geert; Belin, Ruth M.; Miller, Debra; Gomez-Valderas, Elisa; Naegeli, April N.; Tuttle, Jay L.; Pollack, Paul F.; Sandborn, William J.; Medicine, School of Medicine
    Background Mirikizumab is a humanized monoclonal antibody targeting interleukin 23p19 with demonstrated efficacy in psoriasis and ulcerative colitis. We investigated the safety and efficacy of mirikizumab in patients with moderate-to-severe Crohn’s disease (CD). Methods Patients (N = 191) were randomized (2:1:1:2) to receive placebo (PBO), 200, 600, or 1000 mg mirikizumab, administered intravenously (IV) every 4 weeks. Patients who received mirikizumab and achieved ≥1 point improvement in Simple Endoscopic Score-CD at Week 12 (rerandomized maintenance cohort) were rerandomized to continue their induction IV treatment (combined IV groups [IV-C]) or receive 300 mg mirikizumab subcutaneously (SC) every 4 weeks. Nonrandomized maintenance cohort included endoscopic nonimprovers (1000 mg) and PBO patients (PBO/1000 mg) who received 1000 mg mirikizumab IV from Week 12. The primary objective was to evaluate superiority of mirikizumab to PBO in inducing endoscopic response (50% reduction from baseline in Simple Endoscopic Score-CD) at Week 12. Results At Week 12, endoscopic response was significantly higher by the predefined 2-sided significance level of 0.1 for all mirikizumab groups compared with PBO (200 mg: 25.8%, 8/31, 95% confidence interval [CI], 10.4–41.2, P = .079; 600 mg: 37.5%, 12/32, 95% CI, 20.7–54.3, P = .003; 1000 mg: 43.8%, 28/64, 95% CI, 31.6–55.9, P < .001; PBO: 10.9 %, 7/64, 95% CI, 3.3–18.6). Endoscopic response at Week 52 was 58.5% (24/41) and 58.7% (27/46) in the IV-C and SC groups, respectively. Frequencies of adverse events (AE) in the mirikizumab groups were similar to PBO. Through Week 52, frequencies of treatment-emergent AEs were similar across all groups. Frequencies of serious AE and discontinuations due to AE were higher in the nonrandomized maintenance cohort. Conclusion Mirikizumab effectively induced endoscopic response after 12 weeks in patients with moderate-to-severe CD and demonstrated durable efficacy to Week 52. A detailed summary can be found in the Video Abstract. ClinicalTrials.gov, Number: NCT02891226
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    Mirikizumab-Induced Transcriptome Changes in Ulcerative Colitis Patient Biopsies at Week 12 Are Maintained Through Week 52
    (Wolters Kluwer, 2023-11-01) Johnson, Travis; Steere, Boyd; Zhang, Pengyue; Zang, Yong; Higgs, Richard; Milch, Catherine; Reinisch, Walter; Panés, Julian; Huang, Kun; D’Haens, Geert; Krishnan, Venkatesh; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
    Introduction: Mirikizumab, an anti-interleukin-23p19 monoclonal antibody, demonstrated efficacy in phase 2 and 3 randomized clinical trials of patients with moderate-to-severe ulcerative colitis (UC). Previous results have shown that 12 weeks of mirikizumab treatment downregulated transcripts associated with UC disease activity and tumor necrosis factor inhibitor resistance. We assessed week-52 gene expression from week-12 responders receiving mirikizumab or placebo. Methods: In the phase 2 AMAC study (NCT02589665), mirikizumab-treated patients achieving week-12 clinical response were rerandomized to mirikizumab 200 mg subcutaneous every 4 or 12 weeks through week 52 (N = 31). Week-12 placebo responders continued placebo through week 52 (N = 7). The limma R package clustered transcript changes in colonic mucosa biopsies from baseline to week 12 into differentially expressed genes (DEGs). Among DEGs, similarly expressed genes (DEGSEGs) maintaining week-12 expression through week 52 were identified. Results: Of 89 DEGSEGs, 63 (70.8%) were present only in mirikizumab induction responders, 5 (5.6%) in placebo responders, and 21 (23.6%) in both. Week-12 magnitudes and week-52 consistency of transcript changes were greater in mirikizumab than in placebo responders (log2FC > 1). DEGSEG clusters (from 84 DEGSEGs identified in mirikizumab and mirikizumab/placebo responders) correlated to modified Mayo score (26/84 with Pearson correlation coefficient [PCC] >0.5) and Robarts Histopathology Index (55/84 with PCC >0.5), sustained through week 52. Discussion: Mirikizumab responders had broader, more sustained transcriptional changes of greater magnitudes at week 52 vs placebo. Mirikizumab responder DEGSEGs suggest a distinct molecular healing pathway associated with mirikizumab interleukin-23 inhibition. The cluster's correlation with disease activity illustrates relationships between clinical, endoscopic, and molecular healing in UC.