Introduction

Mirikizumab (miri), an anti-IL-23p19 antibody, has shown efficacy in patients with moderately-to-severely active Crohn’s disease (CD) to Week (W)52. We explored the potential relationship between early histologic and endoscopic responses on long term clinical outcomes after 2 years of miri treatment in a double-blind, placebo (PBO)-controlled Phase 2 trial (NCT02891226) in patients with CD.

Aims & 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 (SC) 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 and with clinical remission based on the Crohn’s Disease Activity Index (CDAI), patient-reported outcomes (PRO), and hospitalization rates at W104. Non-responder imputation for CDAI or PRO at W104 was used for patients who have observed histologic and endoscopic outcome value at W52 or W12. Hospitalizations were summarized by observed value. P-values for categorical values were determined with Fisher’s exact test.

Results

At W104, 56.9% patients (N=137) achieved CDAI remission compared to 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).

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

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 Week 52, but not at Week 12. The small sample size was likely a limitation. This data will be further studied in Phase 3 trials.

Disclosure

VJ reports consulting/advisory board fees from AbbVie, Alimentiv Inc (formerly Robarts Clinical Trials), Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Reistone Biopharma, Roche, Sandoz, Second Genome, Takeda, Teva, Topivert, Vividion; speaker’s fees from, Abbvie, Ferring, Galapagos, Janssen, Pfizer, Shire, Takeda, Fresenius Kabi. 
WR reports lecture fees from AbbVie, Actelion, Alpha Wasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grunenthal, Johnson & Johnson, Millennium, Merck, NovoNordisk, Nycomed, Pfizer, Pharmacosmos, Schering-Plough, Salix, Takeda, UCB Pharma, and Vifor; consultant fees from AbbVie, Actelion, Alpha Wasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grunenthal, Johnson & Johnson, Millennium, Merck, NovoNordisk, Nycomed, Pfizer, Pharmacosmos, Schering-Plough, Salix, Takeda, UCB Pharma, and Vifor; and serves as an advisory board member for AbbVie, Actelion, Alpha Wasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grunenthal, Johnson & Johnson, Millennium, Merck, NovoNordisk, Nycomed, Pfizer, Pharmacosmos, Schering-Plough, Salix, Takeda, UCB Pharma, and Vifor.
GDH reports that his institution has received fees for his clinical trial activities with Centocor J&J.
NH has served as an advisory board member or consultant for Eli Lilly and Company, Abbvie Inc., Bristol Meyer Squibb, Inc., and PathAI, Inc.
RP reports consulting fees from Seres Therapeutics, Eli Lilly, Protagonist, Genentech, and Robarts Clinical Trials.
MP, ZL, RH, HC are employees and minor shareholders of Eli Lilly and company. 
FM served as speaker for Abbvie, Arena, Biogen, Bristol-Myers Squibb, Falk, Ferring, Hospira, Janssen, Laboratórios Vitoria, Pfizer, Lilly, Merck Sharp & Dohme, Sandoz, Takeda, UCB, Vifor.

Introduction

Vedolizumab (VDZ) is a gut-selective humanised monoclonal anti-α₄β₇ integrin antibody for treatment of ulcerative colitis (UC) and Crohn’s disease (CD). The GEMINI Long-Term Safety (LTS) study demonstrated the durable efficacy and safety of vedolizumab for inflammatory bowel disease (IBD) treatment. Patients experiencing clinical benefit from vedolizumab in GEMINI LTS (NCT00790933) or VERSIFY (NCT02425111) studies could continue treatment in the vedolizumab extended access programme (XAP).

Aims & Methods

​​​​​​The XAP study was a phase 3b/4, prospective, open-label, multinational, interventional study (NCT02743806)^1,2 conducted from Aug 2016 to Jan 2023 to investigate long-term treatment persistence and safety of vedolizumab 300mg IV every 4 weeks (Q4W) or every 8 weeks (Q8W) in adults with UC or CD.

Results

The study enrolled 331 patients (UC=142; CD=189) including 20 rolling over from VERSIFY and 311 patients from GEMINI LTS. Patients treated with vedolizumab in the XAP study had either dose frequency reduction Q4W to Q8W or were maintained on their current Q8W or Q4W dosing; 297 patients started the XAP study on Q8W dosing, of which 295 received at least one dose of vedolizumab in XAP. At XAP study baseline, mean (SD) disease duration was 13.9 (6.8) and 13.2 (6.8) yrs for patients with UC and CD, respectively; most patients were in clinical remission (Table 1). In total, 283/295 patients (95.9%) were persistent on Q8W dosing for ≥6 months without relapse (UC: 129/132 [97.7%] and CD: 154/163 [94.5%]). Median (range) duration of vedolizumab treatment in the XAP study was UC: 3.8 (0–6) and CD: 4.2 (0–6) yrs. Only 27 patients (9.2%) were re-escalated from Q8W to Q4W dosing during the study (UC: 11/132 [8.3%] and CD: 16/163 [9.8%]); median (range) duration from last dose in the qualifying study to dose escalation in XAP was 1.5 (0.6–3.0) and 1.2 (0.2–5.2) yrs for UC and CD groups, respectively; the corresponding duration from last dose in the qualifying study to relapse was 1.4 (0.4–4.0) and 1.2 (0.06–5.4) yrs. Adverse events (AEs) after enrolment into XAP occurred in 61.3% of patients with UC and 62.4% with CD (treatment-related in 2.1% UC and 4.2% CD) but only 4.2% UC and 1.6% CD had AEs leading to study discontinuation (treatment-related: 0.7% UC, 0.5% CD); 13.4% UC and 16.4% CD had serious AEs (treatment-related: 0.7% UC, 0.5% CD). Severe infections occurred in 2 patients with UC (1.4% including 1 patient with COVID-19) and in 1 patient with CD (0.6%), none were considered treatment-related. There was 1 death from COPD reported during the study.

Conclusion

This long-term, prospective study reported high patient persistence on vedolizumab Q8W after the reduction of dosing frequency, together with low rates of dose frequency escalation to Q4W and relapse. Safety results were consistent with the known safety profile of vedolizumab; no new safety signal was identified.

References

1. Vermeire S, et al. J Crohns Colitis 2020;14(8):1066-73.
2. Danese S, et al. Aliment Pharmacol Ther 2021;53(2):265-72.

Disclosure

Silvio Danese: Lecture fees: AbbVie, Ferring, Hospira, Johnson & Johnson, Merck, MSD, Takeda, Mundipharma, Pfizer Inc, Tigenix, UCB Pharma, Vifor, Biogen, Celgene, Allergan, Celltrion, Sandoz, Boehringer Ingelheim; Consultancy: AbbVie, Ferring, Hospira, Johnson & Johnson, Merck, MSD, Takeda, Mundipharma, Pfizer Inc, Tigenix, UCB Pharma, Vifor, Biogen, Celgene, Allergan, Celltrion, Sandoz, Boehringer Ingelheim. Grazyna Rydzewska: Lecture fees: AbbVie, Ferring, Johnson & Johnson, Takeda, Pfizer Inc, Celltrion, Sandoz, Boehringer Ingelheim; Alfa Sigma, ProMed, Biocodex, Sanprobi; Consultancy: AbbVie, Ferring, Johnson & Johnson, Takeda, Pfizer Inc, Celltrion, Sandoz, Sobi, ProMed. Stephen Jones: consultant to Takeda. Shashi Adsul and Dirk Lindner: employees of Takeda and hold Takeda stock/stock options; medical writing support was provided by Excel Medical Affairs and funded by Takeda. Séverine Vermeire: Grants: AbbVie, Galapagos, Johnson & Johnson, Pfizer, Takeda; consulting/and or speaker fees: AbbVie, AbolerIS, AgomAb, Alimentiv, Arena, AstraZeneca, Avaxia, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, CVasThera, Cytoki, Dr Falk, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, Johnson & Johnson, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillots, Zealand.

Introduction

The efficacy and safety of mirikizumab (miri) for moderately to severely active ulcerative colitis (UC) was demonstrated in the Phase 3 LUCENT trials (LUCENT-1 and -2; NCT03518086, NCT03524092). 1,2 Some patients may improve more slowly and require a prolonged course of induction before achieving clinical response. Therefore, we evaluated clinical response in patients who had not responded by the end of the 12-week(W) induction period and who received extended induction treatment for an additional 12W.

Aims & Methods

^​Patients not responding to intravenous (IV) administration of 300 mg miri every 4 weeks (Q4W) (n=272) at W12 (LUCENT-1), received extended 12-W induction treatment of open label 300 mg miri IV Q4W for 3 additional doses (LUCENT-2). Patients responding at W24 (n=144) of continuous IV treatment, entered open label maintenance and received 200 mg miri Q4W subcutaneously (SC) until W52. Key outcomes through 52W are reported (Definitions in Table).

Results

Among the 272 patients who failed to achieve a clinical response after 12W of induction treatment, 72.4% had a Mayo endoscopic subscore of 3, indicating severe disease. Of these patients, 146 (53.7%) achieved a clinical response and 31 (11.4%) achieved clinical remission at W24. Of the 144 responders at 24W entering the open label maintenance study, 52 (36.1%) patients achieved clinical remission, 104 (72.2%) achieved clinical response, 62 (43.1%) achieved endoscopic remission and 60 (41.7%) patients achieved histologic improvement at W52. Furthermore, for these patients, there was a 3.8 (±2.7) point reduction from baseline in bowel urgency (BU) severity and 58.8% achieved clinically meaningful improvement in BU (defined as change from baseline in Urgency Numeric Rating Scale ≥3 in patients with Urgency Numeric Rating Scale ≥3 at induction baseline). Among these patients, 38.3% demonstrated treatment-emergent adverse events (TEAEs). Most TEAEs were mild (21.4%), while only 5.4% were serious. Overall, there was a 3.2% of discontinuation due to TEAEs. No new safety signals or deaths were reported.

Table: Clinical outcomes for the mirikizumab induction non-responder patient population at Weeks 12, 24 and 52 of extended induction

Conclusion

^​Among patients who did not initially respond to induction treatment with miri at 12W, 3 additional miri induction doses induced clinical response and remission in patients, highlighting the potential benefit of extended induction treatment with miri in those patients with more severe inflammation at baseline.

References

1. D’Haens et al., OP26: Efficacy and safety of mirikizumab as induction therapy in patients with moderately to severely active Ulcerative Colitis: Results from the Phase 3 LUCENT-1 study, Crohn's and Colitis, Vol. 16, Iss. Supplement_1, Jan. 2022, i028–i029
2. Dubinsky et al., 867e: Efficacy and safety of mirikizumab as maintenance therapy in patients with moderately to severely active Ulcerative Colitis: Results from the Phase 3 Lucent-2 study, Gastroenterology, Vol. 162, Iss. 7, S-1393-94

Disclosure

G. D’Haens has served as an advisor for: AbbVie, Ablynx, Active Biotech, Agomab Therapeutics, Allergan, AlphaBiomics, AM-Pharma, Amaken, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, AstraZeneca, Avaxia Biologics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb/Celgene, Celltrion, Cosmo Pharmaceuticals, Dr. Falk Pharma, DSM Pharma Solutions, Echo Pharmaceuticals, Eli Lilly and Company, enGene, Exeliom Biosciences, Ferring Pharmaceuticals, Galapagos NV, Genentech/Hoffmann-La Roche, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Immunic Therapeutics, Johnson & Johnson, Kintai Therapeutics, Lycera, Medimetrics, Medtronic, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Mundipharma, Nextbiotics, Novo Nordisk, Otsuka, Pfizer, PhotoPills, ProciseDx, ProDigest, Progenity, Prometheus Laboratories/Nestlé, Protagonist Therapeutics, RedHill, Robarts Clinical Trials, Salix Pharmaceuticals, Samsung Bioepis, Sandoz, Seres Therapeutics/Nestec/Nestlé, Setpoint Medical, Shire, Takeda, Teva, TiGenix, Tillotts Pharma AG, Topivert, Versant and Vifor Pharma; and has received speaker fees from: AbbVie, Biogen, Ferring Pharmaceuticals, Galapagos NV/Gilead Sciences, Johnson & Johnson, Merck Sharp & Dohme, Millenium/Takeda, Mundipharma, Norgine, Pfizer, Samsung Bioepis, Shire, Tillotts Pharma AG and Vifor Pharma; P. Higgins has served as an advisor for: AbbVie, Arena Pharmaceuticals, Eli Lilly and Company, Genentech/Hoffmann-La Roche, Johnson & Johnson, Lycera and Pfizer; L. Peyrin-Biroulet has received consulting fees and/or grants and/or support for attending meetings and/or honoraria from and/or has participated on a data safety monitoring board or advisory board for: AbbVie, Alimentiv, Allergan, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly and Company, Enthera, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos NV, Genentech, Gilead Sciences, Gossamer Bio, InDex Pharmaceuticals, Inotrem, Janssen, Merck Sharp & Dohme, Mylan, Norgine, Ono Pharmaceutical, OSE Immunotherapeutic Pandion Therapeutics, Pfizer, Roche, Samsung Bioepis, Sandoz, Takeda, Theravance Biopharma, Thermo Fisher Scientific, Tillotts Pharma AG, Viatris and Vifor Pharma; and is a shareholder of: CTMA; B. E. Sands has served as a consultant or received speaker’s fees from: AbbVie, Abivax, Adiso Therapeutics, Alimentiv, Amgen, Arena Pharmaceuticals, Artizan Biosciences, Artugen Therapeutics, AstraZeneca, Bacainn Therapeutics, Biora Therapeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Calibr/Scripps Research, Celltrion, ClostraBio, Connect Biopharma, Cytoki Pharma, Eli Lilly and Company, Enthera, Evommune, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos NV, Genentech, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Highlightll Pharma, HMP Acquisition, Imhotex, Immunic Therapeutics, InDex Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Ironwood Pharmaceuticals, Janssen, Johnson & Johnson, Kaleido Biosciences, Kallyope, Merck, MiroBio, Morphic Therapeutic, MRM Health, OSE Immunotherapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, RedHill, Sun Pharma, Surrozen, Synlogic Operating Company, Takeda, Target RWE, Theravance Biopharma, USWM Enterprises, Ventyx Biosciences and Viela Bio; and has stock options from: Ventyx Biosciences; S. Lee has received consulting fees and/or grants from: AbbVie, Applied Molecular Transport, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly and Company, Janssen and Protagonist Therapeutics; R. E. Moses, I. Redondo, R. Escobar and N. Morris are employees and shareholders of: Eli Lilly and Company; T. Kobayashi has received grants and/or contracts from: AbbVie, ActivAid, Alfresa Pharma, Bristol Myers Squibb, EA Pharma, Eli Lilly Japan K.K., Gilead Sciences, Google Asia Pacific, Janssen Pharmaceutical K.K., JIMRO, JMDC, Kyorin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Otsuka, Pfizer Japan K.K., Takeda and Zeria Pharmaceutical; has received lecture payments or honoraria from: AbbVie, ActivAid, Alfresa Pharma, Galapagos NV, Janssen Pharmaceutical K.K., JIMRO, Kyorin, Mitsubishi Tanabe Pharma, Nippon Kayaku, Pfizer Japan K.K., Takeda, Thermo Fisher Scientific and Zeria Pharmaceutical; has received payment for expert testimony from: AbbVie, ActivAid, Alfresa Pharma, EA Pharma, Janssen Pharmaceutical K.K., Kissei, Kyorin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Pfizer Japan K.K. and Takeda; and has participated on data safety monitoring boards or advisory boards for: Bristol Myers Squibb, EA Pharma, Eli Lilly and Company and Janssen.