Introduction

Mirikizumab (miri), an anti-IL-23p19 antibody, demonstrated robust efficacy in improving clinical, endoscopic, and inflammatory biomarker endpoints, and an acceptable safety profile for patients with moderately to severely active Crohn’s disease (CD) in the Phase 3 VIVID-1 study. Here, we investigate the onset of symptomatic improvement and the safety of miri as induction therapy through Week 12 (W12) for patients with moderately to severely active CD.

Aims & Methods

In VIVID-1 (NCT03926130), patients (N=1065) had moderately to severely active CD (unweighted daily average stool frequency (SF) ≥4 [loose and watery stools defined as Bristol Stool Scale Category 6 or 7] AND/OR unweighted daily average abdominal pain (AP) ≥2 at baseline) and had prior failure to biologic and/or conventional therapy. Patients were randomized in a 6:3:2 ratio to receive miri (a single 900mg intravenous (IV) dose at W0, W4, and W8 followed by a subcutaneous (SC) dose of 300mg at W12 and then every 4 weeks), ustekinumab (uste) (6mg/kg IV at W0 and SC dose of 90mg at W8 and then every 8 weeks), or placebo (PBO). Results for the co-primary endpoints and major secondary endpoints versus PBO, as well as for the 2 major secondary endpoints versus uste, have been reported previously ^1,2. This analysis focuses on comparisons of clinical response by Patient Reported Outcome (PRO) (defined as at least a 30% decrease in SF and/or AP with neither score worse than baseline), clinical remission by PRO (defined as SF≤3 and not worse than baseline [as per Bristol Stool Scale Category 6 or 7] and AP ≤1 and no worse than baseline), change from baseline (CFB) in SF, and CFB in AP up to W12 in patients who were randomized to miri or PBO.

Results

Baseline characteristics were balanced across the miri (N=579) and PBO (n=199) treatment groups¹. Compared to PBO, a greater proportion of patients on miri achieved clinical response by PRO at W4, 6, 8, and 12, and clinical remission by PRO at W6, 8, and 12. Treatment with miri resulted in significant improvements in SF at W6, 8, and 12, and in AP at W4, 6, 8, and 12 when compared to PBO (Table 1). The overall safety was consistent with the known safety profile of miri. The most common treatment-emergent adverse events (TEAEs) during induction period in miri-treated patients were COVID-19, anaemia and headache. There were lower frequencies of SAEs (miri: 5.9%, PBO: 9.0%) and discontinuations due to adverse events (miri: 2.4%, PBO:4.7%) in miri-treated patients versus PBO. There were no malignancies, no MACEs, no Hy’s law cases or deaths in the miri arm up to W12. One death was reported in the induction period in the PBO group.

Conclusion

In patients with moderately to severely active CD, miri induction was associated with higher rates of clinical response and greater improvement in AP as early as W4, and higher rates of clinical remission and greater improvement in SF as early as W6 versus PBO. Increasing treatment effect was observed through W12. The safety of miri induction therapy was consistent with its known favourable safety profile.

References

1. M Ferrante, S Danese, M Chen, G D'Haens, S Ghosh, T Hisamatsu, V Jairath, J Kierkus, L Peyrin-Biroulet, B Siegmund, S M Bragg, W Crandall, T Hunter Gibble, Z Lin, M Ugolini Lopes, N Morris, H Carlier, B Sands, VIVID Study Group, OP05 Primary efficacy and safety of mirikizumab in moderate to severe Crohn’s Disease: results of the treat-through VIVID 1 study, Journal of Crohn's and Colitis, Volume 18, Issue Supplement_1, January 2024, Pages i7–i9, https://doi.org/10.1093/ecco-jcc/jjad212.0005
2. V Jairath, B E Sands, P Bossuyt, F Farraye, M Ferrante, T Hisamatsu, A Kaser, J Kierkus, D Laharie, W Reinisch, B Siegmund, S M Bragg, E Hon, Z Lin, M Ugolini Lopes, N Morris, M Protic, S Danese, VIVID Study Group, OP35 Efficacy of mirikizumab in comparison to ustekinumab in patients with moderate to severe Crohn’s disease: Results from the phase 3 VIVID 1 study, Journal of Crohn's and Colitis, Volume 18, Issue Supplement_1, January 2024, Pages i62–i64, https://doi.org/10.1093/ecco-jcc/jjad212.0035

Disclosure

Bruce E Sands: reports consulting fees from Abbvie, Alimentiv , Amgen, Arena Pharmaceuticals, Artugen Therapeutics, Astra Zeneca, Boehringer Ingelheim, Boston Pharmaceuticals, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Evommune, Fresenius Kabi, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Kaleido, Kallyope, Merck, Morphic Therapeutics, MRM Health, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Sun Pharma, Surrozen, Target RWE,Teva, TLL Pharmaceutical, Ventyx Biosciences; consulting and speaking fees from Abivax; consulting and speaking fees and other support from Lilly; research grants, consulting and speaking fees and other support from Bristol Myers Squibb, Janssen, Pfizer, Takeda; research grants and consulting fees from Theravance Biopharma; and stock options from Ventyx Biopharma.
Minhu Chen: provided educational activities for AbbVie, China Medical System, IPSEN, Janssen, and Takeda; served on an advisory board for Boehringer Ingelheim and Janssen; and has support for clinical research from Janssen and Takeda.
Silvio Danese: has consulting fees from AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals Inc., Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB Inc., Vial, and Vifor; has lecture fees from Abbvie, Amgen, Ferring Pharmaceuticals Inc., Gilead, Janssen, Mylan, Pfizer, and Takeda.
Monika Fischer: has served as an Advisor, Review Panel Member, Speakers Bureau, or DSMB for AbbVie, BMS, Lilly, Ferring, Janssen, Pfizer, Rebiotix, Scioto, Seres
Tadakazu Hisamatsu: has joint research agreement from Kissei Pharmaceutical and EA Pharma; has received research grants from AbbVie, Daiichi Sankyo, EA Pharma, JIMRO, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Takeda, Boston Scientific, and Zeria Pharmaceutical; and has received consulting and lecture fees from AbbVie, EA Pharma, Gilead Sciences, Janssen Pharmaceuticals, JIMRO, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical, Pfizer, Kissei Pharmaceutical, and Takeda.
Sami Hoque: Reports advisory to Eli Lilly and Company and advisory and lecture fees to Tillots.
Laurent Peyrin-Biroulet: Reports the following: personal fees from Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillots, Pharmacosmos, Celltrion, Takeda, Boerhinger Ingelheim, Pfizer, Index Pharmaceuticals, Sandoz, Celgene, Biogen, Samsung Bioepis, Alma, Sterna, Nestle, Inotrem, Enterome, Allergan, MSD, Roche, Arena, Gilead, Hikma, Amgen, BMS, Vifor, Norgine, Mylan, Lilly, Fresenius Kabi, Oppilan Pharma, Sublimity Therapeutics, Applied Molecular Transport, OSE Immunotherapeutics, Enthera, and Theravance; grants from Abbvie, MSD, and Takeda; and stock options from CTMA
Frank Siebold: has consulting fees from Abbvie, Amgen, BMS, Dr. Falk, Eli Lilly, Geilead, Janssen, Pfizer, Takeda.
Geert D’Haens: has served as adviser and/or speaker for Abbvie, Alimentiv, Amgen, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Ferring, Eli Lilly, Engene, Galapagos, Glaxo Smith Kline, Immunic, Index Pharmaceuticals, Johnson and Johnson, Merck, Polpharm, Prometheus biosciences, Prometheus Laboratories, Procise diagnostics, Protagonist, Sandoz, Takeda, Tillotts, and Ventyx.
Frederick Durand, Emily Hon, Zhantao Lin, Nathan Morris, and Michelle Ugolini Lopes are all Eli Lilly and Company employees and stockholders.

Introduction

Drug-induced liver injury (DILI) caused by metamizole has gained increasing attention in recent years^{1, 2}. However, causality assessment remains a challenge, in particular in patients with multiple drug intake.

Aims & Methods

We further characterized metamizole DILI cases with the goal to identify typical patterns that can help adjudication. To this end, the data of 88 patients with metamizole intake from our prospective study on acute liver injury with potential drug-related cause were analysed. DILI diagnosis and causality assessment was based on clinical, laboratory and histological features as well as expert adjudication³. Alternative causes of liver injury were identified or ruled out by a thorough hepatological work-up.

Results

DILI was associated with metamizole in 63 of 324 DILI patients from our cohort (prevalence 19.4%). Out of the remaining 25 patients with metamizole intake, nine patients suffered from non-metamizole DILI and 16 patients from an alternative cause for liver injury (mainly autoimmune hepatitis [n=10] and biliary obstruction [n=4]). A distinctive phenotype was observed in 45 of the 63 metamizole DILI cases, which was characterized by a relatively long latency from the start of drug intake until recognition of liver injury (median: 51 days), high transaminases at onset (aspartate aminotransferase [AST] 36.9xULN, alanine aminotransferase [ALT] 42.5xULN) and a delayed peak of bilirubin with a median of 7 days after DILI recognition. Patients with this phenotype had higher rates of jaundice (100.0% vs. 62.8%, p<0.001), coagulopathy (73.7% vs. 20.9%, p<0.001) and acute liver failure (40.0% vs. 7.0%, p<0.001) when compared to metamizole DILI cases without this clinical picture, non-metamizole DILI and non-DILI controls, however remission rates did not differ significantly when compared to the controls (71.1% vs. 76.7%, p=0.481) or to the recovery rates described in larger registry studies on DILI in general⁴. Overall, adverse outcome as defined by death or liver transplantation was observed in nine patients with metamizole DILI (14.3%). On multivariate analysis, AST and INR at DILI recognition were the only parameters independently associated with this endpoint. Regarding prediction of an adverse outcome INR had the highest discrimination (c-statistic 0.89, 95% confidence interval [CI]: 0.74-0.99) and with this performed better than Hy’s law, transaminases, bilirubin or the model for end-stage liver disease (MELD) score at baseline in terms of prognosis. INR at a cut-off of ≥1.95 showed a sensitivity and specificity as high as 77.8% and 93.5% for an adverse outcome.

Conclusion

Patients with DILI due to metamizole can present with a specific pattern which can help to identify metamizole as the causative agent and avoid erroneous association of liver injury with innocent bystander medication. Outcome, however, is not associated with this clinical picture and should rather be predicted by AST and especially INR at onset.

References

1 Sebode M, Reike-Kunze M, Weidemann S, et al. Metamizole: An underrated agent causing severe idiosyncratic drug-induced liver injury. Br J Clin Pharmacol. 2020;86(7):1406-15.
2 Weber S, Benesic A, Neumann J, et al. Liver injury associated with metamizole exposure: features of an underestimated adverse event. Drug Saf. 2021;44(6):669-80.
3 Bjornsson ES, Stephens C, Atallah E, et al. A new framework for advancing in drug-induced liver injury research. The Prospective European DILI Registry. Liver Int. 2023;43(1):115-26.
4 Chalasani N, Bonkovsky HL, Fontana R, et al. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN prospective study. Gastroenterology. 2015;148(7):1340-52 e7.

Disclosure

Sabine Weber and Alexander L. Gerbes received funding from TransBioLine (Translational Safety Biomarker Pipeline (TransBioLine): Enabling development and implementation of novel safety biomarkers in clinical trials and diagnosis of disease; Grant Agreement ID: 821283). The TransBioLine project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 821283. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.