Introduction
Upadacitinib (UPA) is an oral, reversible Janus kinase inhibitor (JAKi) approved for the treatment of moderately to severely active Crohn’s disease (CD) and ulcerative colitis (UC).1-4 Abnormal levels of liver enzymes are frequently encountered in patients with inflammatory bowel disease. However, data on liver enzyme elevations in UC and CD patients treated with JAKi are limited.
Aims & Methods
This post hoc analysis evaluated changes in liver enzymes over time in phase 3 trials of UPA in CD (U-EXCEL, U-EXCEED, U-ENDURE) and UC (U-ACCOMPLISH, U-ACHIEVE). Patients were randomized 2:1 to receive once-daily (QD) UPA 45 mg (UPA45) or placebo (PBO) induction therapy for 12 weeks (wks) in the CD trials and 8 wks in the UC trials.3,4 Patients who achieved clinical response to UPA induction therapy were rerandomized (1:1:1) to PBO, UPA 15 mg (UPA15), or UPA 30 mg (UPA30) QD for the 52-wk maintenance studies.3,4 Data from the induction studies were pooled, as were data from the maintenance studies. Least-squared (LS) mean changes from baseline (BL) in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TBili) were calculated using ANCOVA models with treatment as a main factor, and BL and indication as covariates for induction and maintenance periods. The proportions of UPA-treated patients with Grade 3-4 liver enzyme elevations (ALT, AST, and ALP: >5.0 x upper limit normal [ULN]; TBili: >3.0 x ULN) were assessed.
Results
This analysis included 2,118 patients. At induction, BL mean [SD] ALT (PBO 19.4 [15.7] U/L; UPA45 18.2 [15.4] U/L), AST (PBO 19.5 [26.4] U/L; UPA45 17.8 [13.4] U/L), ALP (PBO 74.5 [25.8] U/L; UPA45 74.7 [35.2] U/L), and TBili (PBO 6.9 [4.4] μmol/L; UPA45 6.8 [4.0] μmol/L) were similar across treatment arms and within normal ranges. LS mean changes [SE] from BL in ALT, AST, ALP, and TBili were 4.7 [0.4] U/L, 4.7 [0.5] U/L, -8.7 [0.5] U/L, and 1.8 [0.1] μmol/L, respectively, by wk 4 of UPA induction and remained relatively stable across all treatment groups through wk52 of maintenance (Table). Incidences of Grade 3 or 4 elevations in liver enzymes were low throughout induction and maintenance (ALT: UPA45 1.1%, UPA15 2.1%, UPA30 1.0%; AST: UPA45 1.4%, UPA15 1.3%, UPA30 1.5%; ALP: UPA45 <0.1%, UPA15 0%, UPA30 0.2%; TBili: UPA45 0.4%, UPA15 0.4%, UPA30 0.6%). There were no events of drug-induced liver injury (DILI) in CD; 1 event was reported in UPA45 in UC induction, 1 event each in UPA15 and UPA30 in UC maintenance, all were nonserious and possibly attributed to other underlying conditions (i.e., alcohol) and/or concomitant medications (i.e., isoniazid, estrogen-containing contraceptive) (see Table footnotes).
Parameter
Timepoint | Induction,
LS Mean Change (SE) |
Parameter
Timepoint | Maintenance,
LS Mean Change (SE) |
PBO
(n = 725) | UPA45
(n = 1393) | PBO
(n = 468) | UPA15
(n = 471) | UPA30
(n = 480) |
ALT, U/L
Week 4
Week 8 |
0.0 (0.6)
0.5 (0.6) |
4.7 (0.4)
4.7 (0.5) | ALT, U/L
Week 12
Week 52 |
2.5 (1.1)
2.2 (1.6) |
5.1 (1.0)
7.7 (1.2) |
5.9 (1.0)
9.1 (1.1) |
AST, U/L
Week 4
Week 8 |
-0.4 (0.7)
0.2 (0.5) |
4.7 (0.5)
4.7 (0.3) | AST, U/L
Week 12
Week 52 |
2.6 (0.9)
2.4 (1.1) |
6.2 (0.8)
7.5 (0.8) |
7.2 (0.8)
9.5 (0.7) |
ALP, U/L
Week 4
Week 8 |
0.3 (0.7)
1.9 (0.9) |
-8.7 (0.5)
-11.0 (0.7) | ALP, U/L
Week 12
Week 52 |
1.7 (2.1)
5.2 (1.8) |
-9.3 (1.9)
-8.0 (1.3) |
-12.2 (1.8)
-11.1 (1.1) |
TBili, μmol/L
Week 4
Week 8 |
0.0 (0.1)
0.6 (0.2) |
1.8 (0.1)
2.5 (0.1) | TBili, μmol/L
Week 12
Week 52 |
0.4 (0.2)
3.0 (0.6) |
1.9 (0.2)
5.5 (0.4) |
1.7 (0.2)
4.8 (0.4) |
| DILI, n (%) [SSA%] | n = 378
0 | n = 719
1 (0.1) [0.2]a | DILI, n (%) [SSA%] | n = 245
0 | n = 250
1 (0.4) [0.4]b | n = 251
1 (0.4) [0.4]c |
ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; CD, Crohn’s disease; DILI, drug-induced liver injury; LS, least square; PBO, placebo; SSA, study site adjusted; TBili, total bilirubin; UC, ulcerative colitis; UPA, upadacitinib.
Pooled UC+CD data are reported as LS mean change from baseline (standard error). Baseline is defined as the last nonmissing observation before their first dose of study drug. The denominators for DILI are from patients in the UC program only, as there were no reports in CD.
a Liver damage due to concomitant isoniazid use for latent tuberculosis in 52-year-old female with 24 years of UC and was a current alcohol user. Event was reported on day 15 of UPA exposure.
b Drug-induced hepatitis moderate in severity in 32-year-old male with 11 years of UC who was receiving concomitant Mesalazine medication and was a former alcohol user. Event was reported on day 140 of UPA exposure. Study drug was interrupted.
c Drug-induced hepatopathy mild in severity in 28-year-old female with 6 years of UC who was receiving concomitant Pentasa and Triquilar medications. Event was reported on day 259 of UPA exposure. Patient withdrew from treatment. |
Conclusion
Patients with moderately to severely active CD or UC receiving UPA experienced early changes in liver enzymes, which remained stable thereafter. Grade 3-4 elevations were rare and nonserious. Further evaluations of these liver enzyme changes and association with UPA benefit/risk over long-term extension studies are warranted.
References
1. Danese S, Vermeire S, Zhou W, et al. Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials. Lancet. May 26 2022;399:2113-2128.
2. Loftus EV, Jr., Panés J, Lacerda AP, et al. Upadacitinib Induction and Maintenance Therapy for Crohn's Disease. N Engl J Med. May 25 2023;388(21):1966-1980. doi:10.1056/NEJMoa2212728
3. AbbVie. Rinvoq (Upadacitinib): Highlights of Prescribing Information [Package Insert]. AbbVie. Accessed March 21, 2024, //efaidnbmnnnibpcajpcglclefindmkaj/https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/211675s015lbl.pdf
4. AbbVie. Rinvoq (Upacitinib): Summary of Product Characteristics [Package Insert]. AbbVie. Accessed March 21, 2024, efaidnbmnnnibpcajpcglclefindmkaj/https://www.ema.europa.eu/en/documents/product-information/rinvoq-epar-product-information_en.pdf
Disclosure
AbbVie Disclosure: AbbVie Inc. funded these studies (U-EXCEL, NCT03345849; U-EXCEED, NCT03345836; U-ENDURE, NCT03345823) and UC (U-ACCOMPLISH, NCT03653026; U-ACHIEVE, NCT02819635) and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, writing 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.
Acknowledgments: AbbVie and the authors thank all the trial investigators and the patients who participated in these clinical trials. Paulette Krishack, PhD, and Jeanie Meckes, PhD, of AbbVie, provided medical writing assistance for the development of this publication.
Declaration of Interests:
Marla Dubinsky is a consultant for AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Eli Lilly, Gilead Sciences, Janssen Pharmaceuticals, Pfizer, Prometheus Labs, Sanofi, Shire, Takeda, and receives research grants from AbbVie and Janssen Pharmaceuticals.
Miguel Regueiro has served as a consultant, speaker and advisory board member for AbbVie
Christina Ha has received financial support from advisory board fees from AbbVie, Bristol Myers Squibb, Bausch Health, Roivant, Janssen, Pfizer, and Takeda; consultant fees from AbbVie; educational grant funding from Bristol Myers Squibb, Pfizer, Janssen, AbbVie and the Helmsley Charitable trust.
Gil Y. Melmed is a consultant for AbbVie, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Dieta, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, Lilly, Janssen, Oshi Health, Pfizer, Prometheus Labs, Samsung Bioepis, Shionogi, Takeda, and Techlab, Viatris He has received research grants from Pfizer.
Alessandro Armuzzi has received consulting and/or advisory board fees from AbbVie, Allergan, Amgen, Arena, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead, Janssen, Lionhealth, MSD, Mylan, Nestlé, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sandoz, and Takeda; lecture and/or speaker bureau fees from AbbVie, Amgen, Biogen, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead, Janssen, Merck & Co, Mitsubishi Tanabe, Novartis, Pfizer, Roche, Samsung Bioepis, Sandoz, Takeda and Tigenix; and research grants from Biogen, Merck & Co, Pfizer, and Takeda.
Peter M. Irving has received lecture fees from AbbVie, BMS, Celgene, Celltrion, Falk Pharma, Ferring, Galapagos, Gilead, MSD, Janssen, Pfizer, Takeda, Tillotts, Sapphire Medical, Sandoz, Shire, Warner Chilcott; Financial support for research: Celltrion, MSD, Pfizer, Takeda; Advisory fees: AbbVie, Arena, Boehringer Ingelheim, BMS, Celgene, Celltrion, Genentech, Gilead, Hospira, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Prometheus, Roche, Sandoz, Samsung Bioepis, Takeda, Topivert, VH2, Vifor Pharma, and Warner Chilcott.
Samuel I. Anyanwu, Elena Dubcenco, Fernando Aponte, Isheeta Shah, Tao Wang, Smitha Suravaram,and Hannah Palac are AbbVie employees and may own AbbVie stock and/or stock options.
David T. Rubin has served as a consultant for AbbVie, Altrubio, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Dizal Pharmaceuticals, Galapagos, Ichnos Sciences S.A., InDex Pharmaceuticals, Iterative Health, Janssen, Lilly, Pfizer, Prometheus Biosciences, Reistone, Syneos, and Takeda. He has received grant support from Takeda.