Introduction
Many patients (pts) with moderately to severely active ulcerative colitis (UC) treated with biologics fail to respond or lose response and require alternative therapy.1,2 Upadacitinib (UPA), an oral reversible JAK inhibitor approved for treatment of adults with moderately to severely active UC, has shown efficacy in pts with an inadequate response, loss of response or intolerance to ≥1 biologic (biologic failure) or anti-TNF agent.3−5 However, data on the efficacy of UPA by the number and type of prior biologic therapies are limited.
Aims & Methods
This post hoc analysis evaluated clinical, endoscopic and safety outcomes of UPA in pts with UC with biologic failure by the number and type of prior biologics. After 8 weeks’ (wks’) induction therapy in the Phase 3 U-ACHIEVE or U-ACCOMPLISH trials, pts with clinical response to UPA 45 mg once daily (QD) were randomised to placebo (PBO), UPA 15 mg QD (UPA15) or UPA 30 mg QD (UPA30) for 52 wks in U‑ACHIEVE Maintenance. In this study, efficacy was analysed by number (0 prior biologics failed [Non-Bio-IR], 1 or ≥2) of prior biologics. Outcomes were assessed after 8 wks’ induction (pooled) and 52 wks’ maintenance. Results are presented using non-responder imputation incorporating multiple imputation to handle missing data.
Results
Baseline pt (induction [n=988]; maintenance [n=681]) characteristics were similar across treatment arms in each subgroup by number of prior biologics, except pts who failed ≥2 prior biologics who had longer disease duration. Clinical and endoscopic outcomes were achieved by more pts who received UPA vs PBO after induction and maintenance, and by more pts who received UPA30 vs UPA15 in the ≥2 prior biologics group after maintenance. Furthermore, more pts who received UPA30 vs UPA15 and failed ≥2 prior biologics maintained clinical remission from Wk 0 of maintenance to Wk 52 (Table). Adverse events (AEs) occurred at numerically higher rates for pts receiving UPA who failed ≥2 biologics in induction and maintenance studies. During induction, no malignancies or major adverse cardiovascular events (MACE) were reported, and there was 1 venous thromboembolic event (VTE) in the PBO group. During maintenance, across subgroups, rates of AEs of special interest were: malignancies (Non-Bio-IR: UPA15, 1.0 events/100 PY [E/100 PY]; UPA30, 1.8 E/100 PY; 1 prior biologic: PBO, 3.3 E/100 PY; UPA30, 5.5 E/100 PY; ≥2 prior biologics: UPA30, 1.8 E/100 PY), MACE (Non-Bio-IR: UPA30, 0.9 E/100 PY; 1 prior biologic: PBO, 3.3 E/100 PY) and VTE (Non-Bio-IR: UPA30, 1.8 E/100 PY), respectively. No AEs leading to death occurred in either study.
Table. Efficacy after 8 weeks’ induction and 52 weeks’ maintenance therapy
Efficacy endpoints
n, (%) | Induction (8 weeks) | Maintenance (52 weeks) |
Non-Bio-IR
N=481 | 1 prior biologic
N=203 | ≥2 prior biologics
N=304 | Non-Bio-IR
N=345 | 1 prior biologic
N=142 | ≥2 prior biologics
N=194 |
PBO
n=161 | UPA
45 mg QD
n=320 | PBO
n=65 | UPA
45 mg QD
n=138 | PBO
n=102 | UPA
45 mg QD
n=202 | PBO
n=107 | UPA
15 mg QD
n=116 | UPA
30 mg QD
n=122 | PBO
n=49 | UPA
15 mg QD
n=50 | UPA
30 mg QD
n=43 | PBO
n=67 | UPA
15 mg QD
n=59 | UPA
30 mg QD
n=68 |
Clinical
remission per
Adapted Mayo
scorea
---------------
Clinical
response per Adapted Mayo scoreb,c
---------------
Endoscopic improvementd
---------------
Endoscopic remissione
---------------
HEMIf
---------------Maintenance of clinical remissiong,h
---------------
Steroid-free remissiong,i | 12
(7.5)
------
59
(36.6)
------
20
(12.5)
------
4
(2.5)
------
15
(9.4)
------
─
------
─ | 116
(36.3)
------
259
(80.8)
------
156
(48.9)
------
69
(21.5)
------
130
(40.6)
------
─
------
─ | 0
(0)
------
13
(20.2)
------
2
(3.3)
------
0
(0)
------
2
(3.2)
------
─
------
─ | 39
(28.4)
------
102
(73.9)
------
53
(38.6)
------
13
(9.4)
------
44
(32.0)
------
─
------
─ | 2
(2.3)
------
14
(13.7)
------
3
(3.3)
------
1
(1.1)
------
3
(3.0)
------
─
------
─ | 42
(20.8)
------
125
(61.9)
------
56
(27.8)
------
24
(11.9)
------
47
(23.3)
------
─
------
─ | 16
(15.0)
------
31
(28.5)
------
23
(21.3)
------
10
(9.7)
------
20
(18.7)
------
13
(26.5)
------
13
(26.5) | 49
(42.0)
------
79
(68.3)
------
61
(52.8)
------
33
(28.7)
------
50
(43.0)
------
21
(48.2)
------
21
(48.2) | 65
(53.2)
------
97
(79.4)
------
82
(67.0)
------
38
(31.4)
------
70
(57.2)
------
33
(61.5)
------
32
(59.6) | 4
(8.2)
------
9
(17.3)
------
4
(8.6)
------
0
(<0.1)
------
3
(6.5)
------
2
(10.0)
------
2
(10.0) | 28
(55.1)
------
38
(76.0)
------
29
(57.1)
------
12
(24.3)
------
26
(51.1)
------
13
(76.5)
------
12
(70.6) | 23
(53.1)
------
31
(71.7)
------
25
(57.3)
------
10
(22.8)
------
22
(50.9)
------
10
(75.6)
------
10
(75.6) | 4
(6.2)
------
9
(13.7)
------
4
(6.5)
------
3
(4.7)
------
4
(6.2)
------
1
(6.3)
------
1
(6.3) | 15
(24.7)
------
26
(44.1)
------
19
(32.6)
------
10
(17.7)
------
16
(26.7)
------
7
(43.8)
------
7
(43.8) | 38
(55.5)
------
49
(72.0)
------
41
(60.4)
-------
18
(26.2)
------
39
(57.1)
------
15
(70.5)
------
15
(70.5) |
aAdaptedMayo score ≤2, with stool frequency subscore ≤1 and not greater than baseline, RBS=0 and ES ≤1 without friability.
bThe overall clinical response rate at Week 8 or Week 16 of UPA 45 mg QD induction therapy was 81.8%.
cA decrease in Adapted Mayo score ≥2 points and ≥30% from baseline, and a decrease in RBS ≥1 point or an absolute RBS of ≤1.
dES ≤1 without friability.
eES=0.
fES ≤1 without friability and Geboes Score ≤3.1.
gFor Non-Bio-IR: n=49, 43 and 53 for PBO, UPA 15 mg QD and UPA 30 mg QD, respectively. For 1 prior biologic: n=20, 17 and 13 for PBO, UPA 15 mg QD and UPA 30 mg QD, respectively. For ≥2 prior biologics: n=16, 16 and 21 for PBO, UPA 15 mg QD and UPA 30 mg QD, respectively.
hClinical Remission per Adapted Mayo score at Week 52 among patients who achieved clinical remission at the end of induction therapy.
iClinical remission per Adapted Mayo score at Week 52 and corticosteroid free for ≥90 days before Week 52 among patients who achieved clinical remission at the end of induction therapy.
ES, endoscopic subscore; HEMI, histologic endoscopic mucosal improvement; Non-Bio-IR, 0 prior biologics failed; PBO, placebo; QD, once daily; RBS, rectal bleeding subscore; UPA, upadacitinib. |
Conclusion
Clinical and endoscopic improvements were seen with UPA vs PBO in induction and maintenance therapy in pts with moderately to severely active UC, regardless of the number of prior biologics failed. During maintenance, numerically greater treatment benefits were seen with UPA30 vs UPA15 in the ≥2 prior biologics group. AEs occurred at numerically higher rates in pts who failed more biologics.
References
1. Koo HM, et al. Ther Adv Gastroenterol 2023;16:17562848231201728
2. Ma C, et al. J Clin Gastroenterol 2015;49:675–82
3. Danese S, et al. Lancet 2022;399:2113–28
4. Sandborn WJ, et al. Gastroenterology 2020;158:2139–49
5. Vermeire S, et al. Presentation at ECCO 2023, March 1–4, Copenhagen, Denmark (OP04)
Disclosure
RP has received consulting fees, speaker fees and research support from Abbott, AbbVie, Abivax, Alimentiv, Allergan, Amgen, AnaptysBio, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Cosmos Pharmaceuticals, Eisai, Élan, Eli Lilly, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, GlaxoSmithKline, Janssen, Landos, LyfeMD, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Sanofi, Satisfai Health, Spyre, Sublimity Therapeutics, Takeda, Theravance, Union Therapeutics and Ventyx.
SD has received consultancy fees from AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Gilead, Hospira, Janssen, Johnson & Johnson, MSD, Mundipharma, Pfizer, Roche, Sandoz, Takeda, TiGenix, UCB and Vifor Pharma.
GP has received personal payments/honoraria/speaker fees and/or accepted travel grants or fellowships from AbbVie, Allergan, Bristol Myers Squibb, Celltrion, Ferring, Galapagos, Janssen, Napp, Takeda and Tillotts; and is a director and shareholder in Ampersand Health.
IB has received consulting fees from AbbVie, Amgen, Arena, Biogen, Bristol Myers Squibb, Celltrion, Ferring, Galapagos, Janssen, Pfizer, Shire and Takeda; and speaker fees from AbbVie, Amgen, Arena, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Ferring, Galapagos, Janssen, Mylan, Pfizer, Shire and Takeda.
DTR has received grant support from Takeda; and has served as a consultant for AbbVie, Altrubio, Arena, Bristol Myers Squibb, Genentech/Roche, Gilead, Iterative Scopes, Janssen, Lilly, Pfizer, Prometheus Biosciences, Takeda and Techlab Inc.
KT has received consulting fees from Thermo Fisher Diagnostics K.K.; research grants from AbbVie and Takeda; and has served as a speaker for AbbVie, Celltrion, EA Pharma, Janssen, Kyorin, Mochida, Takeda, Tanabe Mitsubishi and Zeria.
RV, VR, JK, EC, SS and CH are full-time employees of AbbVie and may hold AbbVie stock and/or stock options.
SV has received grant support from AbbVie, Galapagos, Johnson & Johnson, Pfizer and Takeda; and consulting and/or speaking fees from AbbVie, Abivax, Alimentiv (formerly Robarts Clinical Trials), Arena, Avaxia, Boehringer Ingelheim, Celgene, Dr. Falk Pharma, Ferring, Galapagos, Genentech/Roche, Gilead, Hospira, Janssen, MSD, Mundipharma, Pfizer, Prodigest, Progenity, Prometheus Biosciences, Second Genome, Shire, Takeda, Theravance and Tillotts.
Acknowledgments/Funding: AbbVie and the authors thank all of the trial investigators and patients who participated in these clinical trials. AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, review and approval of this 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. Medical writing support was provided by Carl Davies, MSc, of 2 the Nth (Cheshire, UK) and was funded by AbbVie.
