Introduction
Luminal stenoses with variable degrees of inflammatory and fibrotic components are commonly observed in patients with Crohn’s disease (CD) and may require medical, endoscopic, or surgical management.1 Upadacitinib (UPA), an oral, reversible Janus kinase inhibitor, demonstrated efficacy in 3 randomized, controlled, double-blind studies, and is approved for the treatment of moderately to severely active CD.2-6 We conducted a post hoc analysis of these studies to evaluate the efficacy of UPA in patients with baseline (BL) luminal stenoses.
Aims & Methods
Patients in induction studies U-EXCEL (NCT03345849) and U-EXCEED (NCT03345836) were randomized 2:1 to receive UPA 45 mg (UPA45) or placebo (PBO) once daily (QD) for 12 weeks. Patients with clinical response were re-randomized 1:1:1 in the U-ENDURE maintenance study (NCT03345823) to receive UPA 30 mg (UPA30), UPA 15 mg (UPA15), or PBO QD for 52 weeks. The presence, location, degree of patency, and number of luminal stenoses were assessed by Simple Endoscopic Score for CD (SES-CD) narrowing component (range 0–3; patients with symptomatic stenosis were excluded). Resolution of BL stenosis and achievement of clinical remission and endoscopic response were assessed at week 12 of induction and week 52 of maintenance.
Results
One-third of patients (33.0% [337/1021]) had stenoses at induction BL (UPA45: 34.1% [230/674]; PBO: 30.8% [107/347]). BL demographics and disease characteristics were generally similar in patients with or without stenoses. BL stenoses occurred most frequently in the ileum (161 stenoses) followed by the right colon, transverse colon, sigmoid and left colon, and rectum (116, 39, 53, and 33 stenoses, respectively). At week 12, resolution rates of BL stenosis were nominally greater in the sigmoid and left colon and numerically greater in the ileum, transverse colon, and rectum among patients receiving UPA45 vs PBO (Table). UPA45 showed nominally greater efficacy compared with PBO in achieving clinical remission and endoscopic response in patients with or without BL stenoses (Table). Of the 502 patients in the maintenance population, 35.3% (n = 177) had stenoses at induction BL (UPA30: 34.5% [58/168]; UPA15: 35.6% [60/169]; PBO: 35.8% [59/165]). Narrowing was most frequent in the ileum (82 stenoses) followed by the right colon, transverse colon, sigmoid and left colon, and rectum (56, 21, 27, and 20 stenoses, respectively). By week 52, resolution rates of BL stenosis were nominally greater in the sigmoid and left colon and numerically greater in the ileum, right colon, transverse colon, and rectum among patients receiving UPA30 vs PBO (Table). Numerically greater rates of right colon, sigmoid and left colon, and rectum stenosis resolution occurred among patients receiving UPA15 vs PBO (Table). Nominally or numerically greater proportions of patients, with or without BL stenoses, achieved clinical remission and endoscopic response at week 52 with UPA30 and UPA15 vs PBO (Table).
| Table. Key Efficacy Outcomes |
| | Induction, Week 12
(U-EXCEL and U-EXCEED, pooled) | Maintenance, Week 52
(U-ENDURE) |
| | Intestinal Stenosisa | No Intestinal Stenosisb | Intestinal Stenosisa | No Intestinal Stenosisb |
| Variable | UPA
45 mg QD
n = 230 | PBO
n = 107 | UPA
45 mg QD
n = 444 | PBO
n = 240 | UPA
30 mg QD
n = 58 | UPA
15 mg QD
n = 60 | PBO
n = 59 | UPA
30 mg QD
n = 110 | UPA
15 mg QD
n = 109 | PBO
n = 106 |
Resolution of BL stenosisc by intestinal segment type, n/N (%)
Ileum
Right colon
Transverse colon
Sigmoid and left colon
Rectum | 63/109 (57.8)
29/75 (38.7)
21/27 (77.8)
28/41 (68.3)*
15/22 (68.2) | 23/52 (44.2)
18/41 (43.9)
6/12 (50.0)
4/12 (33.3)
6/11 (54.5) |
N/A |
N/A
| 4/21 (19.0)
7/19 (36.8)
5/8 (62.5)
7/8 (87.5)**
6/10 (60.0) | 5/30 (16.7)
6/19 (31.6)
2/7 (28.6)
5/10 (50.0)
1/4 (25.0) | 5/31 (16.1)
3/18 (16.7)
2/6 (33.3)
1/9 (11.1)
1/6 (16.7) |
N/A |
N/A
|
N/A |
Clinical remission, n (%)
CDAId
SF/APSe
Endoscopic responsef, n (%) |
89 (38.7)**
91 (39.6)***
93 (40.6)*** |
26 (24.3)
14 (13.1)
4 (3.8) |
210 (47.2)***
216 (48.6)***
178 (40.1)*** |
61 (25.5)
49 (20.4)
25 (10.4) |
21 (36.2)
21 (36.2)*
21 (36.9)*** |
19 (31.7)
16 (26.7)
11 (18.3) |
15 (25.4)
11 (18.6)
5 (8.5) |
59 (53.6)***
57 (51.8)***
46 (41.8)*** |
44 (40.4)***
44 (40.4)***
36 (32.7)*** |
10 (9.4)
13 (12.0)
7 (6.6) |
APS, abdominal pain score; BL, baseline; CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; NA, not applicable; PBO, placebo; QD, once daily; SES-CD, Simple Endoscopic Score for Crohn’s Disease; SF, stool frequency; UPA, upadacitinib.
aSES-CD presence of narrowing subscore > 0 at BL.
bSES-CD presence of narrowing subscore of 0 at BL.
cChange in SES-CD narrowing subscore from 3, 2, or 1 at BL to a subscore of 0 at end of the respective treatment period.
dCDAI < 150.
eAverage daily SF ≤ 2.8 and average daily APS ≤ 1.0, and both not greater than BL.
fDecrease in SES-CD > 50% from BL (or for patients with a BL SES-CD of 4, ³ 2-point reduction from BL), as scored by a central reviewer.
*P ≤ .05; **P ≤ .01; ***P ≤ .001 vs PBO. Resolution of BL stenosis P-values were calculated according to Fisher’s exact test of association. Clinical remission and endoscopic response P-values were calculated according to the Chi-square test. All P-values are nominal and not multiplicity adjusted. |
Conclusion
Among patients with moderately to severely active CD, UPA induction and maintenance treatment improved the narrowing component of BL luminal stenoses, and clinical and endoscopic outcomes for patients with or without stenoses.
References
- Bettenworth D, et al. Gut. 2019;68:1115–1126.
- Loftus E, et al. United European Gastroenterol J. 2022;10(S8):103.
- Colombel JF, et al. Gastroenterology. 2022;162(7):S-1394.
- Panés J, et al. Am J Gastroenterol. 2022;117:S10.
- RINVOQ. Summary of Product Characteristics. AbbVie Deutschland GmbH & Co. KG; 2023. Accessed 24 April 2023. https://www.ema.europa.eu/en/documents/product-information/rinvoq-epar-product-information_en.pdf
- RINVOQ. Summary of Product Characteristics. AbbVie Inc.; 2023. Accessed 27 March 2023. https://www.medicines.org.uk/emc/product/12830/smpc.
Disclosure
WR has served as a speaker and/or consultant and/or an advisory member for AbbVie, Amgen, AOP Orphan, Arena Pharmaceuticals, Astellas, Astra Zeneca, Bioclinica, Boehringer Ingelheim, Bristol Myers Squibb, Calyx, Celgene, Celltrion, Eli Lilly, Falk Pharma GmbH, Ferring, Janssen, Galapagos Medice, Gatehouse Bio Inc., Genentech, Gilead, Grünenthal, ICON, Index Pharma, Inova, Janssen, Landos Biopharma, Medahead, MedImmune, Microbiotica, Mitsubishi Tanabe Pharma Corporation, MSD, Roche, Novartis, OMass, Otsuka, Parexel, Periconsulting, Pharmacosmos, Pfizer, Pharmacosmos, Protagonist, Provention, Quell Therapeutics, Sandoz, Seres Therapeutics, Setpointmedical, Shire, Sigmoid, Sublimity, Takeda, Teva Pharma, Therakos, Theravance, and Zealand; and has received research funding from AbbVie, Janssen, MSD, Sandoz, Sanofi, and Takeda.
RA has served as a speaker or consultant, or received research grants from AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion Healthcare, Falk Foundation, Ferring, Galapagos, Gilead, InDex Pharmaceuticals, Janssen-Cilag, Kliniksa, Lilly, MSD Sharp & Dohme, Novartis, Pandion Therapeutics, Pfizer, Roche Pharma, Samsung Bioepsis, Takeda Pharma, Tillotts Pharma, and Viatris.
VJ has received consulting/advisory board fees from AbbVie, Alimentiv Inc, Arena Pharmaceuticals, Asieris, Bristol-Myers Squibb, Celltrion, Ferring, Fresenius Kabi, Galapagos, GSK, Genentech, Gilead, Janssen, Lilly, Merck, Mylan, Pandion, Pendopharm, Pfizer, Reistone Biopharma, Roche, Sandoz, Takeda, and Topivert; and speaker fees from, AbbVie, Ferring, Galapagos, Janssen, Pfizer, Shire, and Takeda.
JP has received financial support for research from AbbVie and Pfizer; lecture fees from AbbVie, Ferring, Janssen, and Takeda; and consultancy fees from AbbVie, Arena Pharmaceuticals, Athos, Boehringer Ingelheim, Celltrion, Ferring, Galapagos, Genentech, GSK, Janssen, Mirum, Morphic, Origo, Pandion, Pfizer, Protagonist, Revolo, Robarts, Roche, Takeda, Theravance, and Wassermann.
EVL has received consultancy honoraria from AbbVie, Alvotech, Amgen, Arena, Avalo Therapeutics, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Fresenius Kabi, Genentech, Gilead, GlaxoSmithKline, Gossamer Bio, Iota Biosciences, Iterative Scopes, Janssen, Morphic, Ono Pharma, Pfizer, Protagonist, Scipher Medicine, Sun Pharma, Surrozen, Takeda, and UCB; and has received research support from AbbVie, Bristol-Myers Squibb, Celgene, Genentech, Gilead, Gossamer Bio, Janssen, Pfizer, Receptos, Robarts Clinical Trials, Takeda, Theravance, and UCB.
SH reports no disclosures.
MTA has received consulting fees from Arena AbbVie, Arena Pharmaceuticals, Bristol-Myers Squibb, Celsius, Eli Lilly Pharmaceuticals, Gilead, Janssen, Microba, Pfizer, Prometheus Biosciences, UCB Biopharma, WebMD Global, and Focus Medical.
FR has received consulting/advisory board fees from Adiso, Adnovate, Agomab, Allergan, AbbVie, Arena, Astra Zeneca, Boehringer-Ingelheim, Celgene/BMS, CDISC, Celsius, Cowen, Ferring, Galapagos, Galmed, Genentech, Gilead, Gossamer, Granite, Guidepoint, Helmsley, Horizon Therapeutics, Image Analysis Limited, Index Pharma, Landos, Janssen, Koutif, Mestag, Metacrine, Mopac, Morphic, Organovo, Origo, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Sanofi, Surmodics, Surrozen, Takeda, Techlab, Teva, Theravance, Thetis, UCB, Ysios, and 89Bio.
VPR, EM, ED, SIA, and AG are employees or contractors of AbbVie and may own stock and/or options.
JFC has received research grants from AbbVie, Janssen, and Takeda; payment for lectures from AbbVie, Amgen, Ferring, Shire, and Takeda; consulting fees from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enterome, Ferring, Genentech, Janssen, Medimmune, Merck, Novartis, Pfizer, Protagonist Therapeutics, Sandoz, Second Genome, Seres Therapeutics, Shire, Takeda, Theradiag, and Theravance; and holds stock options in Genfit and Intestinal Biotech Development.
Funding
AbbVie Inc. funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the abstract. All authors had access to relevant data and participated in the drafting, review, and approval of this abstract. No honoraria or payments were made for authorship. AbbVie and authors thank all the trial investigators and the patients who participated in this clinical trial. Medical writing support was provided by Tracy Wetter, PhD, and Akua Adu-Boahene, MD, MPH, of JB Ashtin, and funded by AbbVie.
