Introduction
The efficacy and safety of upadacitinib (UPA), an oral, reversible Janus kinase (JAK) inhibitor approved for the treatment of moderately to severely active Crohn’s disease (CD),1.2 has been demonstrated in two phase 3 induction studies (U-EXCEL, NCT033458493; U-EXCEED, NCT033458364) and a phase 3 maintenance study (U-ENDURE, NCT033458235). An association between shorter disease duration and improved outcomes has been shown in post hoc analyses of clinical trial data with other advanced CD therapies.6,7 We therefore conducted a post hoc analysis of data from these phase 3 UPA studies to assess the potential impact of CD duration on UPA efficacy.
Aims & Methods
Patients in the induction studies were randomized 2:1 to receive UPA 45 mg (UPA45) or placebo (PBO) once daily for 12 weeks.2,3 Patients achieving clinical response per stool frequency and/or abdominal pain score (SF/APS) criteria were re-randomized 1:1:1 in the maintenance study to UPA 30 mg (UPA30), UPA 15 mg (UPA15), or PBO once-daily for 52 weeks.4 Efficacy was evaluated in patient subgroups stratified by CD duration at baseline (< 2 years, 2–5 years, >5–10 years, and >10 years). Endpoints evaluated at week 12 (induction) and week 52 (maintenance) included achievement of clinical remission (per average daily very soft/liquid SF/APS and per Crohn’s Disease Activity Index [CDAI]), normalization of fecal calprotectin and high-sensitivity C-reactive protein levels for patients with elevated baseline levels, endoscopic response, endoscopic remission, and mucosal healing.
Results
Baseline patient and disease characteristics were generally similar across CD duration subgroups during induction (N = 1021). UPA45 demonstrated nominally greater improvement vs PBO in efficacy endpoints across most CD duration subgroups at week 12 (Table). UPA45-treated patients with a shorter disease duration had numerically greater endoscopic improvement vs patients with longer disease duration, and nominally greater endoscopic improvement vs patients receiving PBO at week 12 (Table). Further, the clinical remission rate per CDAI at week 12 was numerically higher with UPA45 vs PBO in patients with CD duration < 2 years, and was nominally higher vs PBO in other CD duration subgroups (Table). Consistent with induction outcomes, UPA30 and UPA15 demonstrated nominally or numerically greater improvement in efficacy endpoints vs PBO regardless of disease duration at week 52 (Table); there was also a general trend towards greater improvements in efficacy outcomes in patients with a shorter disease duration.
Table. Efficacy Outcomes by Baseline CD Duration During Induction and Maintenance Studies
Endpoint by CD duration
at baseline, % (n/N) | Induction, Week 12
(U-EXCEL and U-EXCEED, pooled) | Maintenance, Week 52
(U-ENDURE) |
UPA 45 mg QD
n = 674 | PBO
n = 347 | UPA 30 mg QD
n = 168 | UPA 15 mg QD
n = 169 | PBO
n = 165 |
Clinical remission per SF/APSa
< 2 y
2–5 y
> 5–10 y
> 10 y | 51.0 (52/102)**
58.4 (78/133)***
50.6 (85/168)***
34.0 (92/271)*** | 25.5 (14/55)
23.6 (17/72)
19.5 (16/82)
11.6 (16/138) | 50.0 (10/20)
58.5 (24/41)***
49.0 (25/51)**
33.9 (19/56)** | 51.9 (14/27)
39.3 (11/28)**
28.6 (12/42)
31.9 (23/72)** | 31.6 (6/19)
10.5 (4/38)
15.8 (6/38)
11.1 (8/70) |
Clinical remission per CDAIb
< 2 y
2–5 y
> 5–10 y
> 10 y | 46.1 (47/102)
49.6 (66/133)**
48.0 (81/168)**
38.8 (105/271)*** | 36.4 (20/55)
27.8 (20/72)
29.3 (24/82)
16.8 (23/138) | 50.0 (10/20)*
61.0 (25/41)***
49.0 (25/51)***
35.7 (20/56)** | 55.6 (15/27)**
35.7 (10/28)
28.6 (12/42)
36.1 (26/72)** | 15.8 (3/19)
15.8 (6/38)
13.2 (5/38)
15.6 (11/70) |
FCP normalizationc
< 2 y
2–5 y
> 5–10 y
> 10 y | 40.8 (31/76)***
38.1 (40/105)***
28.5 (35/123)**
34.9 (66/189)*** | 7.3 (3/41)
7.3 (4/55)
9.7 (6/62)
8.1 (8/99) | 33.3 (5/15)*
37.8 (14/37)***
31.4 (11/35)***
34.3 (12/35)*** | 36.4 (8/22)*
20.8 (5/24)*
20.6 (7/34)**
22.2 (12/54)** | 0 (0/13)
0 (0/28)
0 (0/32)
2.0 (1/50) |
hs-CRP normalizationd
< 2 y
2–5 y
> 5–10 y
> 10 y | 53.6 (37/69)***
57.6 (53/92)***
49.6 (60/121)***
46.1 (70/152)*** | 9.1 (3/33)
4.3 (2/47)
11.3 (6/53)
7.7 (6/78) | 38.9 (7/18)
59.4 (19/32)***
20.6 (7/34)**
46.7 (14/30)*** | 70.0 (14/20)**
23.8 (5/21)**
21.2 (7/33)**
26.1 (12/46)* | 12.5 (1/8)
0 (0/27)
0 (0/31)
5.3 (2/38) |
Endoscopic responsee
< 2 y
2–5 y
> 5–10 y
> 10 y | 61.8 (63/102)***
48.1 (64/133)***
36.4 (61/168)***
30.7 (83/271)*** | 14.5 (8/55)
11.1 (8/72)
7.3 (6/82)
5.1 (7/138) | 45.0 (9/20)
53.7 (22/41)***
41.2 (21/51)***
27.5 (15/56)*** | 53.1 (14/27)*
17.9 (5/28)
21.4 (9/42)*
25.4 (18/72)*** | 21.1 (4/19)
10.5 (4/38)
2.6 (1/38)
4.3 (3/70) |
Endoscopic remissionf
< 2 y
2–5 y
> 5–10 y
> 10 y | 40.2 (41/102)***
26.3 (35/133)***
26.8 (45/168)***
15.5 (42/271)*** | 10.9 (6/55)
5.6 (4/72)
4.9 (4/82)
2.2 (3/138) | 40.0 (8/20)
39.0 (16/41)***
21.6 (11/51)**
23.3 (13/56)** | 30.1 (8/27)
10.7 (3/28)
19.0 (8/42)**
18.1 (13/72)* | 21.1 (4/19)
2.6 (1/38)
0 (0/38)
5.8 (4/70) |
Mucosal healingg
< 2 y
2–5 y
> 5–10 y
> 10 y | 37.3 (38/102)***
23.4 (31/133)***
19.2 (32/167)***
15.0 (40/269)*** | 7.3 (4/55)
2.8 (2/71)
3.7 (3/82)
0 (0/137) | 35.0 (7/20)
34.1 (14/41)***
17.6 (9/51)*
18.2 (10/56)* | 22.3 (6/27)
14.3 (4/28)*
14.6 (6/41)
8.7 (6/71) | 10.5 (2/19)
0 (0/38)
2.6 (1/38)
4.4 (3/69) |
APS, abdominal pain score; CD, Crohn’s disease; CDAI, Crohn’s disease activity index; FCP, fecal calprotectin; hs-CRP, high-sensitivity C-reactive protein; PBO, placebo; QD, once daily; SES-CD, Simple Endoscopic Score for Crohn’s Disease; SF, stool frequency; UPA, upadacitinib; y, years.
aAverage daily SF ≤ 2.8 and average daily APS ≤ 1.0, and both not greater than baseline.
bCDAI < 150.
cFCP normalization to ≤ 250 mg/kg among patients with elevated baseline levels.
dhs-CRP normalization to ≤ 5 mg/L, among patients with elevated baseline levels.
eDecrease in SES-CD > 50% from baseline (or for patient with a baseline SES-CD of 4, ³ 2-point reduction from baseline) .
fSES-CD ≤ 4 and ³ 2-point reduction from baseline and no subscore > 1 in any individual variable.
gSES-CD ulcerated surface subscore of 0.
*P ≤ .05; **P ≤ .01; ***P ≤ .001 vs PBO. All P-values are nominal and not multiplicity adjusted. |
Conclusion
Regardless of disease duration, UPA demonstrated positive clinical and endoscopic outcomes in patients with moderately to severely active CD. Achievement of endoscopic endpoints was numerically higher in patients with shorter vs longer duration of CD, suggesting initiation of UPA earlier in the disease course may lead to better outcomes for patients.
References
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- RINVOQ. Summary of Product Characteristics. AbbVie Inc.; 2023. Accessed 27 March 2023. https://www.medicines.org.uk/emc/product/12830/smpc.
- Loftus E, et al. United European Gastroenterol J. 2022;10(S8):103.
- Colombel J-F, et al. Gastroenterology. 2022;162(7):S-1394.
- Panés J, et al. Am J Gastroenterol. 2022;117:S10.
- Faleck DM, et al. Clin Gastroenterol Hepatol. 2019;17(12):2497–2505.
- Peyrin-Biroulet L, et al. J Crohn's Colitis. 2022;16(Suppl 1):i045–i048.
Disclosure
RCU has served as an advisory board member or consultant for AbbVie, Bristol-Myers Squibb, Janssen, Pfizer, and Takeda; received research support from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly, and Pfizer; and is funded by a National Institutes of Health (NIH) K23 Career Development Award K23KD111995-01A1.
LP-B has received personal fees from AbbVie, Allergan, Alma, Amgen, Applied Molecular Transport, Arena, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Enterome, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Hikma, InDex Pharmaceuticals, Inotrem, Janssen, Lilly, MSD, Mylan, Nestle, Norgine, Oppilan Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Pfizer, Pharmacosmos, Roche, Samsung Bioepis, Sandoz, Sterna, Sublimity Therapeutics, Takeda, Theravance, Tillots, and Vifor; research grants from AbbVie, Fresenius Kabi, MSD, and Takeda; and stock options from CTMA.
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.
EJL has received research grants from Janssen, Pfizer, and Takeda; educational grants from AbbVie, Janssen, MSD, and Takeda; speaker fees from AbbVie, Falk, Ferring, Hospira, Janssen, MSD, Pfizer, and Takeda; served on advisory boards for AbbVie, Arena, Celgene, Ferring, Galapagos, Gilead, Hospira, Janssen, MSD, Pfizer, and Takeda; and served as a consultant for AbbVie.
MF has received financial support for research from AbbVie, Amgen, Biogen, EG, Janssen, Pfizer, Takeda and Viatris; consultancy fees from AbbVie, Agomab Therapeutics, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Janssen-Cilag, Medtronic, MSD, Pfizer, Regeneron, Samsung Bioepis, Sandoz, Takeda, and Thermo Fisher Scientific; and speaker fees from AbbVie, Amgen, Biogen, Boehringer Ingelheim, Falk, Ferring, Janssen-Cilag, Lamepro, MSD, Pfizer, Sandoz, Takeda, Truvion Healthcare and Viatris.
TM has received grants and honoraria from EA Pharma, AbbVie, Pfizer, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Nippon Kayaku Co., and Zeria Pharmaceutical Co; honoraria from Kyorin Pharmaceutical Co., JIMRO Co., Nichi-lko Pharmaceutical Co., and Takeda; and grants from Daiichi-Sankyo.
CD, APL, VPR, ED, SIA, and AG are employees or contractors of AbbVie, and may own AbbVie stock and/or stock options.
RP has received consultancy and/or speaking honoraria from Abbott, AbbVie, Abbivax, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Viatris, Ventyx, and UCB.
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.
