Introduction
Upadacitinib, an oral, selective, and reversible Janus kinase inhibitor (JAKi), vedolizumab (VEDO), an α4β7 integrin monoclonal antibody, ustekinumab (UST), an IL-12/23 inhibitor, and tofacitinib (TOFA), a pan JAKi, are all approved therapies for patients with moderately to severely active ulcerative colitis (UC). Evidence on their comparative efficacy and safety during maintenance are lacking.
Aims & Methods
Separate placebo (PBO)-anchored matching-adjusted indirect comparisons (MAIC) of the efficacy and safety of UPA vs VEDO, UST, and TOFA during maintenance were conducted. Induction responders were rerandomized in the phase 3 maintenance studies to oral UPA 15 or 30 mg once daily or PBO in U-ACHIEVE, VEDO 300 mg intravenous or PBO in GEMINI-1, UST 90 mg subcutaneous or PBO in UNIFI, and oral TOFA 5 mg twice daily or PBO in OCTAVE Sustain. Efficacy outcomes at maintenance weeks 44(UST)/46(VEDO)/52(UPA/ TOFA) were adjusted by the likelihood of induction clinical response to assess treat-through efficacy in the intent-to-treat population. Outcomes included clinical response (decrease in Full Mayo score [FMS] ≥3 points and ≥30% and decrease in rectal bleeding score [RBS] of ≥1 or an absolute RBS of 0 or 1), clinical remission (FMS ≤2 with no subscore >1, plus RBS of 0 for UPA vs TOFA [remission]), and endoscopic improvement (EI, endoscopic subscore 0 or 1). Safety outcomes included adverse events (AEs), serious AEs (SAEs), and AEs leading to discontinuation (except for UPA vs VEDO). Select baseline characteristics from the UPA trial were weighted to match the VEDO, UST, or TOFA trials, separately. Numbers needed to treat or harm (NNT or NNH) were calculated as the inverse of the difference in proportions of patients demonstrating each outcome between UPA and VEDO, UST, or TOFA to assess benefit-risk.
Results
Greater proportions of patients receiving UPA 15 mg vs VEDO demonstrated clinical response, clinical remission, and EI (difference in proportions>0; p<0.05) and achieved clinical response and EI with UPA vs TOFA (p<0.05). Significantly greater proportions of patients receiving UPA 30 mg vs VEDO, UST, or TOFA demonstrated all efficacy outcomes (difference in proportions>0; p<0.05), with NNTs <8.7. Difference in proportions of AEs, SAEs, and AEs leading to discontinuation were small and not statistically different between both doses of UPA and the studied comparator therapies.
Conclusion
After 1 year of maintenance, greater clinical efficacy and similar safety was observed with UPA vs VEDO, UST, or TOFA in patients with active UC, suggesting a favourable benefit-risk profile of UPA vs other advanced therapies. Differences in trial design, such as variable timing of rerandomization and dosages and assessment times, and endpoint definitions may persist and impact responder profiles.
| Efficacya Outcome | Treatment comparisons (UPA15 vs comparator) | Proportionb | Difference in proportionsc | NNTd | Treatment comparisons (UPA30 vs comparator) | Proportionb | Difference in proportionsc | NNTd |
| Clinical response | UPA15/ PBO VEDO300/ PBO UPA15 vs VEDO300 UPA15/ PBO UST90/ PBO UPA15 vs UST90 UPA15/ PBO TOFA5/ PBO UPA15 vs TOFA5 | 54.3%/ 5.6% 26.6%/ 6.1% —
44.6%/ 4.6% 43.9%/ 14.0% —
39.9%/ 3.8% 29.7%/ 6.2% — | 0.488
0.206
0.282***
0.400
0.299
0.101
0.361
0.234
0.127** | 2.1
4.9
3.6
2.6
3.4
10.0
2.8
4.3
7.9 | UPA30/ PBO VEDO300/ PBO UPA30 vs VEDO300 UPA30/ PBO UST90/ PBO UPA30 vs UST90 UPA30/ PBO TOFA5/ PBO UPA30 vs TOFA5 | 57.6%/ 5.6% 26.6%/ 6.1% —
52.4%/ 4.6% 43.9%/ 14.0% —
52.8%/ 3.8% 29.7%/ 6.2% — | 0.520
0.206
0.314***
0.478
0.299
0.178***
0.490
0.234
0.255*** | 2.0
4.9
3.2
2.1
3.4
5.7
2.1
4.3
4.0 |
| Clinical remission (or remission for UPA vs TOFA) | UPA15/ PBO VEDO300/ PBO UPA15 vs VEDO300 UPA15/ PBO UST90/ PBO UPA15 vs UST90 UPA15/ PBO TOFA5/ PBO UPA15 vs TOFA5 | 37.5%/ 4.3% 19.7%/ 4.1% —
31.2%/ 2.9% 27.0%/ 7.5% —
25.3%/ 2.2% 19.8%/ 3.4% — | 0.332
0.156
0.176*
0.284
0.195
0.088
0.231
0.163
0.067 | 3.1
6.4
5.7
3.6
5.2
11.4
4.4
6.2
14.9 | UPA30/ PBO VEDO300/ PBO UPA30 vs VEDO300 UPA30/ PBO UST90/ PBO UPA30 vs UST90 UPA30/ PBO TOFA5/ PBO UPA30 vs TOFA5 | 43.3%/ 4.3% 19.7%/ 4.1% —
34.0%/ 2.9% 27.0%/ 7 .5% —
32.5%/ 2.2% 19.8%/ 3.4% — | 0.390
0.156
0.233**
0.311
0.195
0.116*
0.302
0.163
0.139*** | 2.6
6.4
4.3
3.3
5.2
8.7
3.4
6.2
7.3 |
| EI | UPA15/ PBO VEDO300/ PBO UPA15 vs VEDO300 UPA15/ PBO UST90/ PBO UPA15 vs UST90 UPA15/ PBO TOFA5/ PBO UPA15 vs TOFA5 | 48.9%/ 4.5% 24.3%/ 5.0% —
35.8%/ 3.2% 31.6%/ 9.0% —
31.1%/ 2.6% 21.5%/ 4.0% — | 0.444
0.193
0.252***
0.326
0.226
0.100
0.285
0.175
0.110* | 2.3
5.2
4.0
3.1
4.5
10.1
3.6
5.8
9.1 | UPA30/ PBO VEDO300/ PBO UPA30 vs VEDO300 UPA30/ PBO UST90/ PBO UPA30 vs UST90 UPA30/ PBO TOFA5/ PBO UPA30 vs TOFA5 | 51.6%/ 4.5% 24.3%/ 5.0% —
41.7%/ 3.2% 31.6%/ 9.0% —
42.0%/ 2.6% 21.5%/ 4.0% — | 0.471
0.193
0.278***
0.385
0.226
0.159**
0.394
0.175
0.219*** | 2.2
5.2
3.6
2.6
4.5
6.3
2.6
5.8
4.6 |
| Safetye Outcome | Treatment comparisons (UPA15 vs comparator) | Proportionb | Difference in proportionsc | NNHd | Treatment comparisons (UPA30 vs comparator) | Proportionb | Difference in proportionsc | NNHd |
| AEs | UPA15/ PBO VEDO300/ PBO UPA15 vs VEDO300 UPA15/ PBO UST90/ PBO UPA15 vs UST90 UPA15/ PBO TOFA5/ PBO UPA15 vs TOFA5 | 79.7%/ 72.1% 82.0%/ 84.0% —
78.4%/ 77.2% 77.3%/ 78.9% —
78.6%/ 80.3% 72.2%/ 75.3% — | 0.076
–0.020
0.096
0.013
–0.016
0.029
–0.017
–0.031
0.014 | 13.1
–50.0
10.3
80.0
–62.4
35.0
–59.1
–32.2
70.9 | UPA30/ PBO VEDO300/ PBO UPA30 vs VEDO300 UPA30/ PBO UST90/ PBO UPA30 vs UST90 UPA30/ PBO TOFA5/ PBO UPA30 vs TOFA5 | 72.6%/ 72.1% 82.0%/ 84.0% —
71.1%/ 77.2% 77.3%/ 78.9% —
77.0%/ 80.3% 72.2%/ 75.3% — | 0.005
–0.020
0.025
–0.061
–0.016
–0.045
–0.033
–0.031
–0.002 | 204.0
–50.0
40.1
–16.3
–62.4
–22.0
–30.3
–32.2
–500.0 |
| SAEs | UPA15/ PBO VEDO300/ PBO UPA15 vs VEDO300 UPA15/ PBO UST90/ PBO UPA15 vs UST90 UPA 15/ PBO TOFA 5/ PBO UPA15 vs TOFA5 | 11.1%/ 11.6% 8.0%/ 16.0% —
7.1%/ 13.8% 8.5%/ 9.7% —
7.8%/ 10.6% 5.1%/ 6.6% — | –0.006
–0.080
0.075
–0.067
–0.012
–0.055
–0.028
–0.015
–0.013 | –181.8
–12.5
13.4
–14.9
–83.3
–18.1
–35.5
–66.6
–76.3 | UPA30/ PBO VEDO300/ PBO UPA30 vs VEDO300 UPA30/ PBO UST90/ PBO UPA30 vs UST90 UPA30/ PBO TOFA5/ PBO UPA30 vs TOFA5 | 1.0%/ 11.6% 8.0%/ 16.0% —
4.3%/ 13.8% 8.5%/ 9.7% —
4.2%/ 10.6% 5.1%/ 6.6% — | –0.106
–0.080
–0.026
–0.094
–0.012
–0.082
–0.064
–0.015
–0.049 | –9.4
–12.5
–38.1
–10.5
–83.3
–12.1
–15.7
–66.6
–20.6 |
| AEs leading to discontinuationf | UPA15/ PBO VEDO300/ PBO UPA15 vs VEDO300 UPA15/ PBO UST90/ PBO UPA15 vs UST90 UPA15/ PBO TOFA5/ PBO UPA15 vs TOFA5 | N/A
N/A
N/A
2.8%/ 12.3% 2.8%/ 11.4% —
4.2%/ 9.8% 9.1%/ 18.7% — | N/A
N/A
N/A
–0.095
–0.086
–0.009
–0.055
–0.096
0.041 | N/A
N/A
N/A
-10.5
-11.6
–116.2
–18.0
–10.4
24.6 | UPA30/ PBO VEDO300/ PBO UPA30 vs VEDO300 UPA30/ PBO UST90/ PBO UPA30 vs UST90 UPA30/ PBO TOFA5/ PBO UPA30 vs TOFA5 | N/A
N/A
N/A
3.9%/ 12.3% 2.8%/ 11.4% —
4.9%/ 9.8% 9.1%/ 18.7% — | N/A
N/A
N/A
–0.084
–0.086
0.002
–0.049
–0.096
0.047 | N/A
N/A
N/A
-11.9
-11.6
416.6
–20.5
–10.4
21.0 |
| aFor efficacy outcomes, treat-through results are calculated as: (induction MAIC response rate) x (maintenance MAIC efficacy rate). Standard errors were calculated as square root of the variance for product of two independent variables (i.e., induction MAIC response rate and maintenance MAIC efficacy rate). bUPA data are individual patient-level results while VEDO, UST, or TOFA data are aggregated published results. Core baseline characteristics used in the weighting included age, gender, extent and duration of disease, total Mayo score, and prior UC medication/biologic usage. cDifference in proportions between advanced therapies (UPA arms vs comparators) are shown in bold; otherwise, differences are shown vs placebo. dPositive (negative) NNTs denote greater (lower) efficacy of UPA vs comparator, and positive (negative) NNHs denote greater (lower) safety risk of UPA vs comparator. eBroad safety outcomes are included because they were collected consistently across clinical trials. fData were not available in the VEDO GEMINI-1 maintenance phase 3 trial. P‑value equals *<0.05, **≤0.01, ***<0.001. AEs, adverse events; EI, endoscopic improvement; N/A, not applicable; NNH, number needed to harm; NNT, number needed to treat; PBO, placebo; SAEs, serious adverse events; UPA15, upadacitinib 15 mg; UPA30, upadacitinib 30 mg; UST90, ustekinumab 90 mg; TOFA5, tofacitinib 5 mg; VEDO300, vedolizumab 300 mg. |
Disclosure
AbbVie funded this study and participated in the study design; study research; collection, analysis and interpretation of data; and writing, reviewing, and approving of this publication. All authors had access to the data, and participated in the development, review, and approval, and in the decision to submit this publication. No honoraria or payments were made for authorship. Medical writing services provided by Brandy Menges, PhD of Fishawack Facilitate Ltd, part of Fishawack Health, and funded by AbbVie.
Walter Reinisch has received support for speaker, consultant, and/or advisory board member for Abbott, AbbVie, Aesca, Algernon, Amgen, AM Pharma, AMT, AOP Orphan, Aptalis, Arena, Astellas, Avaxia, AZ, BI, Bioclinica, Biogen IDEC, BMS, Celgene, Cellerix, Celltrion, Centocor, Chemocentryx, Covance, Danone Austria, DSM, Elan, E&Y, Falk, Ferring, Galapagos, Genentech, Gilead, Grünenthal, ICON, Immundiagnostik, Index, Inova, Janssen, J&J, Kyowa Hakko Kirin, Lilly, Lipid, LivaNova, Mallinckrodt, Medahead, MedImmune, Millennium, Mitsubishi Tanabe, MSD, Nash, Nestle, Nippon Kayaku, Novartis, Ocera, OMass, Otsuka, Parexel, PDL, Periconsulting, Pharmacosmos, Philip Morris Institute, Pfizer, PLS Education, P&G, Prometheus, Protagonist, Provention, Robarts Clinical Trials, Roland Berger, Sandoz, Schering-Plough, Second Genome, Seres, Setpointmedical, Sigmoid, Sublimity, Takeda, Therakos, Theravance, Tigenix, UCB, Vifor, Yakult, Zealand, Zyngenia, and 4SC.
Gil Y. Melmed is a consultant for AbbVie, Arena, BI, BMS, Ferring, Fresenius Kalbi, Genentech, Gilead, Lilly, Janssen, Pfizer, Prometheus, Samsung Bioepis, Takeda, and Techlab.
Hiroshi Nakase reports receiving personal fees from Abbvie Inc., Kissei Pharmaceutical Co., Ltd., KYORIN Pharmaceutical Co., Ltd, Mitsubishi Tanabe Pharma Corporation, Janssen Pharmaceutical K.K, Takeda Pharmaceutical Co., Ltd., Pfizer Japan Inc., Celgene K.K., EA Pharma Co., Ltd., Zeria Pharmaceutical CO., Ltd., Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., D Daiichi Sankyo Co., Ltd JIMRO Co., Ltd., as well as grants for commissioned/joint research from Hoya Group Pentax Medical, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd.
Jakob Seidelin has received research grants from Takeda and Janssen, and is a national coordinator of studies from AbbVie, Arena Pharmaceuticals, Ely Lilly, and Boehringer Ingelheim.
Christopher Ma has received consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma Inc, BioJAMP, Bristol Myers Squibb, Celltrion, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Pendopharm, Pfizer, Prometheus Biosciences Inc., Roche, Sanofi, Takeda, Tillotts Pharma; speaker's fees from AbbVie, Amgen, AVIR Pharma Inc, Alimentiv, Bristol Myers Squibb, Ferring, Fresenius Kabi, Janssen, Organon, Pendopharm, Pfizer, Takeda; royalties from Springer Publishing; research support from Ferring, Pfizer.
Si Xuan, Dapo Ilo, Lani Wegrzyn, Gwen Levy, Yuri Sanchez Gonzalez are employees of AbbVie and may own stock or options.
Jacinda Tran is a funded PhD student at the University of and contractor for AbbVie.
Remo Panaccione has received support for consulting, speaker, advisory board member for, and/or research/educational support 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, UCB.