Introduction
Per the STRIDE II consensus, mucosal healing and normalization of quality of life are considered long-term treatment goals in ulcerative colitis (UC). Results from Phase 2/3 induction and maintenance trials (U‑ACHIEVE and U‑ACCOMPLISH) showed that patients with moderately to severely active UC treated with upadacitinib (UPA) had significant improvements in these outcomes individually. However, there is a need to understand better the extent to which patients treated with UPA can achieve both treatment goals jointly within one year of maintenance therapy.
Aims & Methods
In the U-ACHIEVE and U-ACCOMPLISH trials, patients with a clinical response after 8-week induction treatment with UPA 45 mg QD were re-randomized 1:1:1 to UPA 15 mg QD, UPA 30 mg QD or placebo (PBO) QD. Long-term treatment goals were determined based on the percentage of patients who achieved the composite endpoint of endoscopic remission (ER), complete symptom resolution (CSR), and Inflammatory Bowel Disease Questionnaire (IBDQ) remission at the end of induction week 8 and maintenance week 52. ER was defined as an endoscopic score of 0; CSR as stool frequency subscore ≤1, rectal bleeding subscore of 0, no bowel urgency, no abdominal pain; and IBDQ remission as IBDQ total score ≥170. The response rate between PBO and UPA was calculated using the Cochran-Mantel-Haenszel test, adjusting for baseline characteristics. The percentage of patients who maintained vs achieved ER+CSR+IBDQ remission during maintenance week 52 was also calculated.
Results
At induction week 8, a significantly greater percentage of patients treated with UPA 45 mg achieved ER+CSR+IBDQ remission vs PBO (6.4% vs 0.9%, respectively, p<0.001, Table). At maintenance week 52, the percentage of induction responders who achieved ER+CSR+IBDQ remission reached 18.3% with UPA 30 mg and 13.1% with UPA 15 mg vs 4.5% with PBO (p<0.001). Of the patients who achieved ER+CSR+IBDQ remission by week 0 of maintenance, 42.1% (8/19), 23.5% (4/17), and 22.2% (4/18) in the UPA 30 mg, UPA 15 mg, and PBO groups, respectively, sustained the composite endpoint at week 52. Among patients who did not achieve this composite endpoint by week 0 of maintenance, 16.2% (35/214), 12.3% (26/208), and 2.9% (6/205) in the UPA 30 mg, UPA 15 mg, and PBO groups, respectively, achieved it at week 52.
Conclusion
Results of this post hoc analysis indicate that the rigorous, long-term treatment goals of ER+CSR+IBDQ remission can be achieved with UPA in some patients with moderately to severely active UC by week 8 of induction. By maintenance week 52, nearly one in five patients treated with UPA 30 mg and approximately one in eight patients treated with UPA 15 mg achieved the stringent target. Sustained maintenance treatment with UPA results in an increasing proportion of patients achieving or maintaining these long-term goals of treatment after only one year.
| Percentage of patients who achieved composite endpoint of endoscopic remission and complete symptom resolution and IBDQ remission at week 8 of induction and week 52 of maintenance |
| | Responder, n/N (%) | Adjusted rate diffa, % (95% CI) |
| Induction week 8 |
|
|
| PBO | 3/328 (0.9) | 5.5 (3.3, 7.7)* |
| UPA 45 mg QD | 42/660 (6.4) |
|
| Maintenance week 52b |
|
|
| PBO | 10/223 (4.5) |
|
| UPA 15 mg QD | 30/225 (13.1) | 8.5 (3.4, 13.7)* |
| UPA 30 mg QD | 43/233 (18.3) | 13.7 (8.1, 19.3)* |
*p ≤ 0.001 for UPA vs PBO.
aAt week 8, the adjusted response rate between PBO and UPA 45 mg was calculated using the Cochran-Mantel-Haenszel (CMH) test adjusting for baseline corticosteroid use, Adapted Mayo score, and inadequate response to biologic (Bio-IR) status. At week 52, the rate difference between PBO and UPA 30 mg and 15 mg was calculated using CMH adjusted for Bio-IR status at induction baseline, and clinical remission status and corticosteroid use at week 0 of maintenance. Calculations were based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or non-responder imputation if there were no missing data due to COVID-19. bThe maintenance study population comprises patients who achieved clinical response after UPA 45 mg QD 8-week induction treatment in the Phase 2 and 3 programs and were enrolled in the 52-week maintenance treatment period. CI, confidence intervals; IBDQ, Inflammatory Bowel Disease Questionnaire (IBDQ), PBO, placebo; QD, once daily; UPA, upadacitinib. |
Disclosure
J Panes received financial support for research from AbbVie and Pfizer; consultancy fees/honorarium from AbbVie, Arena, Athos, Atomwise, Boehringer Ingelheim, Celgene, Celsius, Celltrion, Ferring, Galapagos, Genentech/Roche, GlaxoSmithKline, Janssen, Mirum, Morphic, Nestlé, Origo, Pandion, Pfizer, Progenity, Prometheus, Protagonist, Revolo, Robarts, Sanofi, Takeda, Theravance and Wasserman; reports payment for lectures including service on speaker bureau from Abbott, Ferring, Janssen, Pfizer and Takeda; and reports payment for development of educational presentations from Abbott, Janssen, Pfizer Roche and Takeda.
R Panaccione has received consulting fees, speaker fees, research/educational support from, and/or advisory board member for AbbVie, Abbott, Alimentiv (formerly Robarts), Amgen, Arena, AZ, BI, BMS, Celgene, Celltrion, Cosmos, Eisai, Elan, Ferring, Galapagos, Genentech, Gilead, GSK, Janssen, Lilly, Merck, Mylan, Oppilan, Pandion, Pfizer, Progenity, Protagonist, Roche, Satisfai, Sandoz, Schering-Plough, Shire, Sublimity, Theravance, Takeda, and UCB.
MC Dubinsky has received consultancy fees from AbbVie, Allergan, Amgen, BI, Celgene, Gilead, Janssen, Lilly, Pfizer, Prometheus, Roche, Takeda, and UCB; and is a shareholder of Trellus Health.
Y Ishiguro has received a research grant from Mitsubishi Tanabe Pharmaceutical; speaker/consultation fees from AbbVie, Janssen, Daiichi-Sankyo, Kissei Pharmaceutical and EA Pharma.
J Tran is currently a contractor at AbbVie and a funded PhD candidate at the University of Washington.
D Ilo, J Eccleston, Y Sanchez Gonzalez are full-time employees of AbbVie and may hold AbbVie stock and/or stock options.
B Feagan is a consultant, member of the speakers bureau, and/or member of the scientific advisory board for AbbVie, AbolerIS, AgomAB, Allianthera, Amgen, AMT, AnaptysBio, Arena, Atomwise, Avoro Capital Advisors, Axio, BI, BioJamp, Biora, Boxer, Celgene/BMS, Celsius, Connect BioPharma, Cytoki, Disc Medicine, Duality, EcoR1, Equillium, Ermium, First Wave, First Word Group, Galapagos, Galen Atlantica, Genentech/Roche, Gilead, Gossamer, GSK, Hinge Bio, Hot Spot, Imhotex, Immunic, Index, JAKAcademy, Janssen, Japan Tobacco, Kaleido, Landos, Leadiant, L.E.K. Consulting, Lenczner Slaght, LifeSci Capital, Lilly, Lument AB, Millennium, MiroBio, Morgan Lewis, Morphic, Mylan, OM Pharma, Origo BioPharma, Orphagen, Pandion, Pendopharm, Pfizer, Prometheus, Play to Know AG, Progenity, Protagonist, PTM, Q32 Bio, Rebiotix, REDX, Roche, Sandoz, Sanofi, Seres, Silverback, Surrozen, Takeda, Teva, Thelium, Tigenix, Tillotts, Ventyx, VHSquared, Viatris, Ysios, Ysopia, and Zealand; is a stock shareholder for Gossamer; is an employee of Western University; and is Senior Scientific Director of Alimentiv Inc.
