In a poster presented by Panaccione and colleagues, the safety of upadacitinib in patients with inflammatory bowel disease was analyzed through a pooled analysis of 2 phase 3 maintenance studies, U-ACHIEVE and U-ENDURE.1 Both studies demonstrated the efficacy and safety of upadacitinib vs placebo as maintenance treatment in either moderately to severely active UC (U-ACHIEVE) or Crohn’s disease (U-ENDURE).2,3 Both trials examined 2 doses of upadacitinib maintenance therapy (15 mg once daily or 30 mg once daily), each administered for up to 52 weeks in patients who achieved a clinical response to 8 weeks of induction therapy (45 mg once-daily upadacitinib). This pooled analysis was conducted to better understand the long-term safety data available from these trials.
The integrated patient population consisted of 471 patients treated with 15 mg upadacitinib (353.1 patient-years), 480 patients treated with 30 mg upadacitinib (395.7 patient-years), and 468 patients treated with placebo (246.4 patient-years). Overall, the investigators concluded that there were no new safety signals observed in this integrated safety population. The exposure-adjusted event rate (EAER) of treatment-emergent adverse events (TEAEs), calculated as the number of events per 100 patient-years, were higher with placebo (EAER, 482.9) compared with either 15 mg upadacitinib (EAER, 330.2) or 30 mg upadacitinib (EAER, 319.9) (Table). This trend was also observed for patients with a serious TEAE (placebo: EAER, 28.0; 15 mg upadacitinib: EAER, 17.3; 30 mg upadacitinib: EAER, 14.4) as well as a severe TEAE (placebo: EAER, 27.6; 15 mg upadacitinib: EAER, 15.9; 30 mg upadacitinib: EAER, 13.6). Further, the rate of TEAEs resulting in discontinuation of upadacitinib was highest with placebo (EAER, 13.8) compared with either 15 mg upadacitinib (EAER, 8.5) or 30 mg upadacitinib (EAER, 8.3). Serious infections occurred at a similar EAER. Overall, the most frequently reported infections included nasopharyngitis (EAER, 11.6-14.2), upper respiratory infection (EAER, 6.8-7.3), COVID-19 infection (EAER, 6.9-7.6), herpes zoster infection (EAER, 1.6-7.1), and urinary tract infection (EAER, 2.5-6.1).
Table.
Overview of Treatment Adverse Events at Week 52 From the U-ACHIEVE and U-ENDURE Studies in Patients With Moderately to Severely Active Ulcerative Colitis or Crohn’s Disease
| UC data | CD data | Integrated safety (UC + CD) data | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Parameter, n (%) | PBO n=245 | UPA 15 mg QD n=250 | UPA 30 mg QD n=251 | PBO n=223 | UPA 15 mg QD n=221 | UPA 30 mg QD n=229 | PBO n=468 | UPA 15 mg QD n=471 | UPA 30 mg QD n=480 |
| PY | 135.0 | 199.4 | 218.5 | 111.5 | 153.7 | 117.2 | 246.4 | 353.1 | 395.7 |
| Exposure-adjusted event rates, E (E/100 PY) | |||||||||
| Any AE | 674 (499.4) | 626 (313.9) | 691 (316.2) | 516 (462.8) | 540 (351.3) | 575 (324.5) | 1190 (482.9) | 1166 (330.2) | 1266 (319.9) |
| Any serious AE | 28 (20.7) | 24 (12.0) | 22 (10.1) | 41 (36.8) | 37 (24.1) | 35 (19.7) | 69 (28.0) | 61 (17.3) | 57 (14.4) |
| Any severe AE | 29 (19.3) | 18 (9.0) | 23 (10.5) | 39 (35.0) | 38 (24.7) | 31 (17.5) | 56 (15.9) | 56 (15.9) | 54 (13.6) |
| Any AE leading to discontinuation of study drug | 26 (19.3) | 11 (5.5) | 19 (8.7) | 8 (7.2) | 19 (12.4) | 14 (7.9) | 30 (8.5) | 30 (8.5) | 33 (8.3) |
| Any AE with possibility of being related to the study drug | 192 (142.3) | 178 (89.3) | 233 (106.6) | 134 (120.2) | 139 (90.4) | 147 (82.9) | 317 (89.8) | 317 (89.8) | 380 (96.0) |
| COVID-19 infection-related AE | 9 (6.7) | 6 (3.0) | 13 (5.9) | 11 (9.9) | 16 (10.4) | 23 (13.0) | 22 (6.2) | 22 (6.2) | 36 (9.1) |
| Any deaths | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
AE, adverse event; CD, Crohn’s disease; E, events; PBO, placebo; PY, patient-years; QD, once daily PBO; UC, ulcerative colitis; UPA, upadacitinib. Adapted from Panaccione et al. Abstract P3631. Presented at: ACG 2023; October 20-25, 2023; Vancouver, Canada.1
A second poster, presented by Dubinsky and colleagues, examined the time to relapse among patients with UC who initially had a response to upadacitinib induction therapy but lost that response over the maintenance period.4 A total of 681 patients who had an induction response entered the maintenance trial (U-ACHIEVE), of whom 618 comprised this analysis, which included 248 patients classified as induction remitters.
Among induction responders, more patients in the placebo arm (73.1%) experienced a relapse by week 52 than either the 15 mg or the 30 mg upadacitinib arms (32.8% and 20.6%, respectively). Similarly, among induction remitters, more patients in the placebo arm (68.4%) experienced a relapse by week 52 than either the 15 mg or 30 mg upadacitinib arms (23.2% and 16.7%, respectively). The median time to relapse for patients in the placebo arm was 169 days for induction responders and 210 days for induction remitters. The median time to relapse was not estimable for either upadacitinib arm. Overall, compared with placebo, patients treated with either upadacitinib dose had a lower probability of relapse. The HR for 15 mg upadacitinib was 0.30 (95% CI, 0.22-0.41) for induction responders and 0.23 (95% CI, 0.13-0.40) for induction remitters. The HR for 30 mg upadacitinib was 0.18 (95% CI, 0.13-0.25) for induction responders and 0.16 (95% CI, 0.09-0.29) for induction remitters. The investigators concluded these results demonstrated that the probability of relapse with either dose of upadacitinib was lower throughout maintenance than with placebo, for both induction responders and the subset of patients in remission after induction therapy.
References
- Panaccione R, Panes J, Peyrin-Biroulet L Safety of upadacitinib in IBD: pooled analysis of phase 3 maintenance studies, U-ACHIEVE and U-ENDURE, in patients with moderately to severely active ulcerative colitis or Crohn’s disease. Abstract P3631. 2023. Presented at: ACG 2023 Annual Scientific Meeting; October 20-25. Vancouver, Canada.
- Danese S, Vermeire S, Zhou W et al. Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials. Lancet. 2022;399(10341):2113–2128. doi: 10.1016/S0140-6736(22)00581-5. [DOI] [PubMed] [Google Scholar]
- Loftus EV, Jr, Panés J, Lacerda AP et al. Upadacitinib induction and maintenance therapy for Crohn’s Disease. N Engl J Med. 2023;388(21):1966–1980. doi: 10.1056/NEJMoa2212728. [DOI] [PubMed] [Google Scholar]
- Dubinsky MC, Axelrad J, Kujawski MR Time to relapse during upadacitinib maintenance therapy in patients with ulcerative colitis who had a clinical response to induction therapy. Abstract P3604. 2023. Presented at: ACG 2023 Annual Scientific Meeting; October 20-25. Vancouver, Canada.