Introduction

Emerging evidence indicates an immunomodulatory role of the appendix in ulcerative colitis (UC). Previous studies suggest a beneficiary effect for appendectomy in inducing and maintaining remission. Therefore, appendectomy might be considered as an alternative treatment in these patients.

Aims & Methods

Aim: To evaluate the efficacy of appendectomy in maintaining remission in UC patients.
Methods: Adult patients with established UC in complete clinical and endoscopic remission (defined as Mayo score <3 with endoscopic subscore of 0 or 1) after being medically treated for disease relapse within 12 months prior to randomization were enrolled in the Netherlands and United Kingdom. Patients were randomized (1:1) to undergo additional appendectomy (intervention group) or continue current medical therapy (control group). The primary outcome was the one-year UC relapse rate, defined as a total Mayo-score score ≥5 with endoscopic subscore of 2 or 3. To detect a clinically relevant decrease in relapse rate from 40% to 20%, 82 patients per study arm were needed. Trial progress and safety reports with accumulated number of (serious) adverse events in both groups were presented to the Data Safety Monitoring Board (DSMB) annually, and therefore data are available. Last patient was included in August 2022, so the final analyses will commence in September 2023.

Results

Between September 2012 and September 2022, 198 patients were randomized. A total of 99 patients were included in the intervention group and 99 patients in the control group. The one-year follow-up data were complete for 183 patients in April 2023.
There were 86 males and 112 females, with a median age of 41 years (IQR 33-52). Baseline characteristics were comparable in both groups, with the majority of patients having been treated for either proctitis (38.9%) or left sided colitis (35.9%) (Table 1). A total of three serious adverse events (SAE) were reported in the appendectomy group, of which two were related to the surgical procedure (reintervention for mechanical ileus and postoperative hematoma) and one hospitalisation for clostridium infection. One SAE was reported within the first year in the control group (appendicitis). During follow up there were no colectomies in the appendectomy group, whereas three patients underwent colectomy for therapy-refractory disease in the control group. In addition, the one-year reported colitis-associated adverse event rate was significantly lower in the appendectomy group when compared to the control group (43.4% vs. 62.7%, P=0.01).

Conclusion

Appendectomy in patients with UC has the possibility to decrease the rate of colitis-associated (serious) adverse events significantly. This suggests that the final analysis of the primary outcome parameter (relapse rate) in September 2023 could demonstrate that appendectomy is superior to standard medical therapy alone in maintaining remission in these patients.

Introduction

Upadacitinib 15 mg once daily (UPA15) and 30 mg once daily (UPA30) have demonstrated efficacy vs placebo across clinical, endoscopic, and histologic endpoints after 52 weeks of maintenance therapy in the U-ACHIEVE Maintenance study.^1,2

Aims & Methods

This interim analysis presents efficacy and safety data from patients receiving continuous therapy with UPA15 or UPA30 for 1 year in the maintenance study, and an additional 48 weeks (approximately 2 years in total) in the ongoing, 288-week, long-term extension (LTE) study U-ACTIVATE. Patients who underwent dose escalation or de-escalation at Week 48 of the LTE study were excluded from this analysis. Efficacy and safety endpoints were analyzed at Week 48 of the LTE study. Overall safety data and treatment-emergent adverse events (TEAEs) of special interest are presented as exposure-adjusted event rates (EAERs; events/100 patient-years [PYs]) of TEAEs, except for some TEAEs that typically occur as a single instance, which are presented as exposure-adjusted incidence rates (EAIRs; n/100 PYs).

Results

The proportions of patients achieving efficacy endpoints, including clinical remission per Adapted Mayo score, endoscopic remission, and endoscopic improvement, were similar for UPA15 vs UPA30, while maintenance of endoscopic remission was achieved by a greater proportion with UPA30 vs UPA15 (Table). For safety, 238 (UPA15, n=101; UPA30, n=137) patients, who achieved 426.5 (UPA15, 186.0; UPA30, 240.5) PYs of exposure, were analyzed. Across treatment groups, EAERs of serious TEAEs and TEAEs leading to treatment discontinuation were similar (Table). No TEAEs leading to death occurred in either group. The EAERs for TEAEs of special interest were generally lower with UPA15 vs UPA30, including for serious infections (1.6 vs 4.6, respectively), herpes zoster (3.8 vs 5.8), neutropenia (1.6 vs 4.2), and creatine phosphokinase elevation (2.7 vs 6.2), although the EAER for hepatic disorder was higher with UPA15 vs UPA30 (8.6 vs 4.2, respectively). No adjudicated major adverse cardiovascular events occurred on either dose; no adjudicated venous thromboembolic events occurred on UPA15 and one event occurred on UPA30 (EAIR: 0.4). One event of malignancy excluding non-melanoma skin cancer occurred in both UPA15 (papillary thyroid carcinoma; EAIR: 0.5) and UPA30 (squamous cell carcinoma of uterine cervix; EAIR: 0.4).

Conclusion

Achievement of clinical and endoscopic endpoints observed with UPA15 and UPA30 after the 52-week maintenance study^1,2 was sustained through Week 48 of the LTE study, demonstrating continued benefit for up to 2 years of maintenance therapy with both doses. The safety profile of UPA at Week 48 of the LTE study was consistent with previous analyses, and no new safety signals were identified.

References

1. Danese S, et al. Lancet 2022;399:2113–28
2. Vermeire S, et al. Presented at UEGW [OP001], 8–11 October 2022

Disclosure

RP has received consulting fees, speaker fees, and research support from Abbott, AbbVie, Alimentiv (formerly Robarts Clinical Trials), Amgen, Arena Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Élan, Eli Lilly, Ferring, Galapagos, Genentech, Gilead, GlaxoSmithKline, Janssen, Merck, Mylan, Oppilan Pharma, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Schering-Plough, Shire, Sublimity Therapeutics, Takeda, Theravance, and UCB.
PDRH has received grants from AbbVie, the Crohn’s & Colitis Foundation, the National Institutes of Health, and Takeda; and has served as a consultant for Eli Lilly, the Gastrointestinal Health Foundation, Imedex, Pfizer, Takeda, and Vindico Medical Education.
GL has received research support and/or funding from Celgene, Janssen Orthobiotech, Pfizer, Takeda, and UCB; consulting fees from AbbVie, American Regent, Cellceutix, Celgene, Eli Lilly, Endo Pharmaceuticals, Ferring, Gilead, Janssen Orthobiotech, Merck, Morphic Therapeutics, Pfizer, Prometheus Laboratories, Romark, Salix/Valeant, Shire, Takeda, and UCB; honoraria from the American College of Gastroenterology, American Regent, Merck, Romark, Springer Science and Business Media, and Up-To-Date; and royalties from Professional Communications Inc. and SLACK Inc.
HN has received support from AbbVie, Celgene, Daiichi Sankyo, EA Pharma, Janssen, JIMRO, Kissei Pharmaceutical, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Takeda, and Zeria Pharmaceutical; as well as grants for commissioned/joint research from Boehringer Ingelheim, Bristol Myers Squibb, and Hoya Group Pentax Medical.
MK, EC, DI, GL, and JE are full-time employees of AbbVie, and might hold AbbVie stock or stock options.
SCG has served as a consultant for Bristol Myers Squibb and Janssen.
SD has served as a speaker, consultant, and/or advisory board member for AbbVie, Alfa Wassermann, Allergan, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Gilead, Hospira, Johnson & Johnson, Merck, MSD, Mundipharma, Pfizer, Sandoz, Takeda, Tigenix, UCB and Vifor.
JFC has received personal fees from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Celltrion, Enterome, Ferring, Genentech, Janssen, Johnson & Johnson, MedImmune, Merck, Pfizer, PPM Services, Protagonist Therapeutics, Second Genome, Seres, Shire, Takeda, and Theradiag; has received grant support from AbbVie, Janssen, Johnson & Johnson, and Takeda; and holds stock options in Genfit and Intestinal Biotech Development.
SS has received consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Falk Pharma, Ferring, Galapagos/Gilead, Genentech/Roche, GlaxoSmithKline, I–MAB Biopharma, MSD, Pfizer, Shire, and Takeda.
AbbVie and the authors thank all of the trial investigators and patients who participated in these clinical trials. AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, review, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. Medical writing support was provided by Carl Davies, MSc, of 2 the Nth (Cheshire, UK), and Fraser Harris, MRes, on behalf of 2 the Nth (Cheshire, UK), and was funded by AbbVie.

Introduction

Upadacitinib (UPA) is an oral, selective JAK inhibitor that demonstrated efficacy compared to placebo (PBO) in two induction (U-EXCEED and U-EXCEL) and one maintenance (U-ENDURE) phase 3 studies.^1-3 UPA is approved for patients with moderate to severely active Crohn’s disease (CD).^4,5 Symptom improvement was seen as early as Day 5-6 with UPA 45 mg (UPA45) compared with PBO, an important treatment target.^6,7 Here, we evaluated the effect of achieving early response to UPA45 on clinical and endoscopic outcomes at the end of the induction and maintenance studies.

Aims & Methods

In U-EXCEED and U-EXCEL, patients were randomized (2:1) to UPA45 or PBO for 12 weeks (wks); results from the induction studies were pooled for this post hoc analysis. Clinical responders to 12-wk induction treatment were randomized (1:1:1) to receive UPA 15 mg (UPA15), UPA 30 mg QD (UPA30) or PBO maintenance treatment for 52 wks. Early clinical responders were defined as those patients who achieved a daily very soft/liquid stool frequency (SF) < 3 and daily abdominal pain score (APS) ≤ 1 within the first 15 days and maintained this status for >5 consecutive days until Day 19 (inclusive). Endpoints were assessed at Wk 12 of induction and Wk 52 of maintenance (Table 1). Due to unbalanced patient numbers between PBO and UPA45 in induction, only descriptive analyses were performed.

Results

Of the overall study population^1,2, 17.1% (n=115) of UPA-treated and 6.3% (n=22) of PBO-treated patients were early responders. Baseline demographics and characteristics were similar for both populations. Early responders to UPA45 (84.0%) or PBO (81.8%) had higher rates of SF/APS clinical remission at Wk 12 compared with the overall population (45.5% UPA45; 18.2% PBO). At Wk 52, greater SF/APS clinical remission rates were observed during maintenance for early responders treated with UPA15 (54.8%) or UPA30 (71.1%) vs PBO (25.9%); these rates were higher than what was observed for the overall population (33.9% UPA15; 49.3% UPA30, 15.2% PBO). For endoscopic outcomes, early clinical responders treated UPA45 achieved higher rates of endoscopic response (54.1% vs 40.3%), endoscopic remission (36.6% vs 24.2%), and mucosal healing (34.0% vs 21.1%) vs the overall population at Wk 12; this was also seen for PBO-treated early responders (see Table). These high rates of endoscopic remission (36.8%), response (50.0%), and mucosal healing (28.9%) were maintained with UPA30 for early responders at Wk 52 and were numerically greater than the overall population rates or PBO (see Table). When compared to the overall study population,the treatment effects at Wk 52 across clinical and endoscopic outcomes for both doses were generally higher for the early responder population evaluated here.

Conclusion

Early clinical responders to upadacitinib therapy had high rates for clinical and endoscopic endpoints at Weeks 12 and 52, suggesting that early symptom improvement with upadacitinib may indicate promising durability in outcomes for patients with CD.

References

1. Colombel, JF et al. Abstract 867f. Gastroenterology [Abstract] 162(7): 2022; S-1394.
2. Loftus, EV Jr. et al. Abstract. United European Gastroenterology Journal. [Abstract] 10: 2022; 103.
3. Panes, J. et al. American Journal of Gastroenterology. [Abstract] 117: 2022. S11.
4. Medicines & Healthcare Products Regulatory Agency. RINVOQ 45 mg prolonged-release tablets (Great Britain). 09 Feb 2023. Retrieved 15 March 2023 from https://www.medicines.org.uk/emc/product/13935/smpc.
5. Annex I: Summary of Product Characteristics (RINVOQ). European Medicines Agency.
24 April 2023. Retrieved 25 April 2023 from https://www.ema.europa.eu/en/documents /product-information/rinvoq-epar-product-information_en.pdf
6. Turner D, et al. Gastroenterology 2021;160:1570–1583.
7. J F Colombel et al, Journal of Crohn's and Colitis. [Abstract] 17: S1 2023; i102–i103.

Disclosure

Jean-Frederic Colombel reports receiving research grants from AbbVie, Janssen Pharmaceuticals and Takeda; receiving payment for lectures from AbbVie, Amgen, Allergan, Inc. Ferring Pharmaceuticals, Shire, and Takeda; receiving consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, BMS, Celgene Corporation, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, Genentech, Glaxo Smith Kline, Janssen Pharmaceuticals, Kaleido Biosciences, Imedex, Immunic, Iterative Scopes, Merck, Microbia, Novartis, PBM Capital, Pfizer, Protagonist Therapeutics, Sanofi, Takeda, TiGenix, Vifor; and hold stock options in Intestinal Biotech Development
Tadakazu Hisamatsu has received research grants from AbbVie, Alfresa Pharma, Daiichi Sankyo, EA Pharma, JIMRO, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Takeda, and Zeria Pharmaceutical; consulting fees from AbbVie, Celgene, EA Pharma, Janssen, Nichi-Iko, and Pfizer; and lecture fees from AbbVie, EA Pharma, Janssen, JIMRO, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer, and Takeda.
Raja Atreya has been a consultant and/or speaker for AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion Healthcare, DrFalk Pharma, Ferring, Fresenius Kabi, Galapagos, Gilead, GlaxoSmithKline plc, InDex Pharmaceuticals, Janssen-Cilag, Kliniksa Pharmaceuticals, Lilly, MSD Sharp & Dohme, Novartis, Pandion Therapeutics, Pfizer, Roche Pharma, Samsung Bioepsis, Stelic Institute, Takeda Pharma, Tillotts Pharma AG, Viatris and has received research/educational support from AbbVie, Biogen, InDex Pharmaceuticals, Takeda Pharma, Tillotts Pharma AG.
Lena Thin is an advisory board member for AbbVie; receives advisory board/steering committees fees for education from AbbVie, Takeda, Janssen, Ferring, BMS, Pfizer, Celltrion, Chiesi; receives research grants from Celltrion, Takeda, Pfizer; and is an executive member of the Australian New Zealand IBD consortium.
Rogerio S. Parra has served as a consultant, speaker, and advisory board member for AbbVie, Janssen, Takeda, Ferring, and Pfizer.
Sharanya Ford, Valencia Remple, Ana Paula Lacerda,Samuel I. Anyanwu,Madhuja Mallick, and AndrewGarrisonare employees of AbbVie and may own stock options.
Miguel Regueiro has served as a consultant, speaker, and advisory board member for AbbVie.
Funding: AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship.
Acknowledgments: AbbVie and authors thank all the trial investigators and the patients who participated in this clinical trial. Paulette Krishack, PhD of AbbVie Inc., provided medical writing assistance for the development of this publication.

Introduction

Owing to the multiplication of therapeutic options in ulcerative colitis (UC), how sequencing the drugs is a burning question. For chosing the best treatment, efficacy is a key point. However, only one head-to-head randomized controlled trial is available (VARSITY) and network meta-analyses are difficult to interpret. Then, real-world data are necessary to help ranking the treatment in UC.

Aims & Methods

We aimed to compare the effectiveness of tofacitinib and ustekinumab in patients with ulcerative colitis (UC) previously exposed to at least one anti-TNF agent.
In this multicenter study, we retrospectively included consecutive UC adult patients previously exposed to at least one anti-TNF agent, with partial Mayo score (pMS) > 2, having who started tofacitinib or ustekinumab between January 2019 and June 2022.
The primary endpoint was steroid-free clinical remission (pMS ≤ 2) (CFREM) at week 16 (W16). Secondary endpoints were endoscopic remission (CFREM + Mayo endoscopic score (MES) ≤ 1), and histological remission (CFREM + MES ≤ 1 + Nancy index ≤ 1).
Comparisons were performed using propensity score analyses adjusted on potential confounders.

Results

Overall, 289 patients were included (tofacitinib = 124 patients, ustekinumab = 165 patients). The groups were comparable (tofacitinib vs vedolizumab) for male gender (50.8% vs 43.3%), mean age (40.7 vs 42.9 years), median UC duration (8.6 vs 9.3 years), concomitant use of 5-ASA (13.7% vs 9.7%), steroids (25.0% vs 29.7%), immunosuppressants (7.3% vs 5.5%), and ≥ 2 prior biologics (85.5% vs 82.4%). Tofacitinib group had more pancolitis (55.6% vs 42.4%, p = 0.026) and UC with pMS > 6 (64.5% vs 50.3%, p = 0.016). In our study, 42.1 % of the patients treated with tofacitinib continued using a dose of 10 mgx2/day until W16 while 47.3% of the patients on ustekinumab required dose escalation to 90 mg/4 weeks before W16.
After propensity score analysis, the rate of CFREM at W16 was 37.8% and 35.6% in the tofacitinib and ustekinumab arms, respectively arm (p=0.75). CFREM at W16 was achieved in 43.3% vs 57.1% (p = 0.48) after failure of one biologic, 20.7% vs 37.9% (p=0.16) two biologics and 46.7% vs 23.2% (p=0.047) if ≥ 3 biologics, in tofacitinib and ustekinumab arms, respectively. After primary failure to at least one biologic, the rate of CFREM at W16 was 46.3% on tofacitinib vs 25.9% on ustekinumab (p = 0.13). CFREM at W16 was similar with tofacitinib and ustekinumab in case of more severe UC such as pMS ≥ 6 (40.6% vs 41.5%) and CRP > 30 (27.2% vs 33.0%).
No predictor of tofacitinib effectiveness has been identified. Factors associated with no CFREM at W16 on ustekinumab were male gender (p=0.035), ≥ 3 prior biologics (p=0.013), prior use of tofacitinib (p=0.03), primary failure to at least one biologic (p=0.013).
After propensity score analysis, endoscopic remission was achieved in 17.0% vs 11.7% (p =0.47) and histological remission in 4.4% vs 7.8% (p=0.32) of the patients treated with tofacitinib and ustekinumab, respectively.
At last follow-up, we did not observe any difference between the two groups regarding the time to drug discontinuation, time to hospitalization and time to colectomy.

Conclusion

Tofacitinib and ustekinumab have similar effectiveness at short and long-term in UC after anti-TNF failure. However, the efficacy of ustekinumab could be more impacted by prior therapeutic failures but not by UC severity.

Disclosure

Anthony Buisson: Consulting fees for Abbvie, Amgen, Arena, Biogen, Celtrion, CTMA, Fresenius-Kabi, Galapagos, Janssen, MSD, Nexbiome, Pfizer, Roche, Takeda and Tillotts. Lecture fees for Abbvie, Amgen, Biogen, Fresenius-Kabi Galapagos, Janssen, Mayoli-Spindler, MSD, Norgine, Pfizer, Roche, Takeda, Tillotts and Vifor Pharma. Research grants from Abbvie, Celltrion, Janssen, Pfizer, Takeda.
Maria Nachury: MN received board membership, consultancy, or lecture fees from Abbvie, Adacyte, Amgen, Arena, Biogen, CTMA, Celltrion, Ferring, Fresenius-Kabi, Janssen, Mayoli-Spindler, MSD, Pfizer, Takeda
Thomas Guilmoteau: None
Romain Altwegg: Received lecture and consulting fees from Abbvie, Janssen, MSD, Pfizer, Takeda.
Xavier Treton: Received honoraria from Abbvie, MSD, Takeda, Ferring, Norgine and Janssen.
Mathurin Fumery: Consulting/lecture fees for Abbvie, Amgen, Arena, Biogen, Celtrion, CTMA, Galapagos, Janssen, MSD, Pfizer, Takeda, Tillotts. MSD, Gilead, Celgene, Sandoz and Ferring.
Mélanie Serrero: Declared fees from Pfizer, Abbvie, Takeda, Janssen, MSD, Amgen, Ferring, Tillotts, Celltrion
Ludovic Caillo: Declared fees from Janssen, abbvie, Takeda, amgen, Pfizer, norgine
Bruno Pereira: None
Aurélien Amiot: Has served as a consultant, served on the advisory board, received lecture fees, and received travel fees from AbbVie, Hospira, Takeda, Gilead, Biocodex, Janssen, Ferring, and MSD.
Guillaume Bouguen: Received lecture fees from Abbvie, Ferring, MSD, Takeda and Pfizer and consultant fees from Takeda, Janssen.