Introduction

Consistent associations between higher remission rates and shorter disease duration have been reported for advanced therapies in Crohn’s disease (CD), but no direct comparisons between newer advanced treatments and efficacy with respect to CD duration have been examined. The efficacy of risankizumab (RZB), an interleukin (IL)23p19 inhibitor, and ustekinumab (UST), an IL12/23p40 inhibitor, in pts with CD have been reported.^1–3 Herein, using data from the phase 3 SEQUENCE study, the clinical and endoscopic efficacy of RZB vs UST, stratified by baseline (BL) CD duration, is reported.

Aims & Methods

The SEQUENCE open-label, multicenter, randomized, efficacy assessor-blinded study compared the efficacy and safety of RZB vs UST in pts with moderate to severe CD and prior anti-TNF failure (NCT04524611). Pts were randomized 1:1 to receive recommended induction and maintenance doses of RZB (N=255) or UST (N=265). A mandatory steroid taper began at week (W)2. Randomization was stratified by BL steroid use and number of failed anti-TNFs. This post hoc analysis evaluated CDAI clinical remission and endoscopic remission at W24 and W48, and endoscopic response, steroid-free CDAI clinical remission, and steroid-free endoscopic remission at W48, in pts stratified by disease duration (<2 years [Y], 2-5Y, 5-10Y, >10Y) (endpoints defined in Table footnote). Missing data due to COVID-19 and/or geopolitical conflict was handled using non-responder imputation while incorporating multiple imputation. P values are nominal.

Results

BL, baseline; CD, Crohn's disease; CDAI, CD activity index; CI, confidence interval; FCP, fecal calprotectin; hs-CRP, high-sensitivity C-reactive protein; SES-CD, simple endoscopic score for CD; TNF, tumor necrosis factor CDAI clinical remission - CDAI < 150; endoscopic remission - SES-CD ≤ 4 and ≥ 2 point reduction versus BL and no subscore > 1 in any individual variable, as scored by central reviewer; endoscopic response - decrease in SES-CD > 50% from BL (or for patients with isolated ileal disease and a BL SES-CD of 4, ≥ 2 point reduction from BL), as scored by central reviewer; Steroid-free CDAI clinical remission - CDAI clinical remission without receiving steroids; steroid-free endoscopic remission - endoscopic remission without receiving steroids Efficacy population includes all patients randomized to either ustekinumab (i.e., weight-based induction dose IV followed by maintenance dose 90-mg SC), or the selected dosing regimen for risankizumab (600 mg for induction, 360 mg for maintenance), and who received at least one dose of study drug. 5% CI for response rate is the synthetic result based on Student's t-distribution from PROC MIANALYZE procedure if there are missing data due to COVID-19 and/or geopolitical conflict or is based on the normal approximation to the binomial distribution if there are no missing data due to COVID-19 and/or geopolitical conflict. Response rate difference = (risankizumab - ustekinumab); 95% CI for difference is calculated based on normal approximation to the binomial distribution for the comparison of two treatment groups. P-value is based on Chi-square test. The calculations are based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 and/or geopolitical conflict. Pooled p-value from Chi-square is calculated following Li et al., Statistica Sinica. 1991; 1, 68-92. All P-values are nominal.

BL Demographic and Disease Characteristics

Disease Duration at Baseline (BL)

<2 years

2-5 years

>5-10 years

>10 years

RZB N=36

UST N=43

RZB N=59

UST N=62

RZB N=67

UST N=71

RZB N=93

UST N=89

Age (years), mean (SD) Sex (male), n (%) Body mass index (kg/m2), mean (SD) Average daily stool frequency, mean (SD) Average daily abdominal pain, mean (SD) CDAI, mean (SD) SES-CD, n; mean (SD) Fecal calprotectin (mg/kg), median (IQR) hs-CRP (mg/L), n; median (IQR) Anti-TNF failure history (> 1), n (%) Corticosteroid use (yes) - n %) Crohn's disease location per SES-CD, n (%) Ileal only Colonic only Ileal-colonic

36.7 (13.9) 18 (50) 21.6 (4.2) 5.1 (2.5) 1.9 (0.5) 312.5 (58.3) n = 36 14.4 (8.2) n = 33 1429 (2877) n = 35 5 (30) 2 (6) 11 (31) 6 (17) 20 (56) 10 (28)

34.2 (13.2) 18 (42) 22.9 (5.4) 5.0 (2.6) 2.0 (0.6) 314.8 (55.3) n = 43 15.5 (7.7) n = 41 2116 (2811) n = 40 19 (45) 5 (12) 14 (33) 9 (21) 16 (37) 18 (42)

33.1 (12.6) 35 (59) 23.1 (5.9) 5.3 (2.4) 2.0 (0.5) 318.6 (56.1) n = 59 12.9 (6.7) n = 47 1453 (2552) n = 58 10 (22) 11 (19) 11 (19) 9 (15) 23 (39) 27 (46)

36.0 (13.7) 35 (56) 25.4 (6.6) 5.6 (2.8) 2.0 (0.5) 314.6 (63.3) n = 62 15.2 (8.3) n = 49 1535 (2079) n = 60 10 (25) 11 (18) 16 (26) 12 (19) 20 (32) 30 (48)

36.3 (13.5) 42 (63) 24.1 (4.8) 6.0 (3.2) 2.0 (0.5) 317.4 (65.1) n = 67 14.0 (7.4) n = 53 1016 (2217) n = 63 9 (31) 19 (28) 16 (24) 9 (13) 25 (37) 33 (49)

35.1 (13.8) 35 (49) 23.3 (5.8) 5.2 (2.4) 1.9 (0.6) 304.0 (68.3) n = 71 13.7 (7.4) n = 57 1515 (2070) n = 71 8 (15) 14 (20) 15 (21) 10 (14) 28 (39) 33 (46)

43.0 (11.3) 41 (44) 24.9 (5.9) 5.5 (2.6) 1.9 (0.5) 296.8 (62.7) n = 93 13.2 (6.6) n = 74 593 (1472) n = 90 7 (13) 27 (29) 20 (21) 18 (19) 34 (37) 41 (44)

44.3 (12.2) 43 (48) 26.6 (5.6) 6.3 (2.3) 1.8 (0.6) 309.7 (61.3) n = 89 13.1 (6.4) n = 68 1115 (2306) n = 86 8 (20) 31 (35) 26 (29) 14 (16) 42 (47) 33 (37)

RZB N=36

UST N=43

Response Rate Difference % (95% CI) P-value

RZB N=59

UST N=62

Response Rate Difference % (95% CI) P-value

RZB N=67

UST N=71

Response Rate Difference % (95% CI) P-value

RZB N=93

UST N=89

Response Rate Difference % (95% CI) P-value

CDAI clinical remission at week 24, n/N; % (95% CI) CDAI clinical remission at week 48, n/N; % (95% CI) Endoscopic response at week 24, n/N; % (95% CI) Endoscopic response at week 48, n/N; % (95% CI) Endoscopic remission at week 48, n/N; % (95% CI) Steroid-free CDAI clinical remission at week 48, n/N; % (95% CI) Steroid-free endoscopic remission at week 48, n/N; % (95% CI)

23/36 63.9% (48.2, 79.6) 23/36 63.9% (48.2, 79.6) 19/36 52.8% (36.5, 69.1) 19/36 52.8% (36.5, 69.1) 11/36 30.6% (15.5, 45.6) 23/36 63.9% (48.2, 79.6) 11/36 30.6% (15.5, 45.6)

22/43 51.2% (36.2, 66.1) 19/43 44.2% (29.3, 59.0) 14/43 32.6% (18.6, 46.6) 11/43 25.6% (12.5, 38.6) 8/43 18.6% (7.0, 30.2) 19/43 44.2% (29.3, 59.0) 8/43 18.6% (7.0, 30.2)

12.7 (-8.9, 34.4) P =.3 19.7 (-1.9, 41.3) P =.1 20.2 (-1.3, 41.7) P =.1 27.2 (6.3, 48.1) P <.05 12.0 (-7.1, 31.0) P =.2 19.7 (-1.9, 41.3) P =.1 12.0 (-7.1, 31.0) P =.2

30/59 50.8% (38.0, 63.6) 33/59 55.9% (43.3, 68.6) 26/59 44.5% (31.7, 57.2) 24/59 40.7% (28.1, 53.2) 20/59 33.9% (21.8, 46.0) 33/59 55.9% (43.3, 68.6) 19/59 32.2% (20.3, 44.1)

26/62 41.9% (29.7, 54.2) 27/62 43.5% (31.2, 55.9) 12/62 19.4% (9.5, 29.2) 8/62 12.9% (4.6, 21.2) 6/62 9.7% (2.3, 17.0) 26/62 41.9% (29.7, 54.2) 4/62 6.5% (0.3, 12.6)

8.9 (-8.9, 26.6) P =.3 12.4 (-5.3, 30.1) P =.2 25.1 (9.0, 41.2) P <.01 27.8 (12.7, 42.8) P <.001 24.2 (10.1, 38.4) P <.01 14.0 (-3.6, 31.6) P =.1 25.8 (12.4, 39.2) P <.001

40/67 59.7% (48.0, 71.4) 39/67 58.2% (46.4, 70.0) 33/67 49.3% (37.3, 61.2) 31/67 46.3% (34.3, 58.2) 19/67 28.4% (17.6, 39.2) 39/67 58.2% (46.4, 70.0) 19/67 28.4% (17.6, 39.2)

39/71 54.9% (43.4, 66.5) 31/71 43.7% (32.1, 55.2) 23/71 32.4% (21.5, 43.3) 18/71 25.4% (15.2, 35.5) 16/71 22.5% (12.8, 32.3) 31/71 43.7% (32.1, 55.2) 16/71 22.5% (12.8, 32.3)

4.8 (-11.7, 21.3) P =.6 14.5 (-2.0, 31.1) P =.1 16.9 (0.7, 33.0) P <.05 20.9 (5.3, 36.6) P <.05 5.8 (-8.7, 20.3) P =.4 14.5 (-2.0, 31.1) P =.1 5.8 (-8.7, 20.3) P =.4

59/93 63.4% (53.7, 73.2) 60/93 64.5% (54.8, 74.2) 37/93 39.8% (29.8, 49.7) 41/93 44.1% (34.0, 54.2) 31/93 33.3% (23.8, 42.9) 60/93 64.5% (54.8, 74.2) 31/93 33.3% (23.8, 42.9)

26/89 29.2% (19.8, 38.7) 31/89 34.8% (24.9, 44.7) 21/89 23.6% (14.8, 32.4) 21/89 23.6% (14.8, 32.4) 13/89 14.6% (7.3, 21.9) 31/89 34.8% (24.9, 44.7) 13/89 14.6% (7.3, 21.9)

34.2 (20.6, 47.8) P <.0001 29.7 (15.8, 43.6) P <.0001 16.2 (2.9, 29.5) P <.05 20.5 (7.1, 33.9) P <.01 18.7 (6.7, 30.8) P <.01 29.7 (15.8, 43.6) P <.0001 18.7 (6.7, 30.8) P <.01

Baseline characteristics were mostly similar across treatments and disease duration subgroups, except total number of pts and proportion of pts failing >1 anti-TNFs (both lower in the <2Y subgroup), and fecal calprotectin (lower with increasing CD duration) (Table). With RZB vs UST, a numerically greater proportion of pts achieved all endpoints, irrespective of disease duration (Table). A greater proportion of pts in all subgroups achieved endoscopic response with RZB vs UST at W48 (<2Y: P<05; 2-5Y, P<001; 5-10Y, P<.05, > 10Y, P<.01), with a similar trend for RZB vs UST observed for most, but not all, disease duration subgroups for W24 endoscopic response and W48 endoscopic remission (Table). The numerically highest rates of endoscopic response were observed with RZB in pts with a disease duration ≤2Y, andwhile the numerically greatest treatment differences with RZB vs UST were observed in pts with a disease duration of ≤5Y (Table). The safety profiles of RZB and UST in CD were previously reported.^1–3

Conclusion

At W24 and W48, numerically higher rates of efficacy were observed with RZB vs UST treatment for all endpoints across disease duration subgroups, with notable consistent differences observed for endoscopic response. Endoscopic response rates with RZB were numerically highest in pts with a disease duration of ≤2Y, supporting early intervention for patients with CD.⁴

References

1 D’Haens, G. et al. The Lancet. 2022; 399, 2015–2030.
2 Ferrante, M. et al. The Lancet. 2022; 399, 2031–2046.
3 Feagan, B. G. et al. N Engl J Med. 2016; 375, 1946–1960.
4 Colombel, J.-F. et al. Gastroenterology. 2017; 152, 351-361.e5.

Disclosure

Jean-Frederic Colombel received research grants from AbbVie, Janssen Pharmaceuticals, and Takeda; payment for lectures from AbbVie, Allergan, Amgen, Ferring Pharmaceuticals, Shire, and Takeda; consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Ferring Pharmaceuticals, Galmed Research, Genentech, GlaxoSmithKline, Imedex, Immunic, Iterative Scopes, Janssen Pharmaceuticals, Kaleido Biosciences, Lilly, Merck, Microbia, Novartis, PBM Capital, Pfizer, Protagonist Therapeutics, Sanofi, Takeda, TiGenix, and Vifor; and holds stock options in Intestinal Biotech Development.
Laurent Peyrin-Biroulet received personal fees from AbbVie, Adacyte, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, BMS, Celltrion, CONNECT Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, HAC-Pharma, IAG Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Nordic Pharma, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par’Immune, Pfizer, Prometheus, Protagonist, Roche, Sanofi, Sandoz, Takeda, Theravance, Thermo Fisher, Tigenix, Tillots, Viatris, Vifor, Ysopia, Abivax, Samsung, Ventyx, Roivant, and Vectivbio
Shomron Ben-Horin has received Advisory Board fees and/or Consulting fees from Janssen, AbbVie, CellTrion, Takeda, Schering Plough, Pfizer, Ferring, Falk Pharma, GSK, BMS, Novartis, Roche, Galmed, Evinature, PredictaMed and Eli Lilli, holds Stocks/options in Galmed, Evinature, PredictaMed and Alma Therapeutics and received research grant support from Janssen, AbbVie, CellTrion, Takeda, Pfizer and Galmed.
Christina Ha has received financial support from advisory board fees from AbbVie, Bristol Myers Squibb, Bausch Health, Roivant, Janssen, Pfizer, and Takeda; consultant fees from AbbVie; educational grant funding from Bristol Myers Squibb, Pfizer, Janssen, AbbVie and the Helmsley Charitable trust
Britta Siegmund has served as consultant for AbbVie, Abivax, Arena, BMS, Boehringer, CED Service GmbH, Celgene, CT Scout, Endpoint Health, Falk, Forga Software, Galapagos, Janssen, Lilly, Materia Prima, Pfizer, Takeda, Pharma Insight, Predictimmune, PsiCro; Speaker fees: AbbVie, BMS, CED Service GmbH, Chiesi, Falk, Ferring, Gilead, Janssen, Lilly, Materia Prima, Takeda, Pfizer and grant support by Arena/Pfizer (served as representative of the Charité).
Fernando Aponte, Kristina Kligys, Javier Zambrano, Toni Anschutz, and Andrew Garrisonare full-time employees of AbbVie and may own AbbVie stock or options.
Funding and Acknowledgments: AbbVie 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 Stephanie Parsons, PhD, and copy editing support was provided by Angela T. Hadsell, BS, both employees of AbbVie.

Introduction

The primary objective of the VERDICT study, a continuing randomized controlled trial (NCT04259138),^1,2 is to determine the optimal treatment target in moderately‑to-severely active ulcerative colitis (UC). Patients are allocated to Group 1 (corticosteroid-free [CSF] symptomatic remission), Group 2 (CSF symptomatic remission + CSF endoscopic remission), and Group 3 (CSF symptomatic remission + CSF endoscopic remission + CSF histologic remission, also termed disease clearance). Patients follow treatment algorithms involving early introduction of vedolizumab (VDZ), without week 10 dosing, nor dose escalation before week 16. Here we report target achievement at weeks 16 and 32 amongst groups.

Aims & Methods

VDZ 300 mg was administered intravenously following a treatment algorithm related to baseline UC treatment until assigned treatment target was reached at week 32, with an escalation step between week 16 and 32 as indicated. CSF symptomatic remission was defined as Mayo rectal bleeding subscore=0, CSF endoscopic remission was defined as Mayo Endoscopic Score [MES]≤1, and CSF histologic remission was defined as Geboes score<2B.0.

Results

As of 29 Feb 2024, 612 patients were enrolled with 154, 198, and 260 patients assigned to target Groups 1, 2, and 3, respectively. Baseline age and disease duration were similar amongst groups, with respective percentages of patients having baseline MES=3 given by 60.4%, 61.6%, and 64.2%, and receipt of concomitant corticosteroids given by 42.9%, 40.9%, and 50.4% (median dose 25.4, 25.3, and 23.7 mg). There were 71.4%, 75.3%, and 83.5% of patients who were bionaïve, respectively. At time of analysis, 63.6%, 71.2%, and 80.8% of randomized patients in the groups had completed the week 32 visit.
In patients with observed data and a week 16 visit, 64.1% (75/117), 42.2% (73/173), and 40.2% (94/234) in Groups 1, 2, and 3, respectively, achieved CSF remission at week 16. In patients with observed data and a week 32 visit, 81.6% (80/98), 61.7% (87/141), and 53.3% (112/210), respectively, achieved CSF remission by week 32, with higher proportions in bionaïve (83.7%, 63.8%, and 55.2%) compared to bio-exposed (66.7%, 52.0%, and 40.7%) (Table 1). In the intention-to-treat population, 48.7%, 36.9%, and 36.2% of patients, respectively, achieved CSF remission at week 16, with higher proportions in patients who were bionaïve (56.4% [62/110], 38.3% [57/149], and 38.2% [83/217]) compared to bio-exposed (29.5% [13/44], 32.7% [16/49], and 25.6% [11/43]). By week 32, 51.9%, 43.9%, and 43.1% of the intention-to-treat population achieved CSF remission, with higher proportions in bionaïve (65.5% [72/110], 49.7% [74/149], and 46.5% [101/217]) compared to bio-exposed (18.2% [8/44], 26.5% [13/49], and 25.6% [11/43]). For patients not achieving target at week 16, treatment escalation occurred in 22.7%, 49.5%, and 53.5% of patients; after escalation, proportions achieving CSF remission by week 32 were 41.9% (13/31), 27.0% (20/74), and 19.0% (23/121), respectively.

Table 1. Summary of Target Achievement by Week 32a
aWeek 32 completer analysis set includes all patients who reached the week 32 visit. Group 1 is defined as CSF symptomatic remission; Group 2 is defined as CSF symptomatic remission + CSF endoscopic remission; and Group 3 is defined as CSF symptomatic remission + CSF endoscopic remission + CSF histologic remission. bRemission target status missing includes patients who ended the study before the week 32 visit, those who had not reached the week 32 visit, and those who reached the week 32 visit but had no status, as of 29 FEB 2024. Abbreviation: CSF, corticosteroid-free.
	Group 1 Bionaïve N=86	Group 1 Bio-exposed N=12	Group 1 Total N=98	Group 2 Bionaïve N=116	Group 2 Bio-exposed N=25	Group 2 Total N=141	Group 3 Bionaïve N=183	Group 3 Bio-exposed N=27	Group 3 Total N=210
CSF remission, n (%)	72 (83.7)	8 (66.7)	80 (81.6)	74 (63.8)	13 (52.0)	87 (61.7)	101 (55.2)	11 (40.7)	112 (53.3)
Non-CSF remission, n (%)	3 (3.5)	0 (0.0)	3 (3.1)	0 (0.0)	0 (0.0)	0 (0.0)	1 (0.5)	0 (0.0)	1 (0.5)
Remission target not achieved, n (%)	11 (12.8)	3 (25.0)	14 (14.3)	40 (34.5)	12 (48.0)	52 (36.9)	81 (44.3)	16 (59.3)	97 (46.2)
Remission target status missing,b n (%)	0 (0.0)	1 (8.3)	1 (1.0)	2 (1.7)	0 (0.0)	2 (1.4)	0 (0.0)	0 (0.0)	0 (0.0)

Conclusion

These interim week 32 results provide evidence of improvement from week 16 to 32 across all endpoints and continue to support the efficacy of VDZ in achieving the stringent endpoint of CSF disease clearance.

References

¹Jairath V, Zou G, Wang Z, et al. Determining the optimal treatment target in patients with ulcerative colitis: rationale, design, protocol and interim analysis for the randomised controlled VERDICT trial. BMJ Open Gastroenterol. 2024;11:e001218. Doi:10.1136/bmjgast-2023-001218
²Jairath V, Zou G, Adsul S, et al. DOP11 Disease clearance after 16 weeks of treatment with vedolizumab in patients with moderate to severe Ulcerative Colitis: An interim analysis from the VERDICT trial. J Crohns Colitis. 2024;18 (Suppl 1):i92-i93. Doi: 10.1093/ecco-jcc/jjad212.0051

Disclosure

VJ has received consulting/advisory board fees from Alimentiv Inc. (formerly Robarts Clinical Trials) and Takeda; and received speaker’s fees from Takeda.
GZ has received consulting fees from Alimentiv Inc.
SA and MF are employees of Takeda Pharmaceuticals.
LPB has received personal fees from Alimentiv Inc. and Takeda.
JFC reports receiving research grants, payment for lectures, and consulting fees from Takeda.
GRD has served as a consultant and/or received speaker fees from Alimentiv Inc. and Takeda.
GWM is a consultant for Alimentiv Inc.
WJS reports receiving consulting fees from Alimentiv Inc.
SS reports receiving research grants from Takeda; and receiving personal fees for speaker role and advisory board meetings from Takeda outside the submitted work.
ST has received grants/research support, consulting fees, and speaker fees from Takeda,
SV has received grants from Takeda; and received consulting and/or speaking fees from Alimentiv Inc. and Takeda.
JH has received consulting fees from Alimentiv Inc. and speaker’s fees from Takeda.
CM has received consulting fees from Alimentiv Inc. and has received consulting fees and speaker's fees from Takeda.
RS has received consulting fees from Alimentiv Inc.
PS is an employee of Alimentiv Inc.
NA reports no conflicts of interest.
MB has received honoraria and advisory board fees from Takeda; and reports clinical trials with Takeda.
PB reports receiving research grants, lecture fees, and consulting fees from Takeda.
SD reports consultancy fees from Alimentiv Inc. and reports consultancy fees and lecture fees from Takeda.
DG has received advisory board fees from Takeda.
WH reports no conflicts of interest.
MH reports no conflicts of interest.
JK reports no conflicts of interest with Alimentiv Inc. or Takeda
AK reports no conflicts of interest.
MK has received personal fees from Shire, a Takeda company, during the conduct of the study, and received personal fees and non-financial support from Takeda.
FM has received fees from Takeda.
RP reports no conflicts of interest with Alimentiv Inc. and Takeda.
MSS has received consulting, speaker, and advisory board fees from Takeda.
LW reports no conflicts of interest.
BGF is a scientific advisory board member for Takeda; has received consulting fees, lecture fees, and grant support from Takeda; and is the Senior Scientific Officer of Alimentiv Inc.

Introduction

Eosinophilic esophagitis (EoE) is a chronic type 2 inflammatory disease with increasing incidence and prevalence. Patients with EoE usually present with symptoms of dysphagia that impact their quality of life. In the 3-part, Phase 3 LIBERTY EoE TREET study (NCT03633617), dupilumab improved histologic, symptomatic, and endoscopic aspects of EoE up to 52 weeks.

Aims & Methods

The aim of this analysis was to assess the effect of dupilumab on symptoms of dysphagia in the 28-week extended treatment period of LIBERTY EoE TREET in patients who switched from placebo to dupilumab at 24 weeks. In Parts A and B, patients received dupilumab 300 mg or placebo weekly (qw) for 24 weeks. Patients who completed Parts A and B entered Part C - a 28-week extended treatment period in which all patients received dupilumab 300 mg qw; patients entering Part C remained blinded to their treatment in Parts A and B. Dysphagia Symptom Questionnaire (DSQ) score and number of days with dysphagia (assessed using the DSQ) were calculated over a 14-day period. Percent change in DSQ score and in number of days with dysphagia from Week 24 through Week 52 vs the Week 24 baseline were assessed for patients who switched from placebo to dupilumab 300 mg qw at Week 24 and or continued on dupilumab 300 mg.

Results

Mean (SD) DSQ score after 24 weeks of placebo was 24.7 (19.6) and 21.5 (18.4) in Parts A (n=37) and B (n=37), respectively. Significant improvements in DSQ score were observed within 4 weeks of the switch to dupilumab 300 mg qw (mean percent reduction: 31.5% and 29.9%). After 28 weeks (at Week 52), mean percent reduction in DSQ score was 63.6% and 59.7%. After 24 weeks of placebo, mean (SD) days with dysphagia was 6.6 (4.7) and 6.0 (4.7) in Parts A and B, respectively. At Week 52, there was a 63.2% and 46.8% mean reduction in the number of days with dysphagia.

Conclusion

In patients who initially received 24 weeks of placebo, weekly treatment with dupilumab 300 mg resulted in rapid (within 4 weeks) and sustained (up to 28 weeks) improvement in symptoms of dysphagia as assessed by the DSQ score. The magnitude of the improvement in dysphagia observed after switching from placebo to dupilumab was similar to that seen at 4 weeks in patients who originally initiated dupilumab in Parts A and B of the study.

Disclosure

Dellon ES. Abbott, Abbvie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Dr. Falk Pharma, Eli Lilly, EsoCap, Eupraxia, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology/Uniquity, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, Upstream Bio – consultant. Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, Shire/Takeda – research funding. Allakos, Aqilion, Holoclara, Invea – educational grants.
Chehade M. Adare Pharma Solutions/Ellodi, Allakos, AstraZeneca, BMS, Nexstone Immunology, Phathom, Recludix Pharma, Regeneron Pharmaceuticals Inc., Sanofi, and Shire/Takeda ‒ consultant. Adare Pharma Solutions/Ellodi, Allakos, AstraZeneca, Celgene/BMS, Danone, Regeneron Pharmaceuticals Inc., and Shire/Takeda ‒ research funding.
Bredenoord AJ. Alimentiv, Aqilion, AstraZeneca, Dr. Falk Pharma, Eupraxia, Laborie, Medtronic, Reckitt, Regeneron Pharmaceuticals Inc., and Sanofi ‒ consultant. Dr Falk Pharma, Norgine, Nutricia, Sanofi, SST, Regeneron Pharmaceuticals Inc., and Thelial ‒ research funding. Alimentiv, Aqilion, AstraZeneca, Dr Falk Pharma, Eupraxia, Laborie, Medtronic, Reckitt, Regeneron Pharmaceuticals Inc., and Sanofi ‒ speaker fees.
Spergel JM. Allakos, DBV Technologies, Novartis, Regeneron Pharmaceuticals Inc., and Shire/Takeda – consultant. DBV Technologies and Regeneron Pharmaceuticals Inc. ‒ research grant support.
Xia C, McCann E, Khodzhayev A, Radwan A. Regeneron Pharmaceuticals Inc. – employees and shareholders.
Tilton ST, Pela T, Jacob-Nara JA. Sanofi – employee, may hold stock and/or stock options in the company.

Introduction

There is growing awareness of the importance of histological outcomes in ulcerative colitis (UC). However, direct comparisons of histological endpoints are lacking. Thus, we aimed to conduct a network meta-analysis (NMA) to compare the effectiveness of various biologics and small molecules in achieving histological endpoints in UC.

Aims & Methods

We searched four online databases to identify all randomized controlled trials (RCTs) investigating advanced therapies for moderate-to-severe UC that reported histological outcomes. The analysis focused on the proportion of patients achieving histological improvement, histological remission, and histo-endoscopic improvement during induction and maintenance therapy. Using a random-effects frequentist model, we conducted a NMA, presenting the results as odds ratios (OR) with 95% confidence intervals. To evaluate the relative effectiveness of each treatment, we calculated the P-score, which ranges from 0 to 1. We also assessed the risk of bias and evidence certainty using established scoring systems.

Results

Twenty-four RCT were included, comprising 15 different therapies, and enrolling over 8800 patients. Of these trials, 19 provided data on induction therapy, while 10 assessed histological outcomes during maintenance treatment. Outcome definitions were similar among studies. We found that etrasimod 2 mg/day ranked highest in achieving histologic response (P-score 0.98) and remission (P-score 0.90) following induction, while guselkumab ranked first for histoendoscopic improvement. In maintenance trials, upadacitinib 30 mg/day ranked highest in achieving histologic and histo-endoscopic outcomes (P-score 0.88 for both endpoints). Etrasimod 2 mg/day ranked second for histologic remission (P-score 0.70) and histo-endoscopic improvement (P-score 0.73), while mirikizumab 200 mg/month ranked second for histologic response.

Conclusion

Our findings underscore the importance of small molecules in treating moderate-to-severe UC, particularly etrasimod and upadacitinib. Nonetheless, additional head-to-head RCTs are imperative to better inform clinical practice and to address unanswered questions.