Introduction

As the number of advanced treatment options for moderately to severely active ulcerative colitis (UC) increases, it is necessary to understand the factors driving gastroenterologist (GE) choice when escalating patients from conventional to advanced therapy.

Aims & Methods

We completed a quantitative analysis of GE therapy attribute preferences when choosing to escalate patients to their first advanced UC therapy. We conducted an online, cross-sectional survey using a discrete choice experiment (DCE) design. Attribute and level selection was informed by a targeted literature search and formative qualitative research with patients and clinicians. Survey responders were practising GEs experienced in treating patients with moderately to severely active UC, recruited from France, Germany, Italy, Spain and the United Kingdom (UK). Preference weights were estimated using a random parameters logit model for varying levels of seven attributes: time to symptom improvement, probability of remission at one year, difference between probability of remission and CS-free remission, five-year risk of malignancy, annual risk of serious infection, annual risk of major adverse cardiovascular events and mode and frequency of administration. Relative importance (RI) was calculated using the difference in preference weights between the most and least preferred level of each attribute, scaled from 0 to 100%. An additional survey section was included to understand GE treatment and prescribing practices.

Results

A total of 397 GEs were included (France n = 140; Germany n = 40; Italy n = 40; Spain n = 47; UK n = 130). The most common GE-reported barriers to prescribing advanced therapies were concerns about contraindications and risks/side effects from patients (54.9%) and GEs (39.8%), perceived patient concerns about receiving injections or infusions (35.5%) and concerns about cost or insufficient reimbursement (32.2%). All DCE attributes factored into GE treatment decisions (see Table for RI and preference weights). The three most impactful attributes were probability of remission at one year (RI 48.4%), followed by 5-year risk of malignancy (RI 11.4%) and time to symptom improvement (RI 11.1%; Table).

Table. Preference weights and RI of attributes influencing advanced UC therapy choice (N = 397)
	Time to symptom improvement	Probability of remission at one year	Difference between probability of remission and CS-free remission	Five-year risk of malignancy	Annual risk of serious infection	Annual risk of MACE	Mode and frequency of administration
Attribute RI,a % (95% CI)b	11.1 (8.9, 13.4)	48.4 (45.7, 51.1)	8.0 (6.1, 10.0)	11.4 (9.5, 13.2)	6.7 (4.9, 8.5)	6.8 (5.0, 8.6)	7.5 (5.4, 10.1)
Preference weight level (95% CI)c
Level 1	2 weeks 0.50 (0.31, 0.69)	20% probability -2.11 (-2.42, -1.81)	0% difference 0.27 (0.13, 0.41)	1/1000 patients 0.49 (0.35, 0.62)	1/100 patients 0.27 (0.14, 0.40)	1/1000 patients 0.27 (0.14, 0.40)	Oral pill 1–2 times daily with potential dose change 0.15 (-0.02, 0.33)
Level 2	4 weeks 0.22 (0.09, 0.34)	35% probability 0.26 (0.18, 0.34)	5% difference 0.12 (0.03, 0.21)	3/1000 patients -0.04 (-0.13, 0.05)	3/100 patients 0.02 (-0.07, 0.10)	3/1000 patients 0.01 (-0.08, 0.10)	Oral pill 1–2 times daily with the same dose throughout 0.23 (0.10, 0.35)
Level 3	8 weeks -0.31 (-0.44, -0.18)	45% probability 1.85 (1.65, 2.06)	15% difference -0.39 (-0.48, -0.29)	5/1000 patients -0.45 (-0.54, -0.35)	5/100 patients -0.28 (-0.38, -0.19)	5/1000 patients -0.28 (-0.38, -0.19)	Injection every 1–2 weeks 0.01 (-0.12, 0.14)
Level 4	12 weeks -0.41 (-0.55, -0.27)	N/A	N/A	N/A	N/A	N/A	Infusion every 4–8 weeks -0.39 (-0.52, -0.26)
The DCE model included seven attributes, each with several preference weight levels. aRI is calculated as the difference in preference weights between the most preferred and least preferred level divided by the sum of the differences across all attributes; estimates sum to 100%. b95% CIs that do not include zero indicate a statistically significant RI of an attribute. All seven attributes were statistically significantly important when selecting an advanced therapy. 95% CIs that do not overlap for pairs of attributes indicate a statistically significant difference in importance between attributes. Probability of remission at one year was statistically significantly more important than all other attributes. cPreference weight levels are effects coded; zero indicates the mean effect across all attribute levels. CI, confidence interval; CS, corticosteroid; DCE, discrete choice experiment; MACE, major adverse cardiovascular events; N, total number of patients; N/A, not applicable; RI, relative importance; UC, ulcerative colitis.

Conclusion

All attributes factored into the trade-offs GEs consider when escalating patients with moderately to severely active UC to their first advanced therapy. Whereas risk of side effects was the most stated GE barrier to prescribing advanced therapy, probability of remission outweighed all other DCE attributes.

Disclosure

SS has received lecture/speaker fees from AbbVie, Arena, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Falk, Fresenius, Janssen, MSD, Pfizer Inc and Takeda; and consultancy/advisory fees from AbbVie, Arena, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Falk, Fresenius, Gilead Sciences, IMAB, Janssen, MSD, Mylan, Pfizer Inc, Protagonist, Provention Bio, Takeda, Theravance and Ventyx Biopharma. AW has received grant/research support from AbbVie, Pfizer, Lilly, Janssen, Buhlmann, BMS and Takeda. PH is an employee and shareholder of Pfizer Inc; shareholder of Liquidia, Idorsia, Clene Nanomedicine, Proctor Gamble, Longboard Pharmaceuticals and Haleon; and has IP/Patents for US 2022/0257594 A1. LP is an advisory/review panel member for ISPOR Planning Committee; a consultant, employee and shareholder of PrecisionAQ; and has received grant/research support from American Cancer Society, NIH, NCI, Fred Hutchinson Cancer Research Center, Microsoft, AHRQ, Gordon and Betty Moore Foundation. BH, JC, JCC and XG are employees and shareholders of Pfizer Inc. GG and NP are consultants for PRECISIONheor. KW is an employee and shareholder of Pfizer Canada Inc. AB has received lecture and consulting fees for AbbVie, Amgen, Arena, Biogen, Janssen, MSD, Mayoly-Spindler, Norgine, Pfizer, Roche, Takeda and Tillots.

Introduction

Therapeutic sequencing is a burning question in patients with ulcerative colitis (UC) requiring an advanced therapy. Whether starting with a less effective but safer and more convenient drug is a loss of chance for UC patients or can be rescued by later treatments is key point.

Aims & Methods

In the APPETISER study, we compared the effectiveness of two strategies based on the choice of the first biologic owing to either the drug efficacy in network meta-analyses and randomized controlled trials (vedolizumab or infliximab) or better acceptability (full subcutaneous therapy: adalimumab and golimumab) to induce and maintain steroid-free clinical remission during the first 24 months.
We collected real-world data from an IBD referral center including all consecutive UC patients ≥ 18 years-old who started a first line of biologic for active UC with follow-up > 6 months. Prior colectomy or severe acute colitis were excluded. Patients were included in either effectiveness-based sequencing (EBS) if they started with infliximab or vedolizumab, or in acceptability-based sequencing (ABS) if they received adalimumab or golimumab as first-line biologic.
The primary endpoint was remission defined according to PRO2 (PRO2-remission) as the absence of bleeding, normalization of transit (Mayo stool frequency subscore = 0) and no steroid. PRO2-remission was defined as a binary criterion each month (the statistical unit being the month and not the patient).
The secondary endpoints concerned the analysis by patient and were CFREM (partial Mayo score ≤ 2 without steroid) at week 12 and 52, endoscopic remission (CFREM + score Endoscopic Mayo ≤ 1) at week 12, time to drug discontinuation and time to colectomy.
All comparisons were adjusted using propensity scores on potential confounders. Analysis by month was performed using mixed models to account for repeated data.

Results

Overall, 130 patients were included including 60 patients in the EBS group (IFX= 50 and VDZ= 10) and 70 in the ABS group (ADA= 48 and GLM= 22).
The populations had similar characteristics at baseline apart from concomitant immunosuppressant more frequent in EBS group (55.9% vs 21.7%). 2^nd line treatment was started in 26.7% of patients in EBS group (ADA in 48.8%, VDZ 25.5% and ustekinumab 18.8%) and 87.1% of patients in ABS group (IFX in 54.1%, VDZ 31.1%).
After adjustment, the rate of CFREM was significantly higher in EBS arm than in ABS arm at week 12 (70.8% vs 33.0%, p < 0.001) and week 52 (72.8% vs 42.1%, p = 0.017). The rate of endoscopic remission at W12 was 22.1% and 10.0% in EBS and ABS arms, respectively (p =0.086).
For the primary endpoint, 3350 months were analyzed (1180 in EBS arm and 1175 in ABS arm). The percentage of months spent in PRO2-CFREM in the first 24 months (primary endpoint) was greater in EBS arm than in ABS arm (74.2% vs 46.6%; p<0.001). The percentage of months spent in CFREM was higher in the IV arm in the first 6 months (60.4% vs 18.9%), and was not rescued later: between M7 and M12 (73.1% vs 38.6%), M13 and M18 (79.9% vs 57.0%) or M19 and M24 (83.3% vs 64.6%) (p < 0.001 for all comparisons).
Regarding long-term data, EBS group had a lower risk to first-line biologic discontinuation (aHR=6.5 [2.8-15.3], p <0.001) and a clear trend for lower risk of colectomy (aHR=4.5 [0.9-22.3], p =0.068).

Conclusion

Our data highlight that the choice of first-line biological therapies is highly impacting the evolution of ulcerative colitis and cannot be rescued by later treatments. Thus, the results of the APPETISER study advocate for the use of the most effective therapeutic option as first line of biologic.

Disclosure

Anthony BUISSON: Consulting fees for Abbvie, Amgen, Arena, Biogen, Celltrion Healthcare, CTMA, Galapagos/Alfa Sigma, GutyCare/Resilience, Janssen, MSD, Nexbiome, Pfizer, Roche, Sandoz, Takeda, Tillotts. And Viatris. Lecture fees for Abbvie, Amgen, Biogen, Celltrion Healthcare, Galapagos/Alfa Sigma, Janssen, Mayoli-Spindler, MSD, Nordic Pharma, Norgine, Pfizer, Roche, Takeda, Tillotts and Vifor Pharma. Research grants from: Abbvie, Celltrion Healthcare, Galapagos/Alfa Sigma, Janssen, Lessaffre, Lilly, Pfizer, Takeda.

Introduction

Ulcerative colitis (UC) is increasing in prevalence and incidence in Korea, and each patient shows a different course and treatment response. Since the 2000s, biologics have been developed and treatment options have diversified. Biologics and small-molecule therapeutics for immunological targets are currently under research and development. In the past, the goal was clinical improvement, including symptoms, but now endoscopic mucosal healing and, furthermore, the continuation of histological remission are gradually suggested. Accordingly, the purpose of this study was to identify clinical factors that could predict histological remission in patients receiving a first-line biologic agent, as well as confirm the patient's response to treatment and prognosis.

Aims & Methods

We retrospectively analyzed the medical records of 440 patients who had been diagnosed with UC and exposed to biologics for the first time in our hospital without using biologics at other hospitals between January 01, 2010 and December 31, 2022. Patients who did not undergo pre- and post-exposure endoscopy and biopsy or whose follow-up was discontinued were excluded. Clinical characteristics, blood tests, endoscopic findings, and pathological examination results of a total of 72 patients were collected. Endoscopic response was defined as a decrease in the Mayo Endoscopic Subscore (MES) compared to the score before the first exposure to the biological agent. Histological remission was defined as the result of no cryptitis, no crypt abscess, or no inflammatory cells observed on histological examination, and histological response was defined as remission in patients previously observed with active inflammation.

Results

The ratio of males to females was 53:19, and the median age at the time of diagnosis was 41 years. The average Mayo score at the time of diagnosis was 7.2, and the group with a histological response was 6.0, showing a statistically significant difference. The average albumin was 3.88 and was 4.06 in the histological response group, with a statistically significant difference. The median time to exposure to the first biologic was 1520 days. A colectomy was performed in three cases. Biologics were started with infliximab in 46.7% of patients, followed by adalimumab and vedolizumab in 22.7% and 21.3%, respectively. There was no statistical correlation between histological response and each biologic agent.
MES before exposure to biological agents was 50% in 2 and 44.4% in 3, but there was no statistical difference between each group. Multivariate logistic regression analysis was performed to identify predictors of endoscopic and histological responses after the first exposure to biological agents. As a result, it was confirmed that the Mayo score, ESR, and albumin had a causal relationship with the endoscopic response, respectively, and the odds ratio was 0.781, 1.051, and 3.319, respectively (p-value 0.044, 0.007, 0.049). In addition, it was confirmed that the Mayo score had a causal relationship with the histological response with an odds ratio of 0.796 (p-value 0.046).

Conclusion

This study confirmed that disease activity before treatment was a predictor of histological remission in UC patients using first-line biologics. It was confirmed that the histological response as well as the endoscopic response were well induced when the disease activity was low. Therefore, early escalation to biologics before the patient's condition worsens may be the basis for improving the overall prognosis.

References

Park, Sang Hyoung et al. “Clinical Characteristics and Long-term Prognosis of Elderly-Onset Ulcerative Colitis in a Population-Based Cohort in the Songpa-Kangdong District of Seoul, Korea.” Gut and liver vol. 15,5 (2021): 742-751. doi:10.5009/gnl20289
Park, Sunhee et al. “Histological Disease Activity as a Predictor of Clinical Relapse Among Patients With Ulcerative Colitis: Systematic Review and Meta-Analysis.” The American journal of gastroenterology vol. 111,12 (2016): 1692-1701. doi:10.1038/ajg.2016.418

Introduction

As a first-line biotherapy, vedolizumab showed superior efficacy compared to adalimumab in the VARSITY trial, which, combined with a favorable safety profile, should position it in a privileged position in bionaïve patients with ulcerative colitis (UC). However, a proportion of patients have an insufficient response and/or intolerance, resulting in the need for a 2nd line of advanced therapy. To date, there are no data on the efficacy of biotherapies and small molecules in the 2nd line treatment of UC, after vedolizumab has failed. The objective of our study was to compare the efficacy of anti-TNFs, ustekinumab and JAKi in 2nd line in UC, after prior exposure to vedolizumab.

Aims & Methods

We conducted a retrospective multicenter study in 27 French and Belgian GETAID centers. All UC patients treated with vedolizumab in the first-line setting who received a second-line of anti-TNFs, ustekinumab and JAKi were retrospectively included. The primary outcome was corticoid-free remission at induction (week 14) defined by a clinical partial Mayo score of 2 or less, with no subscore greater than 1, in patients still receiving 2nd line therapy. The response was defined as a decrease in partial Mayo score of at least 30%. We also assessed the persistence rate of second-line treatments using the Kaplan-Meier method.

Results

203 patients were included with a median follow-up of 5 months (IQR: 3.0-11.0). Of the 203 patients, 123 (60.6%), 64 (31.5%) and 16 (7.9%) were treated with anti-TNF, ustekinumab and JAKi in the second-line setting. The median duration of disease progression was 39 months prior to the introduction of the second line (IQR 15-137.0). Vedolizumab was discontinued in 109 patients for primary failure (53.7%), 81 patients for secondary failure (34.9%), and 14 patients for adverse reaction (7.4%).
At week 14, 31/95 (32.6%) patients on infliximab, 7/27 (25.9%) on SC antiTNF, 20/63 (31.7%) on ustekinumab and 7/16 (43.8%) treated with JAKi achieved corticosteroid-free remission. Remission rates were 37.9% for patients on infliximab, 33.3% on SC antiTNF, 50% on JAKi, and 38.1% on ustekinumab. Response rates were 51.6%, 40.8%, 52.4%, and 62.5%, respectively, for the infliximab, antiTNF SC, ustekinumab and JAKi groups.
At 1-year, overall treatment persistence was 41.9% [IC 95% 34.7-50.6%]. Treatment persistence was 45.2% [35.0-58.4] in patients treated with infliximab, 43.3% [27.8-67.5] for antiTNF SC, 40.4% [28.2-58.0] in the Ustekinumab group and 18.8% [5.5-64.3] for the JAKi.
Second-line therapy was discontinued in 37 patients (34.9%) for primary failure, 53 (50%) for secondary failure and 16 (15.1%) for adverse reaction.
The overall adverse reaction rate was 31/203 (15.3%), of which 16 resulted in discontinuation (15.1%). In patients on infliximab, the overall rate was 19/96 (19.8%), and infliximab was discontinued in 10 patients (10.4%) due to adverse reactions. With JAKi, the overall rate was 1/16 (6.3%) with no cases of herpes zoster or thrombo-embolic events. Finally, in the 64 patients treated with ustekinumab, only 5 side effects especially arthralgias were reported (7.8%).

Conclusion

This is the largest real-world study of the efficacy of second-line treatments after vedolizumab in UC. Corticosteroid-free remission rates at induction appeared to be similar between the different treatment groups. About forty percent of patients remained on second-line treatment at one year. Discontinuation of second-line treatment was predominantly related to primary or secondary failures. Efficacy at induction appeared to be similar between the different treatment groups. ​

Introduction

To examine the evolution of the ulcerative colitis (UC) treatment pathway in advanced therapy (AT) naïve and later line EU4+UK patients over time, as well as identifying how treatment goals may have changed.

Aims & Methods

A multi-centre online medical chart review study of patients with UC was conducted between Jan – Mar 2018, Jul – Sep 2020 and Jan – Mar 2023, among EU4+UK (UK, FR, DE, IT & ES) gastroenterologists practicing across hospital and private practices. Recruited physicians were screened for duration of practice in their specialty and caseload. Respondents completed patient record forms of their next 4 UC patients seen following receipt of the survey.

Results

The total number of sampled gastroenterologists recruited in this survey and reported UC patients are in Table 1.

Table 1: Sampled physician and reported patient sample size

Timepoint	Q1 2018	Q3 2020	Q1 2023
Surveyed gastroenterologists	207	211	220
Reported UC patients	816	844	880

Between Q1’18 – Q3’20 - Q1’23 the percentage usage of total adalimumab volume in reported UC patients dropped (30% vs 15% vs 13%, respectively), as well as the proportion of these patients reported as first line adalimumab patients (90% vs 88% vs 87%, respectively). In addition, the proportion of reported patients who experienced a switch from one TNF to another also drops between Q1’18 – Q3’20 (14% vs 10%, respectively). Conversely, the proportion of reported UC patients receiving a non-TNF therapy increases over time (12% vs 29% vs 43%, respectively); specifically, the proportion of reported non-TNF first line patients increased (5% vs 12% vs 25%, respectively). Switches from non-TNFs to TNFs increased between Q1’18 – Q3’20 (8% vs 11%, respectively). The proportion of the overall sample occupied by first line patients decreased between Q1’18 – Q3’20 (84% vs 77%, respectively).

Conclusion

In this study cohort, use of adalimumab molecule decreases over time, seemingly in favour of non-TNF therapies, as more products become available in the gastroenterology landscape. This trend is seen across both the overall market and at first line of therapy, suggesting a move away from use of the more ‘traditional’ therapies in general, as well as more frequently choosing a non-TNF as a first line option. The increasing proportion of non-TNF 1st line patients, as well as the increasing proportion of those switching from non-TNFs to TNFs, suggests an increasing proclivity to use non-TNF products earlier in the treatment algorithm. TNF cycling also decreases, suggesting an increased tendency to use non-TNF products. This, along with the decreasing proportion of the sample occupied by first line patients, could indicate an increased propensity by gastroenterologists to switch patients between therapies sooner. Further investigation using comparator cohort is warranted to further investigate impact of increasing numbers of approved UC treatment options.