Introduction

Precision medicine aims to expand upon the summary average treatment effects reported in clinical trials by providing more refined, individualised estimates of treatment effects. The phase IIb TUSCANY-2 study (NCT04090411), which examined the efficacy and safety of afimkibart (RO7790121/RG6631; previously PF-06480605/RVT-3101), an anti-TL1A antibody, in patients (pts) with moderate to severe ulcerative colitis (UC), previously reported clinically meaningful treatment effects at UEGW 2024.¹ Here, we report post hoc analyses of the relationship between baseline clinical characteristics and Week 14 efficacy in pts enrolled in TUSCANY-2.

Aims & Methods

Pts were randomised to receive subcutaneous afimkibart 50mg, 150mg, 450mg or matched placebo (PBO) monthly during induction. In this post hoc analysis, all afimkibart doses were pooled, and the endpoint of interest was clinical remission by modified Mayo score (mMS; defined as stool frequency subscore=0 or 1; rectal bleeding subscore=0; and endoscopic subscore [ES]=0 or 1) at Week 14. Our investigation of more patient-specific treatment effects was guided by the Predictive Approaches to Treatment effect Heterogeneity (PATH) statement.² We developed a regularised logistic regression model to predict the probability of Week 14 remission and to help examine heterogeneity of treatment effects based on the following baseline characteristics: mMS, C-reactive protein (CRP), serum albumin, Robart’s Histopathology Index (RHI), number of failed advanced therapy classes, corticosteroid use, disease extent, disease duration, age and sex. Baseline faecal calprotectin (FCP) was investigated separately due to the extent of missing data.

Results

The proportion of pts achieving clinical remission by mMS at Week 14 in the afimkibart pooled dose arm was 32.5% (65/200; 90% confidence interval [CI]: 27.3 to 38.1) compared with 13.3% (6/45; 90% CI: 7.1 to 23.8) of pts in the PBO arm (treatment delta: 19.2%; 90% CI: 7.6 to 27.9). Based on calibrated predictions from the multivariate model, all of the individual TUSCANY-2 pts (both treated with PBO and afimkibart) had anywhere between a 2–76% probability of Week 14 remission at baseline. The clinical characteristics included in the model explained ~10% of the variability in the observed outcomes. There was no evidence that the clinical characteristics were associated with heterogeneous treatment effects on the relative scale (odds ratios appeared to be constant; p-value >0.5). On the clinically meaningful absolute scale, the treatment delta in the top 50% of pts with a higher baseline probability of remission (27–76%) was 28.5% (90% CI: 8 to 42; 45.2% in afimkibart pooled dose arm vs 16.7%, in PBO arm), compared with a treatment delta of 7.6% (90% CI: –7 to 18; 18.8% in afimkibart pooled dose arm vs 11.1%, in PBO arm) in pts with a lower baseline probability of remission (2–27%). Lower baseline CRP, lower RHI and higher serum albumin contributed to a greater probability of remission and absolute benefit from treatment with afimkibart.

Conclusion

Pts with inflammatory bowel disease (IBD) have diverse baseline characteristics that are associated with variability of treatment outcomes, yet clinicians rely on reported averages from clinical trials to make individual treatment decisions. This analysis demonstrates how precision medicine approaches, that account for diverse characteristics, may improve interpretation of positive IBD clinical trial results. Integrating genetic and novel biomarkers alongside clinical features could help to better predict individual outcomes for pts with IBD.

References

1. Danese S, et al. Presented at UEGW 2024 (Oral presentation OP079).
2. Kent D, et al. The Predictive Approaches to Treatment effect Heterogeneity (PATH) Statement. Ann Intern Med 2020;172:35–45.

Disclosure

This study was sponsored by F. Hoffmann-La Roche Ltd. Third-party medical writing support, under the direction of the authors, was provided by Victoria Dagwell, MSc, of Ashfield MedComms, an Inizio company, and was funded by F. Hoffmann-La Roche Ltd.
LP-B reports consulting or advisory role/board from AbbVie, Abivax, Adacyte, Alimentiv, Amgen, Applied Molecular Transport, Arena, Banook, Biogen, Bristol Myers Squibb, Celltrion, Connect Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Inc., Gilead, Gossamer Bio, GSK, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Nordic Pharma, Novartis, Oncodesign Precision Medicine, ONO Pharma, OSE Immunotherapeutics, Pandion, Par' Immune, Pfizer, Prometheus, Protagonist, F. Hoffmann-La Roche Ltd, Samsung, Sandoz, Sanofi, Satisfay, Takeda, Telavant, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vectivbio, Ventyx and Ysopia; speakers’ bureau from AbbVie, Alfasigma, Amgen, Arena, Biogen, Celltrion, Ferring, Galapagos, Genentech, Inc., Gilead, Janssen, Kern Pharma, Lilly, Medac, MSD, Nordic Pharma, Pfizer, Sandoz, Takeda, Tillots and Viatris. JRA reports consulting or advisory role/board from Janssen, Pfizer, AbbVie, Vedanta, Genentech, Inc., Seres Therapeutics, Ferring, GSK, Merck, Bristol Myers Squibb, Roivant, Celltrion, TRXBio and Shattuck Labs; speakers’ bureau from AbbVie and Janssen. SD reports consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Lilly, Enthera, Ferring Pharmaceuticals, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, F. Hoffmann-La Roche Ltd, Sandoz, Sublimity, Takeda, Teladoc Health, TiGenix, UCB, Vial and Vifor; lecture fees from AbbVie, Amgen, Ferring Pharmaceuticals, Gilead, Janssen, Mylan, Pfizer and Takeda. PSD reports employment at Northwestern University; consulting or advisory role/board from AbbVie, Adiso, Alimentiv, Celltrion, Genentech/Roche, Geneoscopy, Janssen, Shattuck and Takeda; research funding from Takeda and Bristol Myers Squibb. AB reports employment and stockholder from Pfizer. DEC reports employment and stock ownership from Pfizer. EP reports employment, stock or other ownership interests and patents, royalties, other intellectual property from Pfizer. SN reports employment and stock or other ownership interests from Pfizer. MSV reports employment and shareholder from Pfizer. KH reports no conflict of interest. LU reports employment at Genentech, Inc. CS reports employment, stock or other ownership interests from Genentech/Roche. DB reports employment at F. Hoffmann-La Roche Ltd. KL reports employment and stock or other ownership interests from Genentech, Inc. BES reports honoraria for consulting from AbbVie, Adiso, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, Artugen, AstraZeneca, Biolojic Design, Biora, Boehringer Ingelheim, Boston Pharmaceuticals, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Enveda, Evommune, Ferring, Fresenius Kabi, Fzata, Galapagos, Genentech/Roche, Gilead Sciences, GSK, Gossamer Bio, Imhotex, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Kaleido, Kallyope, Merck, Microbiotica, Mitsubishi Tanabe, Mobius Care, Morphic, MRM Health, Nexus, Nimbus Discovery, Odyssey, OSE Immunotherapeutics, Palisade Bio, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist, Q32 Bio, Rasayana, Recludix, Reistone, Sanofi, Sorriso, Spyre, Surrozen, Target RWE, Teva, TLL Pharmaceutical, Tr1X, Union and Ventyx; consulting/speaking fees from Abivax; consulting/speaking fees/other support from Lilly; research grants/consulting/speaking fees/other support from Bristol Myers Squibb, Lilly, Janssen, Pfizer and Takeda; research grants/consulting fees from Janssen; stock/stock options from Ventyx.

Introduction

Colectomy is the primary treatment for dysplastic lesions in inflammatory bowel disease (IBD). Since the development of advanced endoscopic techniques, the management of dysplasia is evolving. Endoscopic submucosal resection (ESD) could be used in selected cases at referral centres as an alternative to colectomy. However, the feasibility and safety in IBD remains limited.

Aims & Methods

To evaluate en-bloc resection rate and the need of colectomy due to ESD failure in IBD.
Secondary aims: to assess the complications of ESD, the local recurrence of dysplastic lesions, the presence of synchronous and metachronous lesions and the risk of IBD relapse following the procedure.
Multicentre, retrospective study of IBD patients who underwent ESD for suspected colonic dysplastic lesions at least one month before the inclusion date. Patients with total colectomy before ESD, invisible dysplasia at the time of ESD, or pregnancy were excluded. En-bloc resection rate and colectomy due to ESD failure at the short term were evaluated by logistic regression analysis. The risk of IBD relapse was evaluated by Cox regression analysis.

Results

Sixty patients from 22 centres were included: 47 with ulcerative colitis, 11 with Crohn’s disease and 2 with IBD-unclassified. The mean age at ESD was 64 years (SD 13). The majority of the lesions (n=33, 55%) were located in rectum. Fifty lesions (83%) were located in areas previously inflamed. En-bloc and R0 were achieved in 58 (97%) and 50 patients (83%), respectively. Colectomy due to ESD failure was required in 5 patients (8.3%), all of them occurred within 6 months after ESD. No risk factors were associated with colectomy in multivariable analysis, including inflammatory activity, IBD treatments or characteristics of the lesions. Complications occurred in 17 patients (28%): 3 did not required any treatment, 6 required pharmacologic therapy, 6 needed endoscopic or radiologic intervention, and 2 underwent surgery (Table 1). No deaths were reported.
At least one surveillance colonoscopy after ESD was performed in 42 patients (70%). Local recurrence was observed in 2 patients (4.7%) while other dysplastic lesions were detected in 11 (26%) during the follow-up (median 1.5 years, IQR 0.5-3.4). All these lesions were removed endoscopically. Synchronous and metachronous lesions were identified in 4 (20%) and 9 patients (19%), respectively. IBD relapse occurred in 8 patients during the follow-up, with an incidence rate of 7% person-year (CI 95%:3-13). The occurrence of relapses was gradually throughout the follow-up period.

Table 1. Complications of endoscopic submucosal dissection

Conclusion

ESD avoids colectomy in 90% of IBD patients with dysplastic lesions. One-third of the patients experienced complications, all of them resolved with no sequelae. Given the risk of new dysplastic lesions, ongoing monitoring with surveillance colonoscopies is recommended.

Disclosure

María José García has received financial support for travelling and educational activities from Janssen, Pfizer, AbbVie, Takeda, Kern Pharma, Faes Farma and Ferring.
Edoardo Vincenzo Savarino has served as speaker for Abbvie, Abivax, Agave, AGPharma, Alfasigma, Apoteca, Biosline, CaDiGroup, Celltrion, Dr Falk, EG Stada Group, Fenix Pharma, Galapagos, Johnson&Johnson,consultant for Abbvie, Agave, Alfasigma, Biogen, Bristol-Myers Squibb, Celltrion, Dr. Falk, Eli Lilly, Fenix Pharma, Ferring, Giuliani, Grunenthal, Johnson&Johnson, JB Pharmaceuticals, Merck & Co, Nestlè, Pfizer, Reckitt Benckiser, Sanofi/Regeneron, SILA, Sofar, Takeda, Unifarco; he received research support from Bonollo, Difass, Pfizer, Reckitt Benckiser, Sanofi/Regeneron, SILA, Sofar, Unifarco, Zeta Farmaceutici.
Irene González-Partida has received support for conference attendance and speaker fees from AbbVie, Dr. Falk Pharma, Ferring Pharmaceuticals, Janssen, MSD, Kern, Pfizer, Shire, Takeda, Teva and Tillotts Pharma AG.
Alicia López has served as speaker for Chiesi, Takeda, ABBVIE, Lilly. I have received support for conference attendance from Pfizer, Lilly, Kern Pharma, Falk, Ferring, and Janssen
Jordina Llao has received educacional suport from Abbvie, Tillots, Ferring and Lilly.

Introduction

Tumor necrosis factor-like ligand 1A (TL1A) is a member of the Tumor necrosis factor (TNF) superfamily implicated in the pathogenesis of inflammatory bowel disease (IBD) as a key amplifier of the effector function of several immune cells. TL1A can be expressed by various immune cells, including macrophages, dendritic cells, and some T cell subsets, and exists either as a membrane-bound or as a cleaved soluble trimer. TL1A signals predominantly by activating NF-kB pathway via the only known functional receptor, death receptor 3 (DR3), which has restricted expression mostly on effector T cells and innate lymphoid cells (ILCs). Afimkibart is a fully human anti-TL1A antibody that has shown clinical benefit in Phase 2 clinical studies and specifically blocks the activity of trimeric forms of TL1A. Monomeric TL1A has also been described; however, the relevance of monomeric TL1A in DR3 signaling and disease is unclear. This study aimed to understand the functional characteristics of both monomer and trimer TL1A species in primary cells and cell lines.

Aims & Methods

Immunoassays were used to measure the detection of TL1A species in IBD serum. Recombinant human monomeric and trimeric TL1A proteins were assessed for binding to afimkibart using SPR and in cellular assays using primary immune cells and cell lines for nuclear factor-kappa B (NF-κB) signaling and interferon-gamma (IFNγ) production.

Results

In functional cellular assays with primary immune cells, we demonstrate that trimeric recombinant human TL1A (rhTL1A) protein causes significant NF-κB signaling in human peripheral T lymphocytes, and in the presence of interleukin 12 (IL12) and interleukin 18 (IL18) co-stimulation, a significant increase of IFNγ production by human primary peripheral blood mononuclear cells (PBMCs). In line with the mechanism of action, both the NF-κB signaling and IFNγ production are blocked by afimkibart. In contrast, only high concentrations of monomeric rhTL1A, >100 ng/ml, induced moderate NF-κB signal and demonstrated a minimal increase in IFNγ production above IL12 + IL18 stimulation alone. However, this activity was blocked by afimkibart. Lastly, afimkibart blocks endogenous soluble and membrane-bound TL1A.

Conclusion

Herein, we demonstrate that afimkibart blocks NF-kB signaling and IFNγ production induced by TL1A stimulation. While some signaling activity was observed at high concentrations of monomeric TL1A protein, we hypothesize that any signaling observed with monomeric form is likely due to the formation of trimers, which are efficiently blocked by afimkibart. Overall, any monomeric TL1A present should not be functionally active nor be available as a sink for afimkibart, thus preserving the optimal pharmacokinetic (PK) and pharmacodynamic (PD) properties needed for effective target inhibition.

Disclosure

All the authors are employees of Genentech-Roche.