Introduction

While three JAK inhibitors are now available in Ulcerative Colitis (UC), the hierarchy of these treatments according to their effectiveness, remains to be determined.

Aims & Methods

In the JAKARTA study, we aimed to compare the effectiveness of the three available JAK inhibitors (tofacitinib/TOFA, filgotinib/FILGO and upadacitinib/UPA) in bio-exposed patients with UC.
In this retrospective multicenter study (12 centres), we included all consecutive patients with UC ≥18 years-old, partial Mayo score > 2 who had started TOFA, FILGO or UPA after receiving ≥ 1 biologic between JAN2019 and JUN2022. Acute severe UC were excluded.
Following regimen were applied for TOFA (10mg b.i.d until W8 and 5mg or 10 mg b.i.d according to physician’s judgement), FILGO (200mg q.d) and UPA (45mg q.d until W8 and 45mg, 30 mg or 15 mg q.d according to physician’s judgement).
The primary endpoint was symptomatic remission (partial Mayo score ≤ 2) without corticosteroids (CFREM) at W16. Secondary endpoints were clinical and endoscopic remission (CFREM + endoscopic Mayo score ≤ 1), histological and endoscopic mucosal improvement (HEMI) (= clinical-endoscopic and histological remission (Nancy index ≤ 1)), drug retention (treatment discontinuation-free survival using Kaplan-Meier curve), time to colectomy, time to UC-related hospitalization and secondary loss of response among patients in CFREM at W16.
All the comparisons were performed using propensity scores adjustment (IPTW).

Results

A total of 290 patients were included: 150, 79 and 61 in TOFA, FILGO, and UPA arms, respectively. The 3 groups were comparable except for higher proportion of patients with previous exposure to > 3 biologics in UPA group (p < 0.001). TOFA 10 mg b.i.d was continued until W16 in 47.0% of patients. FILGO was maintained at 200 mg in 97.5%. UPA was diminished at 30 mg and 15 mg at W8 in 55.6% and 3.3% of patients, respectively.
After IPTW, CFREM at W16 was higher in UPA (60.1%) compared to TOFA (38.9%) or FILGO groups (36.0%) (p = 0.026 and 0.016, respectively). No predictive factor of efficacy/ failure was identified with these 3 JAK inhibitors.
We failed to show any significant difference regarding clinical-endoscopic remission (UPA:16.5%, TOFA:16.5%, FILGO:12.8%) or HEMI (UPA:11.9%, TOFA: 4.4, FILGO: 12.7%) at W16.
Among patients who reduced the dose to the recommended maintenance regimen (TOFA 5 mg b.i.d and UPA 30 or 15 mg q.d) between W8 and W16, the need for dose re-escalation to the induction dose was 33.8% (27/80) for TOFA, 14.7% (5/34) for UPA30mg and 50.0 % (1/2) for UPA 15 mg. After adjustment, drug retention was longer for UPA compared to TOFA (HR = 0.38 [0.17-0.85], p = 0.019) and FILGO groups (HR = 0.17 [0.08-0.65], p < 0.001) and shorter in FILGO than in TOFA group (HR = 1.57[1.02-2.41], p = 0.038).
No difference was demonstrated in terms of time to hospitalization or surgery between the 3 groups.
Among patients achieving CFREM at W16 (regardless of the dose), secondary loss of response (symptomatic relapse) was similar for TOFA:12.8% (N=47 patients), FILGO: 19.2% (N = 26 patients) and UPA: 10.3% (N = 29 patients) (p=ns after IPTW).

Conclusion

In this real-world evidence multicenter study, UPA was the most effective JAK inhibitor in UC at short and long-term but the large use of off-label maintenance doses in current practice needs further safety investigations.

Disclosure

Consulting fees from: Abbvie, Amgen, Arena, Biocon, Biogen, Celltrion Healthcare, CTMA, Ferring, Galapagos/AlfaSigma, GutyCare/Resilience Janssen, Lilly, MSD, Nexbiome, Pfizer, Roche, Sandoz, Takeda et Tillotts
Lecture fees from : Abbvie, Amgen, Biogen, Celltrion Healthcare Galapagos/AlfaSigma, Ferring, Janssen, Lilly, Mayoli-Spindler, MSD, Nordic Pharma, Norgine, Pfizer, Roche, Takeda, Tillotts and Vifor Pharma
Research grants/fundings from: Abbvie, Celltrion Healthcare, Janssen, Lessaffre, Lilly, Pfizer, Sandoz and Takeda

Introduction

Substantial genetic and clinical evidence indicates that TL1A has a key role in the molecular pathology of IBD. Variants in TNFSF15, the gene encoding TL1A, are associated with IBD, rheumatic, and other diseases. Circulating levels of the protein are elevated in patients with CD and UC. Proof-of-concept for TL1A inhibition in IBD is provided by positive Phase 2 trials of monoclonal antibodies targeting and inhibiting the cytokine in patients with UC and CD (1–3).
SPY002 is an investigational fully human IgG1 monoclonal antibody that specifically binds to TL1A at an epitope that is distinct from other TL1A antibodies in development. SPY002 blocks the interaction of TL1A with its receptor, known as death receptor 3 (DR3), and includes a YTE modification in the Fc domain to increase the binding affinity to FcRn and thereby extend the antibody half-life. A Phase 1, first-in-human study in healthy volunteers is being conducted to characterize the safety, tolerability, PK, and PD properties of SPY002.

Aims & Methods

SPY002-101 is a randomized, double-blind, placebo-controlled single ascending dose (SAD) Phase 1 study in healthy volunteers aged 18 to 65. Study participants were randomized to either SPY002 or placebo in a 3:1 ratio as in dose cohorts as follows: 100 mg SC, 300 mg SC, 300 mg IV, 1000 mg IV, or 1500 mg IV. Blood was collected to evaluate safety, PK, PD (serum soluble TL1A levels), and ADA assessments at scheduled study visits. Interim safety and bioanalytical data with up to three months of follow-up from the first SAD cohort were analyzed.

Results

Interim PK data from Cohorts 1-3 demonstrated dose-proportional pharmacokinetics for SPY002. Noncompartmental[BW1] [JF2] [JL3] [BW4] [JL5] analysis and population PK modeling suggested a half-life extension of approximately 3-fold relative to typical monoclonal antibodies. PD analysis demonstrated saturating effects on soluble TL1A levels beginning with the lowest dose tested (100 mg SC) that extend to the latest time points assessed thus far. Blinded safety data from all cohorts thus far demonstrated SPY002 to be well tolerated with no serious or severe adverse events, with most adverse events being mild in severity and unrelated to study agent.

Conclusion

Interim PK analysis following single doses of SPY002 demonstrated half-life extension supporting potential maintenance dosing at a frequency of every 3 to 6 months with a single SC injection. SPY002 resulted in saturating changes in soluble TL1A levels. SPY002 was well tolerated, with all adverse events being non-serious and typical of a Phase 1 study in healthy volunteers. These results support advancement of SPY002 into clinical trials in IBD, rheumatic, and other potential indications as a monotherapy and as a component of combination therapy.

References

1. B. Sands, L. Peyrin-Biroulet, S. Danese, D. T. Rubin, S. Vermeire, O. Laurent, A. Luo, D. Nguyen, J. D. Lu, A. Wiechowska-Kozlowska, J. Leszczyszyn, R. Kempinski, J. Kierkus, C. Ma, T. Ritter, B. G. Feagan, S. Targan, OP40 PRA023 Demonstrated Efficacy and Favorable Safety as Induction Therapy for Moderately to Severely Active UC: Phase 2 ARTEMIS-UC Study Results. J. Crohn’s Colitis 17, i56–i59 (2023).
2. B. G. Feagan, B. E. Sands, C. A. Siegel, M. C. Dubinsky, R. Longman, J. Sabino, O. Laurent, A. Luo, J. D. Lu, D. D. Nguyen, F. Towfic, A. DuVall, M. Woynarowski, H. A. Kharrat, D. McGovern, S1143 The Anti-TL1A Antibody PRA023 Demonstrated Proof-of-Concept in Crohn’s Disease: Phase 2a APOLLO-CD Study Results. Am. J. Gastroenterol. 118, S875–S876 (2023).
3. S. Danese, M. Klopocka, E. J. Scherl, J. Romatowski, J. R. Allegretti, E. Peeva, M. S. Vincent, U. Schoenbeck, Z. Ye, M. Hassan-Zahraee, N. Rath, G. Li, S. Neelakantan, C. Banfield, C. Lepsy, D. E. Chandra, K. E. Hung, Anti-TL1A Antibody PF-06480605 Safety and Efficacy for Ulcerative Colitis: A Phase 2a Single-Arm Study. Clin. Gastroenterol. Hepatol. 19, 2324-2332.e6 (2021).

Disclosure

All authors are employees of and own stock in Spyre Therapeutics.

Introduction

Despite recent advances in the treatment of IBD, patients still suffer from suboptimal efficacy and are eagering for more effective treatment options. Both human TL1A and IL-23 are clinically validated targets in treating IBD. Here we discovered and characterized SIM0709, a half-life extended bi-specific antibody simultaneously tarting both TL1A and IL-23p19, with the aim to further enhance clinical efficacy and improve patient’s compliance.

Aims & Methods

The binding activities to TL1A protein and IL-23 protein were determined by ELISA and BLI. Cell-based blocking functionalities of TL1A to DR3 and IL-23p19 to IL23R were evaluated by using FACS assays, meanwhile the competitive inhibition of TL1A binding to DcR3 and the inhibition of IL-23 binding to IL12R were also determined by ELISA. TL1A induced TF-1 cell apoptosis and interferon γ (IFNγ) secretion from CD4⁺ T cells stimulated by TL1A in combination with IL-12 and IL-18 were used to evaluate the outcomes of functional blockade of TL1A pathway. In addition, mouse IL-17 secretion from mouse splenocytes stimulated by human IL-23 was also assessed to evaluate the functional blockade of IL-23 pathway. The synergistic effect of dual pathway blockade was measured by Th17 differentiation co-stimulated with human IL-23 and TL1A. A cytokine-induced acute gut inflammation model was used to assess the in vivo efficacy of SIM0709 while the extended half-life was revealed in both human FcRn knock-in mice and non-human primate.

Results

SIM0709 simultaneously bound to both TL1A and IL-23 proteins with sub-nanomolar affinity and demonstrated superior functional activities under various functional assays on both TL1A and IL-23 axes compared to that of benchmark anti-TL1A mAb RG6631 and Guselkumab or its combination, respectively. SIM0709 also exhibited superior dual pathway blockade synergy in vitro in inhibiting Th17 differentiation and in vivo in the cytokine-induced acute gut inflammation model. Further analysis on ileum and colon tissues confirmed relived intestinal inflammation after SIM0709 treatment with significantly reduced inflammatory cytokines/chemokine levels and improved histological scores compared to either the anti-TL1A or anti-IL-23p19 monotherapies. SIM0709 also demonstrated an improved serum half-life in human FcRn knock-in mice compared to that of RG6631. Moreover, SIM0709 showed encouraging PK profile with over 15 days half-life, which together with its excellent developability profile, may support extended dosing interval in the clinic with a patient-friendly subcutaneous formulation.

Conclusion

Taken together, these data support the further development of SIM0709 as a potential FIC and BIC therapeutic agent for the treatment of IBD with expected first-in-human study in H1 2026.

Disclosure

The authors are employees of Jiangsu Simcere Pharmaceutical Co., Ltd and State Key Laboratory of Neurology and Oncology Drug Development.

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.

Introduction

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disease characterized by intestinal inflammation, mainly including Crohn’s Disease (CD) and Ulcerative Colitis (UC), both of which will cause swelling and ulceration in the inner wall of gastrointestinal tract ^[1]. ISM5411 is an oral gut-restrictive small molecule inhibitor targeting PHD2 to stabilize hypoxia inducible factors (HIF-1α), thus promoting the expression of intestinal mucosal protective genes, maintaining the integrity and functions of intestinal barrier to finally achieve the purpose of protecting and repairing intestinal mucosal barrier together with anti-inflammation. Preclinical studies demonstrated that ISM5411 can significantly alleviate the symptoms of multiple animal models of colitis without significant increase in systemic erythropoietin (EPO) or vascular endothelial growth factor (VEGF) ^[2]. The first-in-human Phase I study in Australia was completed to evaluate safety, tolerability, pharmacokinetics and food effect in healthy subjects.

Aims & Methods

ISM5411-101 was a randomized, double-blinded, placebo-controlled, single and multiple-dosed and food effect first-in-human Phase I study conducted in healthy subjects at a single site in Australia. Seven dose levels from 50 mg to 1000 mg of single ascending doses and three dose levels from 200 mg to 800 mg once daily for 14 days of multiple doses of ISM5411 were administrated. Safety and tolerability, pharmacokinetics (PK) parameters (plasma, urine and feces) and biomarkers (EPO and VEGF levels) were evaluated.

Results

Seventy-six subjects were dosed with no serious adverse events (SAEs) or deaths recorded. One treatment emergent adverse event (TEAE) leading to discontinuation of ISM5411 occurred (Grade 1, rectal hemorrhage) in 200 mg once daily ISM5411 cohort was reported and judged as not related to ISM5411. The incidence of TEAEs was 25.0% and 55.0% in ISM5411 pooled cohort (n=56) and placebo cohort (n=20). All TEAEs reported in ISM5411 pooled cohorts were Grade 1. After single and multiple doses administration, ISM5411 was rapidly absorbed and metabolized to metabolite (ISM5411-M15). The plasma exposure of both analytes was very low without apparent dose-proportional manner. ISM5411 was excreted in the feces in its prototypic form by more than 30%. Systemic EPO level increased post-dose in most cohorts then decreased, and most changes were within normal range. No clear trend was observed in the change of mean systemic VEGF levels across cohorts.

Conclusion

ISM5411 tablets were safe and well-tolerated and demonstrated good gut-restrictive property, consistent with the intended PK profile. Another Phase I study in China was also completed. Phase 2a proof of concept study of ISM5411 is under planned in patients with ulcerative colitis to explore the safety, PK and clinical efficacy.

References

1. Chang JT. Pathophysiology of Inflammatory Bowel Diseases. N Engl J Med, 2020 Dec 31;383(27): 2652-2664
2. Fu, Y., Ding, X., Zhang, M. et al. Intestinal mucosal barrier repair and immune regulation with an AI-developed gut-restricted PHD inhibitor. Nat Biotechnol (2024).

Introduction

Crohn's disease (CD) is a heterogeneous condition with potentially complicated course. We aimed to evaluate the rates and risk factors for complicated disease course within a real-world, prospective inception cohort of patients with newly diagnosed CD (ndCD).

Aims & Methods

This prospective, longitudinal cohort study included adults with ndCD managed at a tertiary referral center. Treatment decisions were made at the discretion of the treating physician. The key outcomes were: (1) complicated-disease course - defined as CD-related hospitalization, surgery, steroid dependency, or the use of ≥2 biologics; (2) extra-complicated disease course - defined as recurrent or prolonged hospitalization (>5 days), multiple perianal procedures, intestinal resection, steroid dependency, or the use of ≥3 biologics; and (3) phenotype progression. Kaplan-Meier survival analysis was used to assess rates of complicated course over 5 years, and multivariable Cox regression models were applied to identify baseline risk factors.

Results

A total of 192 patients with ndCD were enrolled; 70% presented with an inflammatory phenotype (B1) (see Table 1). Overall, 150 patients (78.1%) were recommended to start biologic therapy, with half receiving this recommendation within 4.1 months (95% CI: 2.1-6.3) from diagnosis. Of these, 134 patients (89.3%) initiated treatment - 50% within 6 months and 63.6% within 12 months. Cumulative outcome rates at 1, 3, and 5 years post-diagnosis were: complicated course - 24.2%, 35.9%, and 51.3%, respectively; extra-complicated course - 15.6%, 20.5%, and 29.0%, respectively; phenotype progression - 1.6%, 5.5%, and 10.6%, respectively. In a multivariable analysis, patients with a progressive phenotype (B2/B3) at diagnosis had significantly increased risk for complicated (HR 3.3, 95% CI:2.0-5.7) and extra-complicated (HR 6.7, 95% CI:3.1-14.4) disease course. Additional risk factors included elevated inflammatory markers and disease extent at diagnosis. We further analysed the subgroup of 33 patients with a B1 phenotype (~25% of those with a B1 phenotype) who were not recommended biologic therapy by their treating physician. In this subgroup, the complicated course was markedly low, 3.0%, 6.3%, and 11.5% at 1, 3, and 5 years, respectively, and none developed an extra-complicated course. Notably, this subgroup exhibited significantly lower inflammatory indices (CDAI, HBI, CRP, and fecal calprotectin) at diagnosis compared to patients for whom biologics were recommended (all p<0.001).

Table 1:

Conclusion

In this real-world cohort, applying a best-practice treatment approach, over half of patients with ndCD experienced a complicated course within five years, primarily those with a progressive phenotype at diagnosis. Notably, a subset of patients with an inflammatory phenotype and low inflammatory burden had favorable long-term outcomes without biologics, underscoring the importance of early risk stratification to guide individualized treatment strategies.