Introduction

There is a need for more effective treatments for IBD, with advanced therapies having placebo-adjusted clinical remission rates of only 10 to 25%. The combined use of targeted biologic agents could break through this efficacy ceiling while avoiding the risks associated with broad immunosuppression. Towards this end, Spyre Therapeutics is developing half-life extended antibody drug candidates that can be administered in combination, inhibiting the clinically validated IBD targets α4β7 integrin (SPY001), TL1A (SPY002), and IL-23 (SPY003). The efficacy of combined inhibition of integrin β7 and TL1A, integrin β7 and IL-23, and TL1A and IL-23 was evaluated in proof-of-concept studies utilizing the TNBS-induced murine colitis model.

Aims & Methods

Mice were dosed intravenously with surrogate antibodies targeting mouse integrin β7 (25 mg/kg), mouse TL1A (25 mg/kg), mouse IL-23 (25 or 1 mg/kg), pairwise combinations of these three antibodies (integrin β7 + TL1A, integrin β7 + IL-23, TL1A + IL-23), an isotype control antibody, or vehicle on Day -1 and Day 2. TNBS was administered intrarectally (IR) on day 0 to induce colitis in all mice except the non-disease control group, which received IR vehicle. Body weight and disease activity score were recorded daily until the end of the study on Day 6. Colon weight and length were measured at the conclusion of the study. Colon histopathology was scored by a blinded pathologist.

Results

Monotherapy treatment with 25 mg/kg anti-β7 or 25 mg/kg anti-TL1A antibodies resulted in low magnitude, directional improvements in colitis outcome measurements, while treatment with 25 mg/kg anti-IL-23 antibody resulted in significant improvements relative to the vehicle and isotype control groups. Combinations of anti-β7 + anti-TL1A, anti-β7 + anti-IL-23, and anti-TL1A + anti-IL-23 resulted in superior efficacy compared to their constituent monotherapies based upon disease activity scoring. To further explore combination therapy benefit, a lower dose (1 mg/kg) of anti-IL-23 alone or in combination with anti-β7 or anti-TL1A was evaluated. Low dose anti-IL-23 showed minimal activity as a monotherapy, but low dose anti-IL-23 + anti-β7 maintained efficacy similar to the high dose combination. The combination of low dose anti-IL-23 + anti-TL1A was more effective than either monotherapy alone.

Conclusion

Combination therapy with anti-β7 + anti-TL1A, anti-β7 + anti-IL-23 or anti-TL1A + anti-IL-23 resulted in efficacy superior to their constituent monotherapies in the murine TNBS model of colitis. These data support and provide biologic rationale for the advancement of antibody combinations into human clinical trials for inflammatory bowel disease.

Disclosure

All authors are employees and shareholders in Spyre Therapeutics, Inc.

Introduction

Current guidelines provided information on the management of patients with gastrointestinal bleeding, in particular focusing on admission, endoscopic management and medical treatment during the hospital stay. So far, 11-15% of patients treated for GIB required a new hospitalization for a new bleeding episode.

Aims & Methods

The aim of the study is to verify if the management in a dedicated practice after hospital discharge for gastrointestinal bleeding reduces further bleeding and costs. This is an ambispective cohort single center study, including patients observed between May 2022 and September 2023 in our clinical practice dedicated to gastrointestinal bleeding. We enrolled consecutive patients with overt gastrointestinal bleeding or iron deficiency anemia affected by vascular lesions. The effectiveness was defined as a composite endpoint including iron supplementation, blood transfusion, medical treatment and number of hospital stay. Costs were evaluated starting from Diagnosis Related Groups (DRG) codes. The cost effectiveness analysis and ICER has been calculated using the ICERconf.EXE software (Software Prescriptions, c/o Bob Obenchain, California, USA).

Results

In our institute 602 patients with gastrointestinal bleeding were evaluated between May 2022 and September 2023, of these 79 were included in the study. The mean age was 73.8 years (SD±10,8), 46% were female. The source of bleeding was angiodysplasia in 63% of patients, GAVE in 9% (Gastric Antral Vascular Ectasia), erosions in 9%. After the introduction in the dedicated practice, the re-bleeding decrease from 1.3 episodes to 0.2 episodes, p<0.001. The cost average after the practice was 4074 euro (SD ±5485), the average cost before the practice was 4885 euro (SD ±4567), it has been observed a cost saving after the management in the dedicated practice, C diff= -751 euro. The average effectiveness after practice was 8.7 (SD±1.06) and the average effectiveness before the practice was 7.3 (SD ±1.3) with the E diff= 1.47, p<0.001.

Conclusion

The dedicated practice for patients with gastrointestinal bleeding provides effectiveness in reducing transfusion, iron supplementation and hospitalization with a consistent cost reduction.