Introduction

In SBS-IF, patients (pts) depend on parenteral support (PS) to meet nutritional and/or fluid requirements. Apraglutide (APRA) is a long-acting novel GLP-2 analogue dosed once-weekly that stimulates intestinal adaptation, with the potential to reduce PS requirements. This phase 3 trial assessed the efficacy and safety of APRA vs placebo (PBO) in adult pts with SBS-IF.

Aims & Methods

In this phase 3 double-blind, PBO-controlled trial (NCT04627025) conducted in 73 centres and 18 countries, 164 pts were randomized 2:1 to once-weekly subcutaneous APRA (5 mg if pt ≥50 kg, 2.5 mg if pt <50 kg) or PBO, stratified by intestinal anatomy (stoma or colon-in-continuity [CIC]). The primary endpoint was relative change from baseline (BL) in weekly PS volume at Week (Wk) 24. Key secondary endpoints at Wk 24 were reduction of additional ≥1 day/Wk off PS from BL, and in the stoma subgroup, relative change from BL in weekly PS volume. Two other key secondary endpoints at Wk 48 in the CIC subgroup were reduction of ≥1 day/Wk off PS, and percentage of pts reaching total enteral autonomy. Wk 24 clinical responders were defined as proportion of pts with ≥20% PS reduction at Wks 20 and 24. Adverse events (AEs) were collected.

Results

​A total of 163 dosed pts (80 stoma; 83 CIC),155 (95%) completed the study. BL demographics and mean BL weekly PS volume (APRA 13.1 L; PBO 12.9 L) were similar in both arms. At Wk 24, APRA-treated pts had a significantly larger reduction from BL in weekly PS volume vs PBO (APRA -25.5%; PBO -12.5%; p=0.001); both stoma and CIC subgroups demonstrated comparable treatment effects. In pts with stoma, the relative reduction from BL to Wk 24 in weekly PS volume in APRA pts vs PBO was statistically significant (-25.6% vs -7.8%; p<0.001) (Table 1). In pts with CIC, there was a numerical benefit in APRA that did not reach statistical significance (APRA -25.2%; PBO -17.6%; nominal p=0.179). In the overall population, statistically significant PS reductions from BL were seen from Wk 8 onward. A significantly higher proportion of APRA pts achieved a reduction of ≥1 day/Wk off PS at Wk 24 (APRA 43.0%; PBO 27.5%; p=0.040). At Wk 48 in the CIC subgroup, 51.8% of APRA vs 44.4% of PBO-treated pts achieved ≥1 day/wk off PS (p=0.348), and enteral autonomy was reached in 7 of 56 (12.5%) APRA vs 2 of 27 (7.4%). APRA was well tolerated. Of 110 APRA-treated pts, only 4 (3.6%) discontinued APRA due to an AE, vs 1 of 53 (1.9%) PBO-treated pts.

Conclusion

APRA is the first once-weekly GLP-2 analogue to demonstrate efficacy in a phase 3 trial in SBS-IF. At Wk 24, APRA demonstrated significantly greater relative reductions in weekly PS volume from BL and a higher proportion of pts achieved an additional ≥1 day off PS, with comparable treatment effects in pts with stoma or CIC. APRA showed a favourable safety profile consistent with prior APRA studies in SBS-IF.

Disclosure

FJ: Research funding from Takeda Pharma, VectivBio, Zealand, Baxter, Mobile3esolutions, Carembouche Consultant or advisor for Takeda, VectivBio, Ironwood; NorthSea Therapeutics, Hamni, Zealand, Mobile3esolutions, Carembouche. Lecturer for Baxter, BBraun, Fresenius Kabi, Janssen, Theradial; TV: Research Grants for Danone, MyHealth, Takeda, VectivBio. Consultancy for Baxter, BMS, Dr. Falk Pharma, Hanmi Pharm, North Sea Therapeutics, Takeda, Truvion, VectivBio, Zealand Pharma. Lecturer for Abbott, Baxter, Biocodex, Dr. Falk Pharma, Fresenius Kabi, Ipsen, Menarini, MyHealth, Remedus, Takeda, Truvion, VectivBio. DK: Consultant or advisor forTakeda Pharma, VectivBio, OWYN; SL: Investigator-initiated/unrestricted research grants from Fresenius Kabi, Baxter and Takeda. Honoraria and/or educational support from Takeda, Zealand, VectivBio, Fresenius Kabi, B Braun, Baxter, Northsea. KT: Board Member/Advisory Panel/Speaker for Abbott Nutrition Health Institute, Nutricia North America,Takeda Pharmaceuticals, VectivBio – now part of Ironwood Pharmaceuticals, Inc; PJ: Honoraria, educational and/or grants from Albumedix A/S, ArTara Therapeutics, Bainan Biotech, Baxter, Coloplast A/S, Ferring Pharmaceuticals, Fresenius Kabi, GlyPharma Therapeutic, Hanmi Pharmaceuticals, Ironwood, Naia Pharmaceuticals, NPS Pharmaceuticals, Protara Therapeutics, Shire, Takeda, The Novo Nordisk Foundation, Therachon, VectivBio AG, Zealand Pharma A/S; NNY, CL, RS, IS, SH: Ironwood employees; FB: Ironwood consultant; KI: Grant support from Takeda Pharma, VectivBio, NorthSea Therapeutics. Consultant or advisor for Takeda Pharma, VectivBio, Northsea Therapeutics, Hanmi Pharmaceuticals. Speaker or member of speakers bureau for Takeda Pharma.

Introduction

Spasmolytic polypeptide expressing metaplasia (SPEM) is a cell repair lineage and is a very important phenotype of gastric mucosal injury and precancerous lesion.
Previously, parietal cells loss is considered as the first step and followed with chief cells transdiffernation to induce SPEM. But whether chief cells initial loss cause SPEM
needs to be further investigation. Acidic mammalian chitinase (CHIA) belongs to the 18 glycosidase family and is highly expressed in the chief cells. Our previous study showed that CHIA deficiency in the chief cells is the key event to induce SPME to progress to gastric cancer (Liu et al., DDW 2023 and 2024). However, the molecular role of CHIA in the development of SPEM is need further investigated.

Aims & Methods

Electron microscopy, qRT-PCR and single-cell sequencing (scRNA-seq) technology, as well as histopathological and immunofluorescence (IF) stainning with specific markers were performed in chief cells specific CHIA knockout mouse model (CHIA^rox/rox-GIF-Dre) and wild-type mice(CHIA^rox/rox), and in CHIA over - expression mice (CHIA ^rox/rox - GIF - Dre + rAAv - CHIA) and the control group (CHIA ^rox/rox - GIF - Dre + rAAv - control).

Results

Compared with CHIA^rox/rox mice, histological analysis and scRNA-seq technology data showed that loss of chief cells with increased M2 macrophage infiltration and final SPEM formation, but remaining of parietal cells in CHIA^rox/rox-GIF-Dre mice. Electron microscopy showed CHIA deficiency in mice resulted in endoplasmic reticulum was dilated and swollen, as well as the mitochondrial membrane was discontinuous of chief cells, followed with the accumulation of endoplasmic reticulum stress marker, including PERK, XBP-1, eIF2α/P-eIF2α, and GRP78, together with upregulation of pyroptosis-related marker, including NLRP3, ACS, GSDMD, NEK7, Caspase1, Caspase11, IL-1β, and IL-18, which was detected by qRT-PCR. These data indicating that target CHIA deletion caused chief cells pyroptosis. Furthermore, qRT-PCR analysis showed that CHIA deficiency caused the activation of IL33/IL-13 circuit in the mucosa of mice. Moreover, double immunofluorescence staining confirmed that upregulation and colocalization of IL-33 induced M2 macrophage polarization markers, including F4/80 and CD163⁺ with NLRP3 in the base of gastric mucosal of CHIA^rox/rox-GIF-Dre mice when compared with CHIA^rox/rox mice.Notably, CHIA ^rox/rox - GIF - Dre + rAvv - CHIA mice reversed the above process compared with controls.

Conclusion

Chief cells specific CHIA deficiency resulted in endoplasmic reticulum stress mediate NLRP3 inflammasome activation to induce chief cells proptosis.
Chief cells initial loss is sufficient and the key step to activate IL-33/ST2-M2 macrophage polarization axis to induce SPEM, which is independent of parietal cells loss.

Introduction

We conducted a retrospective cohort study to evaluate the risk of serious infections in patients with Ulcerative Colitis (UC) initiating advanced biological or small molecule therapies

Aims & Methods

Using a large U.S. administrative, Optum Labs® database, we identified adult UC patients who initiated treatment with either tumor necrosis factor-α (TNF) antagonists (infliximab, adalimumab, and certolizumab pegol), IL-12/23 antagonists (ustekinumab), IL-23 antagonists (risankizumab), anti-integrin agents (vedolizumab), S1PR modulators (ozanimod), or Janus kinase (JAK) inhibitors (tofacitinib, upadacitinib) between 2016-2023. Eligible patients had at least one year of continuous insurance enrollment before and after treatment initiation. The primary outcome was the incidence and risk of serious infections requiring hospitalization. We used stabilized inverse probability of treatment weighting (IPW) based on multinomial propensity scores to balance baseline patient and disease characteristics. Comparative risk of serious infections was assessed through Cox proportional hazards models incorporating stabilized weights.

Results

A total of 9,430 UC patients were included (mean age: 47.5 ± 17.7 years; 49.2% female; 50% on concomitant corticosteroids), followed for a mean duration of 2.3 ± 0.8 years. The incidence rates (IR) per 100 person-years of serious infections were: TNF antagonists (n = 4,111; IR: 6.08 [5.47; 6.70]), vedolizumab (n = 3,165; IR: 5.03 [0.44; 5.65]), IL-12/23 or IL-23 antagonists (n = 1,342; IR: 4.25 [3.34; 5.21]), S1PR modulators (n = 111; IR: 5.17 [1.03; 10.34]) and JAK inhibitors (n = 701; IR: 4.09 [2.79; 5.49]). Risk of serious infections was lower with JAK inhibitors and IL-12/23, or IL-23 antagonists compared to TNF antagonists, and lower with IL-12/23 or IL-23 antagonists compared to vedolizumab. Hazard ratios are represented in the table 1.

Table 1: Risk of serious infections in patients with ulcerative colitis taking advanced biological therapies

Conclusion

In this large real-world cohort of UC patients, initiation with newly developed efficaeous agents like JAK inhibitors and drugs inhibiting the IL-23 pathway was associated with a lower risk of serious infection compared to TNF antagonists.

Disclosure

CM: Consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma Inc, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Forte Biosciences, Fresenius Kabi, Gilead, Janssen, McKesson, Mirador Therapeutics, Mylan, Pendopharm, Pfizer, Prometheus Biosciences Inc., Roche, Sanofi, Takeda, Tillotts Pharma; speaker's fees from AbbVie, Amgen, AVIR Pharma Inc, Alimentiv, Bristol Myers Squibb, Eli Lilly, Ferring, Fresenius Kabi, Janssen, Merck, Organon, Pendopharm, Pfizer, Sanofi, Takeda, Tillotts Pharma; royalties from Springer Publishing; research support from AbbVie, Eli Lilly, Ferring, Pfizer.
VJ: Consulting/advisory board fees from AbbVie, Alimentiv Inc, Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus, Reistone Biopharma, Roche, Sandoz, Second Genome,Takeda, Teva, Topivert, Ventyx, Vividion; speaker’s fees from, Abbvie, Ferring, Galapagos, Janssen Pfizer Shire, Takeda, Fresenius Kabi
SS: Research grants from Pfizer