Introduction

Functional constipation (FC) occurs in 8.5% Chinese people, seriously affecting their quality of life and mental health. However, there is currently a lack of long-term effective treatment options. As an oral guanylate cyclase-C (GC-C) agonist, plecanatide has been approved by the US FDA for the treatment of adult chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C), but it has not yet been approved for use in constipated populations in China. Considering the potential differences in drug responses between races, and the higher proportion of FC than IBS-C in Chinese with constipation, the efficacy of plecanatide in the Chinese FC population is worth studying.

Aims & Methods

This study aimed to comprehensively assess the efficacy, safety, and pharmacokinetics of plecanatide during the treatment of Chinese FC patients. This phase III, randomized, double-blind, placebo-controlled, multicenter trial was performed in 40 hospitals of China. 648 patients with FC were assigned to the plecanatide or placebo group randomly with a ratio of 1:1 for a 12-week treatment and a 2-week follow-up. The primary efficacy endpoint was the durable overall complete spontaneous bowel movement (CSBM) response rate. Treatment-emergent adverse event (TEAE) and treatment-related emergent adverse event (TRAE) were collected. Concentration of plecanatide and its metabolite SP-338 were detected.

Results

After 12-week continuous administration, the durable overall complete CSBM response rate of the plecanatide and the placebo were 23.5% and 10.5% respectively (p<0.001). Besides, all secondary efficacy endpoints showed statistically significant improvements compared with placebo. The incidence of TEAE and TRAE was 55.7% vs 48.6%, and 13.9% vs 8.7% respectively, in the plecanatide group and placebo group. The most common TRAE was diarrhea, which occurred in 0.6% (placebo) and 4.3% (plecanatide) of patients. The concentrations of plecanatide and its metabolite SP-338 were below the lower limit of quantification (0.500 ng/ml) at all time points.
Table 1: Comparison of durable overall CSBM response rate

Conclusion

Plecanatide had a significant efficacy for the treatment of Chinese FC patients, with a low rate of AEs and no systemic absorption. Plecanatide will be a good option in the management of Chinese FC patients.

References

ClinicalTrials.gov: NCT0515132.

Disclosure

No Conflict of Interests

Introduction

Irritable bowel syndrome (IBS) is defined as a disorders of gut–brain interaction, which shows a high comorbidity tendency with anxiety and depression. Berberine has been suggested in previous studies to alleviate IBS-like symptoms, however, there is currently a lack of research investigating the clinical efficacy of berberine, its modulation of gut microbiota, and its influence on brain functional regulation in IBS patients with comorbid anxiety and depression.

Aims & Methods

We conducted a double-blind, randomized, placebo-controlled clinical trial to evaluate the therapeutic efficacy of berberine on clinical symptoms in patients with IBS comorbid depression and (or) anxiety. Eligible participants with IBS based on Rome IV criteria and comorbid anxiety/depression based on HAMA/HAMD criteria were recruited. Participants were randomly assigned to receive berberine (300mg tid) or placebo for 8 weeks. Follow-up assessments occurred at 4 and 8 weeks. We collected stool samples from patients and performed resting-state functional magnetic resonance imaging (rs-fMRI) for patients and healthy controls (HCs) recruited at the same period at baseline and after 8 weeks of treatment. Fractional amplitude of low-frequency fluctuations (fALFF) was used to assess brain activation.

Results

78 patients (40 berberine, 38 placebo) showed no significant baseline differences. Berberine had higher drug response rates at 4 weeks (61.86% vs. 32.26%, p=0.027) and 8 weeks (73.53% vs. 32.26%, p=0.003). Berberine also had higher drug efficacy rates for anxiety at 8 weeks (79.4% vs. 29.0%, p<0.001). Adverse reactions (constipation, nausea) were higher with berberine (35.00% vs. 13.16%, p=0.025) but not severe. Metagenomic sequencing revealed that, berberine decreased pathogenic bacteria (Eubacterium, Faecalibacterium, Collinsella, Streptococcus, Lachnospira) and increased beneficial bacteria (Bacteroides uniformis etc.). Correlations indicated associations between Streptococcus, Eubacterium and diarrhea and abdominal pain. Berberine suppressed flagella assembly and bacterial chemotaxis, accordingly reduced invasiveness by decreasing the abundance of Eubacterium and Streptococcus, and improved gastrointestinal symptoms. Also berberine may reduce the function of pyrimidine metabolism, one-carbon pool folate, and glycerophospholipid metabolism by suppressing the abundance of Collinsella, Faecalibacterium and enriching Bacteroides uniformis. Patients exhibited decreased activity in several brain regions compared to HC, while increasing activity in brain regions (cingulate gyrus, supplementary motor area, superior frontal gyrus, etc.) after berberine intake was shown. Placebo group showed limited activity increase. Activity in different brain regions negatively correlated with abdominal pain, anxiety scores.

Conclusion

Berberine significantly improves gastrointestinal symptoms and psychometric scale score in IBS patients comorbid depression and (or) anxiety. Berberine reduces the abundance of pathogenetic bacteria, suppresses bacterial chemotaxis, flagella assembly and accordingly decreases bacteria invasiveness, which correlate with symptom improvement. Berberine may affect metabolic pathways linked to anxiety and depression improvement. Following berberine intervention, the activity in these hypoactive brain regions significantly recovers. Moreover, berberine enhances the activity in brain regions related to the functionality of the whole-body action-cognition network and control network, which may serve as important neurobiological foundations for berberine's treatment of the gut-brain comorbidity.

Disclosure

There are no financial conflicts of interest to disclose

Introduction

Despite recent advances in IBD therapy, there is a need for novel effective, safe oral drugs. Mufemilast has demonstrated sustained efficacy and safety in plaque psoriasis¹. Here we report the efficacy and safety of Mufemilast at 12 weeks from this phase 2 trial (NCT05486104).

Aims & Methods

Patients with moderate to severe UC were randomized (1:1:1) to placebo (n=31), mufemilast 45mg (n=31) or 60mg (n=30) twice daily (BD) for 12 weeks. Eligibility criteria required participants to have a modified Mayo score (mMS) of 4-9, including an endoscopy score of ≥ 2 , inadequate /loss of response to conventional therapy (5-ASA, Steroids, immunomodulators), or biologics (anti-TNF, anti-integrin, anti-interleukin 12/23). Stable co-treatment with oral 5'ASAs and corticosteroids was permitted if it was stable for at least ≥2 weeks before microscopy within the screening period and needed to remain stable for the duration of the study. Patients with positive Quantiferon tests were also eligible. Efficacy definitions were according to FDA guidance².

Results

Conclusion

Mufemilast efficacy and safety were consistent across subgroups regardless of previous biologic use, suggesting Mufemilast is a viable potential future treatment option in patients with moderate to severe UC that breaks through the current 20% ceiling for clinical remission. A phase 3 study will be conducted to confirm these results.

References

¹Jones, C.; Zhang, J.; Wang, L.; Dai, X.; Wang, H.; Bi, X.; Duan, X.; Meng, Z.; Tian, Z.; Xu, A.; et al. A Double-Blind, Placebo-Parallel Controlled Phase III Clinical Study of the Efficacy and Safety of Hemay005 Tablets in Patients with Moderate to Severe Chronic Plaque Psoriasis in China. Arthritis Rheumatol ACR Converg. 2023, 75.
² Food and Drug Administration. Ulcerative Colitis: Developing Drugs for Treatment. Guidance for Industry - Draft Guidance; 2022. Accessed May 11, 2025. https://www.fda.gov/media/158016/download

Introduction

Functional dyspepsia (FD) is one of the most common diseases of the digestive system, which comprises two subtypes, postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS). Acid suppression therapy has been recognized as the first-line treatment for H.pylori-negative FD patients. Potassium-competitive acid blocker (PCAB), a novel acid suppressant, has the characteristics of faster onset of effect and more stable acid suppression compared with traditional proton pump inhibitor (PPI). However, there has been no prospective study of PCAB for FD treatment.

Aims & Methods

This study was therefore conducted to investigate the efficacy and safety of PCAB in FD patients, and initially explore the effects of PCAB on gut microbiota. Patients diagnosed with FD were included prospectively. Eligible subjects were randomly assigned to the trial group and placebo group by 2:1, respectively, to receive Tegoprazan or placebo treatment with 50mg once a day for 2 weeks. 7-point global overall symptom scale (GOSS) was used to evaluate the relief of dyspepsia symptoms (primary endpoint) before the trial and at 1 and 2 weeks after randomization. Quality of life was assessed using the short form Nepean dyspepsia index (SFNDI). The generalized anxiety disorder-7 (GAD-7) and patient health questionnaire -9 (PHQ-9) were used to evaluate anxiety and depression, respectively. Stool samples were collected for 16SrRNA sequencing to evaluate gut microbiota alterations. Blood samples were collected to detect blood routine and blood biochemistry, and drug-related adverse events reported by subjects were collected to evaluate the safety of Tegoprazan.

Results

A total of 84 subjects were randomized, including 55 in the trial group and 29 in the placebo group. Among the subjects, 58.3% (49/84) were females, the median age was 51.00 (38.75, 55.00) years, and the mean BMI was 21.21 ± 3.06kg/m². For FD subtypes, EPS accounted for 44.0% (37/84), and no significant difference between the two groups was evident. In addition, there were no significant differences in the GOSS score, GAD-7 score and PHQ-9 score between the two groups at baseline. In the ITT analysis, the overall response rate was 25.5% (14/55) in the trial group and 17.2% (5/29) in the placebo group at 1 week, with no significant difference between the two groups (P =0.392). The 2-week response rate was 38.2% (21/55) in the trial group and 27.6% (8/29) in the placebo group, with no significant difference between the two groups (P =0.331). The results of PP analysis were consistent with ITT analysis. In the analysis of FD subtype, the response rate of EPS receiving Tegoprazan for 1 week was 45.8% (11/24), and that of the placebo group was 7.7% (1/13), with significant difference between the two groups (P =0.027).The response rate at 2 weeks of treatment with Tegoprazan was 50.0% (12/24), and the response rate after 2 weeks of placebo treatment was 15.4% (2/13), with no significant difference between the two groups (P =0.074). No significant difference was found between Tegoprazan and placebo on PDS (P > 0.05). In terms of gut microbiota, after 2 weeks of Tegoprazan treatment, the abundance of fecal genus streptococcus increased significantly (P < 0.001), especially streptococcus salivarius. There were no significant differences in the incidence of adverse events between the trial group and the placebo group (P > 0.05). No severe adverse events occurred in this study.

Conclusion

Tegoprazan is suitable for short course treatment of EPS. For patients requiring long-term treatment with Tegoprazan, the benefits of acid suppression should be weighed against the risk of intestinal microbiota dysbiosis. Tegoprazan had a similar safety profile to placebo.

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

Most patients with irritable bowel syndrome (IBS) are managed in primary care. When first-line therapies are ineffective, the UK National Institute for Health and Care Excellence guidance suggests considering low dose tricyclic antidepressants (TCAs) as second-line treatment, but their effectiveness in primary care is unknown and they are infrequently prescribed in this setting.

Aims & Methods

ATLANTIS was a randomised, double-blind, placebo-controlled trial at 55 UK primary care centres. Eligible patients were ≥18 years with Rome IV IBS of any subtype, with ongoing symptoms (IBS Severity Scoring System (IBS-SSS) score ≥75 points) despite first-line therapies, a normal full blood count and C-reactive protein, negative coeliac serology, and no evidence of suicidal ideation. Participants were randomised (1:1) to low-dose oral amitriptyline (10-30mg once daily) or placebo for 6 months with dose titration over 3 weeks, according to symptoms and tolerability. Participants, primary care physicians and other health-care providers, and investigators were all masked to allocation throughout. Primary and key secondary endpoints were IBS-SSS score and subjective global assessment (SGA) of relief of IBS symptoms at 6 months. Effectiveness analyses were according to intention to treat, safety analyses were according to treatment receipt.

Results

463 patients (mean age 48.5 years (SD 16.1 years), 315 (68.0%) female) were randomised to amitriptyline (232) or placebo (231). Primary outcome analysis showed a significant difference in IBS-SSS score between arms at 6 months (-27.0; 95% CI -46.9 to -7.10, p=0.008) in favour of amitriptyline. For the key secondary endpoint of SGA of relief of IBS symptoms, amitriptyline was superior to placebo at 6 months (125/204 (61.3%) vs. 88/195 (45.1%), odds ratio 1.78; 95% CI 1.19 to 2.66, p=0.005). Amitriptyline was superior to placebo across other secondary endpoints but had no impact on psychological symptom scores (Table). 46 (19.8%) patients discontinued amitriptyline (30 (12.9%) adverse events) and 59 discontinued placebo (25.5%) (20 (8.7%) adverse events). There were 5 serious adverse reactions (2 amitriptyline, 3 placebo).

Conclusion

This is the largest trial of a TCA in IBS ever conducted. Titrated low-dose amitriptyline was superior to placebo as a second-line treatment for IBS in primary care across multiple endpoints and was safe. Primary care physicians should offer low-dose amitriptyline to patients with IBS whose symptoms do not improve with first-line therapies.
Funding: National Institute for Health Research Health Technology Assessment Programme (grant reference: 16/162/01).