Introduction

Small intestinal bacterial overgrowth (SIBO) is a clinical syndrome with abdominal complaints and malabsorption. Despite concerns over cure rates, recurrence, and antibiotic resistance, rifaximin (RIF) remains the primary treatment. Berberine (BBR), an affordable traditional medicine, has demonstrated gut microbiota modulation, making it a promising alternative.

Aims & Methods

We conducted an open-label, non-inferiority randomized controlled trial (BRIEFSIBO) comparing BBR and RIF in SIBO patients. Patients were randomly assigned to receive either RIF or BBR. The primary outcome was breath test (BT) conversion to negative, with symptom scores and the Bristol stool scale as secondary outcomes.

Results

A total of 186 patients completed the study. No significant baseline differences were found between groups in age, gender, BMI, smoking, or alcohol use. BBR demonstrated non-inferior efficacy to RIF for primary outcome (BT eradication) at Week 2 (ITT: BBR 45%, RIF 51%, Z=2.407, P=0.008; PP: BBR 44%, RIF 47%, Z=2.4787, P=0.007) and Week 6 (ITT: BBR 53%, RIF 44%, Z=4.3244, P<0.001; PP: BBR 54%, RIF 45%, Z=4.077, P<0.001). What's more, BBR demonstrated non-inferior efficacy to RIF for secondary outcome (clinical improvement) at Week 2 (ITT: BBR 68%, RIF 75%, Z=2.9209, P=0.0017; PP: BBR 73%, RIF 72%, Z=3.3531, P=0.0004) and Week 6 (ITT: BBR 75%, RIF 80%, Z=2.8514, P=0.0022; PP: BBR 81%, RIF 86%, Z=3.0747, P=0.0011). Following a four-week period of discontinuation, the rate of combined expiratory and symptomatic relapse in patients treated with RIF was 8.57%. In contrast, no such relapses were observed in patients treated with BBR. BT values at 60–90 minutes and AUC decreased in both groups, though RIF showed recurrent peak values during follow-up. A novel breath peak acceleration parameter, reflecting local gut gas load, decreased in both groups. BBR significantly improved bloating at Week 6, whereas RIF improved bowel movement frequency. At Week 6, patients were classified into response, relapse, and nonresponse groups to identify optimal candidates for each drug. RIF responders showed significant improvement in bloating and bowel-related symptoms (P<0.05). Baseline gut microbiota analysis revealed significant β diversity differences between three groups in BBR but not in RIF. Genus-level microbiota composition differed between responders, with BBR responders exhibiting higher baseline proportions of Phascolarctobacterium, Klebsiella, and Haemophilus, and lower Coprobacter. At Week 6, both groups showed enriched Bacteroides, while BBR responders had elevated Phascolarctobacterium, Streptococcus, and Haemophilus, with lower Bifidobacterium.

Conclusion

BBR is non-inferior to RIF for SIBO treatment and offer a promising and cost-effectiveness new option.

References

1. Pimentel M, Saad RJ, Long MD, et al. ACG Clinical Guideline: Small Intestinal Bacterial Overgrowth. Am J Gastroenterol 2020;115(2):165-78. doi: 10.14309/ajg.0000000000000501
2. Bushyhead D, Quigley EMM. Small Intestinal Bacterial Overgrowth-Pathophysiology and Its Implications for Definition and Management. Gastroenterology 2022;163(3):593-607. doi: 10.1053/j.gastro.2022.04.002
3. Quigley EMM, Murray JA, Pimentel M. AGA Clinical Practice Update on Small Intestinal Bacterial Overgrowth: Expert Review. Gastroenterology 2020;159(4):1526-32. doi: 10.1053/j.gastro.2020.06.090
4. Leite G, Rezaie A, Mathur R, et al. Defining Small Intestinal Bacterial Overgrowth by Culture and High Throughput Sequencing. Clin Gastroenterol Hepatol 2024;22(2):259-70. doi: 10.1016/j.cgh.2023.06.001
5. Svedlund J, Sjödin I, Dotevall G. GSRS--a clinical rating scale for gastrointestinal symptoms in patients with irritable bowel syndrome and peptic ulcer disease. Dig Dis Sci 1988;33(2):129-34.
6. Liu ZJ, Wei H, Duan LP, et al. [Clinical features of irritable bowel syndrome with small intestinal bacterial overgrowth and a preliminary study of effectiveness of Rifaximin]. Zhonghua Yi Xue Za Zhi 2016;96(24):1896-902. doi: 10.3760/cma.j.issn.0376-2491.2016.24.005
7. Guo H, Lu S, Zhang J, et al. Berberine and rifaximin effects on small intestinal bacterial overgrowth: Study protocol for an investigator-initiated, double-arm, open-label, randomized clinical trial (BRIEF-SIBO study). Front Pharmacol. 2023;14:1121435. doi:10.3389/fphar.2023.1121435

Introduction

Obefazimod (Obe) is an oral, once-daily (QD), small molecule which enhances expression of microRNA-124 and has been studied in two Phase 2 induction trials and subsequent open-label maintenance studies [1-3] in patients (pts) with moderately to severely active ulcerative colitis (UC). Here we report efficacy and safety of two Phase 3, 8-week, induction trials in adult pts with UC from ABTECT-1 [NCT05507203] and ABTECT-2 [NCT05507216].

Aims & Methods

The multicenter, randomized, double-blind, placebo-controlled ABTECT trials enrolled pts with moderate-to-severe UC (defined as modified Mayo score (MMS)≥ 5, with rectal bleeding sub-score (RBS) ≥ 1 and centrally read endoscopic score >2) who had inadequate response, loss of response, or intolerance to at least one prior therapy (with no upper limit), including corticosteroids, immunosuppressants, biologics, S1P receptor modulators and/or JAK inhibitors. Pts were randomized 2:1:1 to Obe 50 mg QD (Obe-50), Obe 25 mg QD (Obe-25) or placebo (PBO) for 8 weeks. The primary endpoint was clinical remission (per MMS) and secondary endpoints included clinical response, endoscopic improvement, symptomatic remission, and histo-endoscopic mucosal improvement (HEMI).

Results

1272 pts were randomized and treated in ABTECT-1 (636) and ABTECT-2 (636). In both trials, baseline demographics and disease characteristics were similar between groups; 45.3% and 49.3% of pts had inadequate response to 1 or more advanced therapies. A significantly higher proportion of pts receiving Obe-50 (ABTECT-1:21.7%, ABTECT-2: 19.8%) versus PBO (2.5% and 6.3%) achieved clinical remission (Obe-50-PBO difference: ABTECT-1: 19.3%, p<0.0001; ABTECT-2: 13.4%, p=0.0001) and met all key secondary endpoints in both trials. A significantly higher proportion of pts receiving Obe-25 versus PBO achieved clinical remission (Obe-25-PBO difference: 21.4%, p<0.0001) and met all key secondary endpoints in ABTECT-1. In a pooled analysis, both Obe-50 and Obe-25 met all primary and secondary endpoints with nominal significance (p<0.0001) (Table). The overall rate of serious adverse events and treatment emergent adverse events (TEAEs) leading to study drug discontinuation for pts treated with Obe were similar to PBO. Proportions of pts who reported at least one TEAE in ABTECT-1 were 59.4%, 46.9%, and 53.2% for Obe-50, Obe-25, and PBO, respectively. For ABTECT2, TEAEs occurred in 61.0%, 50.9%, and 48.4% for Obe-50, Obe-25, and PBO, respectively. The most frequent TEAE was headache (Obe-50: 20.8-25.8%; Obe-25: 14.5-15.6%; PBO: 5.7). The headaches were mild, transient, short in duration and not a barrier to treat as evidenced by a low discontinuation rate of 0-1.6%. No signal was observed for serious, severe, or opportunistic infections or malignancies.

Table: 8-week induction efficacy of obefazimod in ABTECT-1 and ABTECT-2 Phase 3 studies, and pooled ABTECT-1 and ABTECT-2^‡

Conclusion

In both ABTECT induction trials, primary and secondary endpoints were met; obe treatment led to statistically significant improvements in clinical, endoscopic, symptomatic and combined endoscopic-histologic endpoints at week 8. Obe was well tolerated with no new safety signals identified.

References

1. Vermeire S, et al. J Crohns Colitis. 2023; 17: 1689-1697
2. Vermeire S, et al. The Lancet Gastroenterology & Hepatology. 2022; 7: 1024-1035.
3. Vermeire S, et al. J Crohns Colitis. 2025 ; 19 : jjaf074

Disclosure

Authors reports following potential conflicts of interest:
BES: Abbvie, Abivax, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, Artugen Therapeutics, Astra Zeneca, Biolojic Design, Biora Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Equillium, Enthera, Enveda Biosciences, Evommune, Ferring, Fzata, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Imhotex, Index Pharmaceuticals, Innovation Pharmaceuticals, Kaleido, Kallyope, Lilly, Merck & Co., Microba, Microbiotica, Mitsubishi Tanabe, Mobius Care, Morphic Therapeutics, MRM Health, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, OSE Immunotherapeutics, Janssen, Palisade Bio, Pfizer, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Therapeutics, Reistone Biopharma, Sanofi, Sorriso Therapeutics, Spyre Therapeutics, Takeda, Target RWE,Teva, TLL Pharmaceutical, Tr1X, Trex Bio, Union Therapeutics, Ventyx Biosciences.
SV: AbbVie, Abivax, AbolerIS Pharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Cytoki Pharma, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillots Pharma AG, Zealand Pharma.
LPB: Abbvie, Abivax, Adacyte, Alimentiv, Amgen, Applied Molecular Transport, Arena, Banook, Biogen, BMS, Celltrion, Connect Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, 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 Immunotherapeuthics, Pandion Therapeuthics, Par' Immune, Pfizer, Prometheus, Protagonist, Roche, Samsung, Sandoz, Sanofi, Satisfay, Takeda, Telavant, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vectivbio, Ventyx, Ysopia.
SD: AbbVie, Ferring, Hospira, Johnson & Johnson, Merck, MSD, Takeda, Mundipharma, Pfizer Inc, Tigenix, UCB Pharma, Vifor, Biogen, Celgene, Allergan, Celltrion, Sandoz, Boehringer Ingelheim.
PSD: Abbvie, Abivax, Adiso, Alimentiv, Bristol Meyer Squibb, Celltrion, Genentech, Geneoscopy, Janssen, Pfizer, Takeda.
MD: Abbvie, Abivax, Arena Pharmaceuticals, Astra Zeneca, Boehringer Ingelheim International GmbH, Bristol-Meyer Squibb, Eli Lilly and Company, F. Hoffmann-La Roche Ltd, Genentech Inc, Gilead, Janssen Pharmaceuticals, Merck, Pfizer Inc, Prometheus Biosciences, Takeda Pharmaceuticals.
HT: Abbvie, Abivax, Dr Falk Pharma, ferring, Galapagos, Microbiotica, MSD, Pfizer, Takeda.
BS: AbbVie, Abivax, Boehringer Ingelheim, Bristol Myers Squibb, Dr. Falk Pharma, Eli Lilly, Endpoint Health, Falk, Galapagos, Gilead, Janssen, Landos, Materia Prima, PredictImmune, Pfizer, and Takeda; AlfaSigma, CED Service GmbH, MSD, Ferring, Galapagos, Tr1x bio
TH: Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., AbbVie GK, JIMRO Co. Ltd., Zeria Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc., Mochida Pharmaceutical Co. Ltd., Boston Scientific Corporation, Kissei Pharmaceutical Co. Ltd, Janssen Pharmaceutical K.K., Pfizer Inc., Eli Lilly, Gilead Sciences, Bristol Myers Squibb, Abivax.
XT: Celltrion, AbbVie, Johnson & Johnson, Lilly, Takeda, Alpha Sigma, Dr. Falk, Abivax, Biogen, Fresenius Kabi, MSD, Pfizer, Tillotts, and Thabor Therapeutics.
RA: AbbVie, Abivax, AstraZeneca, Bristol-Myers Squibb, Celltrion Healthcare, Galapagos, Johnson&Johnson, Lilly, MSD, Pfizer, and Takeda Pharma
US: AbbVie, Abivax, Amgen, Galapagos, Janssen, Eli Lilly, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Gilead Sciences, Pfizer, Roche,Takeda Pharmaceuticals
AA: AbbVie, Abivax, AG Pharma, Alfa Sigma, Astra Zeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion, Eli-Lilly, Enthera, Ferring, Galapagos, Gilead, Giuliani, Janssen, Lionhealth, MSD, Nestlé, Novartis, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sanofi, Sandoz, Takeda, Teva Pharmaceuticals, Tillots Pharma
FB: AbbVie, Amgen, Eurogenerics, J&J, Arena Pharmaceuticals, Celltrion, Ferring, Galapagos, Janssen, Merck Sharp & Dohme, Pfizer Inc, Takeda, Celgene, Fresenius Kabi, Sandoz
DTR: Abbvie, Abivax SA, Altrubio, Athos Therapeutics, Inc, Bristol-Myers Squibb, Celltrion, Connect BioPharma, Eli Lilly & Co., Genentech (Roche) Inc., Iterative Health, Janssen Pharmaceuticals, Johnson & Johnson, Merck & Co., Odyssey Therapeutics, Pfizer, Sanofi, Spyre, Takeda Pharmaceuticals, Vedanta Biosciences, and Ventyx.