Therapeutic peptides in inflammatory bowel disease: From mechanistic rationale to clinical translation

Table 1 Potential peptide-based therapies in inflammatory bowel disease with current clinical data

Peptide	Class/mechanism	Route	IBD population	Highest evidence	Study design /n/comparator	Duration	Principal result	Evidence maturity/source
Anti-inflammatory peptides
Icotrokinra[48,49]	Selective IL-23 receptor antagonist; inhibits IL-23 mediated inflammatory signaling	Oral	Moderate-to-severe UC	Phase 2b human interventional study	Phase 2b randomized, double-blind, placebo-controlled, dose ranging RCT (n = 252). 100 mg, 200 mg or 400 mg daily vs placebo	Primary assessment 12 weeks. Exploratory follow up to week 28	All doses met week-12 endpoint (clinical response vs placebo). Clinical, endoscopic and biomarker responses persisted through exploratory week-28 analyses	Level 1: Human interventional. Conference abstract/trial reporting
K(D)PT[50-52]	Tripeptide derivative of α-melanocyte-stimulating hormone; anti-inflammatory and epithelial barrier-supportive effects	Oral	Mild-to-moderate UC	Phase 2a human interventional study	Multicentre phase 2a randomized double-blind, placebo-controlled RCT (n = 162). 20 mg, 50 mg or 100 mg twice daily vs placebo as add-on therapy	12 weeks	Pooled K(D)PT improved remission at weeks 2 and 4 and CAI response at week 8. Remission later converged with placebo because of a high placebo response	Level 1: Human interventional. Peer-reviewed
CGMP[53-55]	Bovine milk-derived glycopeptide; proposed anti-inflammatory, microbiome modifying and barrier-supportive effects	Oral	Active distal UC	Pilot human interventional study	Randomized open-label pilot study (n = 24). CGMP vs mesalamine escalation	4 weeks comparative treatment; follow-up to 8 weeks	At week 4, there were no significant between-group differences in SCCAI improvement or stability, with broadly similar changes in endoscopic disease extent and severity	Level 1: Human interventional. Peer-reviewed
Barrier protective and mucosal healing peptides
GLP-1 receptor agonists (e.g., semaglutide, liraglutide, dulaglutide, exenatide)[96,99,100]	GLP-1 receptor agonist; proposed anti-inflammatory and intestinal barrier-supportive effects, alongside established metabolic actions	Subcutaneous	UC and CD. Predominantly concomitant T2DM and/or obesity	Human observational evidence	Multiple retrospective studies. Largest cohort (n = 3737). Exposed vs non-exposed with adjustment	Longitudinal follow-up; study dependent	GLP-1 agonist exposure was associated with lower composite risk of hospitalisation, surgery, steroid dependence, treatment escalation, mortality	Level 3: Human observational. Peer reviewed observational studies/systematic review
Teduglutide[108-110]	GLP-2 analogue; promotion of intestinal epithelial growth, repair and barrier integrity	Subcutaneous	Moderate-to-severe CD	Phase 2 human interventional study	Pilot randomized, double-blind, placebo-controlled, dose-ranging (n = 100). Teduglutide vs placebo	8 weeks placebo-controlled treatment; optional 12-week extension	Greater clinical remission and response compared to placebo; differences were not statistically significant	Level 1: Human interventional. Peer-reviewed
EGF[111-113]	Growth-factor peptide; promotes epithelial restitution, proliferation and mucosal healing	Topical enema	Mild-to-moderate left sided UC or proctitis	Human interventional RCT	Randomized, double-blind, placebo-controlled RCT (n = 24). EGF vs placebo in conjunction with oral mesalamine	14 days treatment; follow-up to 12 weeks	Week-2 remission was more frequent with EGF than placebo; clinical, endoscopic and histologic outcomes also favoured EGF, with initial response maintained through 12 weeks	Level 1: Human interventional. Peer-reviewed
TFF3[111,112,114]	Intestinal repair peptide; promotes epithelial restitution, mucus integrity and mucosal barrier repair	Topical enema	Mild-moderate left-sided UC	Human interventional RCT	Randomized, double-blind, placebo-controlled RCT (n = 16). TFF3 vs saline placebo in conjunction with oral mesalamine	14 days treatment; follow-up to 12 weeks	No treatment benefit over placebo noted	Level 1: Human interventional. Peer reviewed

CAI: Colitis activity index; CD: Crohn’s disease; CGMP: Casein glycomacropeptide; EGF: Epidermal growth factor; GLP: Glucagon-like peptide; IBD: Inflammatory bowel disease; IL: Interleukin; RCT: Randomized controlled trial; SCCAI: Simple clinical colitis activity index; T2DM: Type 2 diabetes mellitus; TFF3: Trefoil factor 3; UC: Ulcerative colitis.

Table 2 Comparison between therapeutic peptides, small molecules and biologics

	Therapeutic peptides	Small molecule drugs	Biologics
Advantages	High affinity binding	High oral bioavailability	High affinity binding
	High specificity	High membrane permeability	High specificity
	Modulate protein-protein interactions without well-defined binding pocket	High gastric stability	Minimal off-target effects
	Wide range of targets	Lower manufacturing costs
	Predictable degradation products	Low immunogenicity
	Minimal off-target toxicities
	Low immunogenicity
Weaknesses	Low oral bioavailability	Risk of off-target effects	Requires parenteral administration
		Require a well-defined binding pocket
	Short half-life & rapid serum clearance		High immunogenicity-risk of anti-drug antibody formation
	Low membrane permeability		Low membrane permeability
	Low gastric stability		High manufacturing costs

Table 3 Clinical trials of peptide-based therapies in inflammatory bowel disease

Agent	Mechanism	Phase and design	Population	Primary endpoint	Status
Icotrokinra	Oral interleukin-23 receptor antagonist	Phase 2b randomized, double-blind, placebo-controlled, dose-ranging (ANTHEM-UC)	Moderate-to-severe ulcerative colitis	Clinical response at week 12	Completed; reported in conference abstract form
Icotrokinra	Oral interleukin-23 receptor antagonist	Phase 3 programme	Moderate-to-severe ulcerative colitis	Not yet reported	Ongoing; recruiting
K(D)PT	Tripeptide derivative of alpha-melanocyte stimulating hormone	Phase 2a randomized, double-blind, placebo-controlled	Mild-to-moderate ulcerative colitis	Time to sustained clinical remission (colitis activity index 3 or less)	Completed; no confirmatory trial reported
Casein glycomacropeptide	Bovine milk-derived immunomodulatory peptide	Randomized open-label pilot study	Active distal ulcerative colitis	Change in simple clinical colitis activity index and endoscopic activity	Completed
Teduglutide	Glucagon-like peptide-2 analogue	Phase 2 randomized, double-blind, placebo-controlled, dose-ranging	Moderate-to-severe Crohn’s disease	Remission or response by Crohn’s disease activity index at week 8	Completed; not progressed for this indication
Epidermal growth factor enema	Growth-factor peptide promoting epithelial restitution	Randomized, double-blind, placebo-controlled	Mild-to-moderate left-sided ulcerative colitis	Clinical and endoscopic remission	Completed
Trefoil factor 3 enema	Trefoil peptide supporting mucosal repair	Randomized, double-blind, placebo-controlled	Mild-to-moderate left-sided ulcerative colitis	Clinical improvement	Terminated for lack of efficacy