The global therapeutic peptide pipeline has expanded considerably since 2020, driven by improvements in manufacturing scale-up, oral bioavailability formulation technologies, and an expanding understanding of incretin biology, tissue repair signaling, and neuropeptide pharmacology. How a candidate advances through the phases, and which endpoint and regulatory decisions shape that pathway, is the context for reading trial data and for designing preclinical studies meant to support an IND filing.
What phase 1 measures
Phase 1 studies for novel peptides typically enroll 20–100 healthy volunteers or (for oncology or rare disease indications) patients refractory to standard therapy. Primary endpoints are pharmacokinetic parameters: maximum observed plasma concentration (Cmax), time to Cmax (Tmax), area under the curve (AUC0–∞), terminal half-life (t½), and volume of distribution. For subcutaneous peptide delivery, the most common route for GH-axis and metabolic peptides, bioavailability relative to IV reference is a mandatory characterization.
What phase 2 establishes
For metabolic peptides (GLP-1R/GIP-R agonists, Retatrutide), primary efficacy endpoints are typically metabolic: HbA1c reduction, fasting plasma glucose, and body composition measured at 20–24 weeks. Biomarker-enriched designs, pre-specified subgroup analyses by GIP receptor polymorphism status, for example, allow mechanistic hypothesis testing within the efficacy trial. For tissue repair peptides (BPC-157, TB-500), biomarker endpoints present more complexity: validated surrogate markers for tendon repair (MRI tendon signal-to-noise ratio, histopathological scoring) or GI healing (endoscopic mucosal healing index) must be pre-specified and tied to clinical outcome correlations established in prior research. EMA Guideline on Clinical Investigation of Medicinal Products in the Treatment of Diabetes (CPMP/EWP/1080/00) provides the reference standard for endpoint selection in metabolic indications.
What phase 3 has to confirm
Phase 3 confirmatory trials are designed to meet the specific endpoint requirements negotiated with FDA (under SPA agreement, 21 CFR 312.82) or EMA (through Scientific Advice/Protocol Assistance). For peptide-based weight management drugs, FDA requires a pre-specified primary efficacy endpoint with statistical superiority to placebo, and a co-primary cardiovascular safety endpoint demonstrating MACE non-inferiority (HR upper bound <1.8 in interim, <1.3 for label). For peptide antibiotics or antimicrobials, endpoint guidance follows the 2015 FDA ABSSSI/CABP guidances. Non-inferiority margin selection requires prior data establishing the placebo effect size and acceptable clinical margin, typically derived from meta-analysis of historical trials in the same indication.
Compounds with active clinical programmes
Key compounds with active clinical programs: Retatrutide (LY3437943), GLP-1R/GIP-R/GCG-R triple agonist, Phase 2 published (Jastreboff et al., NEJM, 2023). Phase 3 TRIUMPH program ongoing. CagriSema (cagrilintide + semaglutide fixed-ratio combination), Phase 3 REDEFINE program for obesity. Pralsetinib, not a peptide but relevant for comparing peptide vs. small molecule regulatory pathway differences. For tissue repair, no GLP-1-class peptide has cleared Phase 3 in musculoskeletal indications as of 2026; most data remains at Phase 2 or preclinical.
Regulatory milestones
IND (Investigational New Drug) filing under 21 CFR 312 is required before human administration begins. IND exemptions exist for Phase 1 studies meeting specific criteria, but are not applicable to most novel peptide candidates. EMA Voluntary Harmonization Procedure (VHP) enables multi-country Phase 2 trial approvals in Europe. These compounds in their current research-grade formulations are for research and laboratory use only. Not for unsupervised human consumption.