Semaglutide has been available as an oral formulation (Rybelsus) since 2019 for type 2 diabetes management. However, the body-weight reduction efficacy of the standard oral formulation was modest compared to the injectable formulation (Wegovy). The OASIS trial programme was designed to test whether higher oral doses could close this gap.
OASIS Programme Overview
The OASIS (Oral Semaglutide: A Study to Investigate Superior Efficacy) programme comprises multiple Phase 3 trials:
- OASIS 1: High-dose oral Semaglutide vs placebo in adults with overweight/obesity (NCT05035095)
- OASIS 2: Higher-dose oral Semaglutide vs placebo in type 2 diabetes
- OASIS 3: High-dose oral Semaglutide vs injectable Semaglutide, head-to-head
- OASIS 4: High-dose oral Semaglutide in body-weight maintenance after initial body-weight reduction
Key Efficacy Data
Results from OASIS 1, presented at the European Congress on Obesity (ECO) and published in The Lancet, demonstrated:
- Mean weight reduction of 15.1% at 68 weeks with high-dose oral Semaglutide vs 2.4% with placebo [1]
- Approximately 69% of participants achieved at least 10% body weight reduction
- 41% of participants achieved at least 15% body weight reduction
For context, injectable Semaglutide produced approximately 15.3% mean body-weight reduction in the STEP 1 trial [2]. The high-dose oral formulation has therefore achieved near-parity with the injectable version, a finding that was not anticipated given the historically poor bioavailability of oral peptides.
Bioavailability and Absorption Science
Oral peptide delivery faces fundamental challenges. Peptides are rapidly degraded by gastric acid and proteolytic enzymes, and their large molecular size limits passive absorption across the intestinal epithelium. Oral Semaglutide uses SNAC (sodium N-[8-(2-hydroxybenzoyl)amino]caprylate) as an absorption enhancer. SNAC creates a localised pH increase at the gastric epithelium, promoting transcellular absorption of Semaglutide [3].
Even with SNAC, oral bioavailability remains approximately 1%, meaning the high oral dose delivers a systemic exposure broadly comparable to a far smaller quantity of injectable material. The clinical success of the high-dose oral formulation validates this approach but highlights the significant peptide quantities required.
Implications for Oral Peptide Research
The OASIS results have catalysed research interest in oral peptide delivery systems beyond SNAC. Areas of active investigation include:
- Enteric-coated nanoparticle formulations: Protecting peptides through gastric transit and releasing them in the small intestine
- Cell-penetrating peptide conjugates: Covalently attaching sequences that enhance transepithelial transport
- Mucoadhesive delivery systems: Prolonging contact time with the intestinal wall to increase absorption windows
- Ionic liquid formulations: Using deep eutectic solvents to stabilise peptides and enhance permeability
Research laboratories investigating these delivery systems require high-purity Semaglutide as a reference standard. Critical quality parameters include HPLC purity above 99%, confirmed molecular weight by electrospray ionisation mass spectrometry (ESI-MS), and documented stability data under various storage conditions.
Competitive Landscape
Novo Nordisk is not alone in pursuing oral GLP-1 agonists. Pfizer's danuglipron (a small-molecule GLP-1 agonist, not a peptide) and several other oral formulations are in development. The competitive dynamics will likely increase demand for research-grade GLP-1 peptides as comparative studies expand.
Quality Considerations for Oral Peptide Research
Laboratories working on oral delivery formulations face specific quality requirements:
- Peptide stability under acidic conditions (pH 1.2 to 3.0) must be characterised
- Endotoxin testing is essential for any formulation intended for cell permeability assays
- Batch-to-batch consistency becomes critical when optimising absorption enhancer ratios
- Suppliers should provide stability data covering at least 6 months at recommended storage conditions
References
- [1] Knop FK, et al. "Oral Semaglutide 50 mg Taken Once Daily in Adults with Overweight or Obesity (OASIS 1): A Randomised Trial." Lancet. 2023;402(10403):705-719. doi:10.1016/S0140-6736(23)01185-6
- [2] Wilding JPH, et al. "Once-Weekly Semaglutide in Adults with Overweight or Obesity." N Engl J Med. 2021;384(11):989-1002. doi:10.1056/NEJMoa2032183
- [3] Buckley ST, et al. "Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist." Sci Transl Med. 2018;10(467):eaar7047.