Oral Semaglutide at Higher Doses: OASIS Trial Programme and the Future of Non-Injectable Peptides

Semaglutide has been available as an oral formulation (Rybelsus) since its US approval in 2019 for type 2 diabetes management ^[1]. 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 programme comprises multiple Phase 3 trials:

• OASIS 1: Oral Semaglutide 50 mg vs placebo in adults with overweight/obesity without type 2 diabetes (NCT05035095) ^[2]
• OASIS 2: Oral Semaglutide 50 mg vs placebo in East Asian adults with overweight/obesity, with or without type 2 diabetes ^[3]
• OASIS 3: Oral Semaglutide 50 mg vs placebo in Chinese adults with overweight/obesity
• OASIS 4: Oral Semaglutide 25 mg vs placebo in adults with overweight/obesity ^[4]

Key Efficacy Data

Results from OASIS 1, published in The Lancet in June 2023, demonstrated:

• Mean weight reduction of 15.1% at 68 weeks with high-dose oral Semaglutide vs 2.4% with placebo ^[2]
• Approximately 69% of participants achieved at least 10% body weight reduction
• 54% of participants achieved at least 15% body weight reduction

For context, injectable Semaglutide produced a 14.9% mean body-weight reduction in the STEP 1 trial ^[5]. The high-dose oral formulation therefore achieved near-parity with the injectable version in separate trials, a notable result 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. Studies in people and dogs showed that absorption takes place in the stomach, close to the tablet surface: SNAC buffers the local environment, protecting Semaglutide from enzymatic degradation, and absorption is transcellular ^[6].

Even with SNAC, oral bioavailability remains below 1% (estimated at 0.8% in a pharmacokinetic analysis) ^[7], 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

Research into oral peptide delivery systems beyond SNAC continues ^[1]. Areas of active investigation include:

• Enteric-coated nanoparticle formulations: Protecting peptides through gastric transit and releasing them in the small intestine (so far, few nanoparticle prototypes have reached clinical trials ^[1])
• 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 discontinued its candidate danuglipron (a small-molecule GLP-1 agonist, not a peptide) in April 2025 (Pfizer, April 2025), but 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. [1] Brayden DJ, et al. "Systemic delivery of peptides by the oral route: Formulation and medicinal chemistry approaches." Adv Drug Deliv Rev. 2020;157:2-36. PubMed 32479930
2. [2] Knop FK, et al. "Oral semaglutide 50 mg taken once per day in adults with overweight or obesity (OASIS 1): a randomised, double-blind, placebo-controlled, phase 3 trial." Lancet. 2023;402(10403):705-719. doi:10.1016/S0140-6736(23)01185-6. PubMed 37385278
3. [3] Kadowaki T, et al. "Oral Semaglutide in an East Asian Population With Overweight or Obesity, With or Without Type 2 Diabetes: The OASIS 2 Randomized Clinical Trial." JAMA Intern Med. 2025;185(10):1206-1217. PubMed 40758358
4. [4] Wharton S, et al. "Oral Semaglutide at a Dose of 25 mg in Adults with Overweight or Obesity." N Engl J Med. 2025;393(11):1077-1087. PubMed 40934115
5. [5] 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. PubMed 33567185
6. [6] Buckley ST, et al. "Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist." Sci Transl Med. 2018;10(467):eaar7047. PubMed 30429357
7. [7] Overgaard RV, et al. "Clinical Pharmacokinetics of Oral Semaglutide: Analyses of Data from Clinical Pharmacology Trials." Clin Pharmacokinet. 2021;60(10):1335-1348. PubMed 33969456