With the recent approval of the small molecule oral GLP-1 agent orforglipron, one wonders if the market dominance of peptides for this class will continue. Eli Lilly decided to compete in the oral GLP-1 market with a small molecule against Novo’s oral semaglutide Rybelsus, understanding that it could cannibalize tirzepatide’s market. Other oral GLP-1 small molecules are coming. It is expected that 3 or 4 more will be on the market by 2030. There are cost and logistics advantages of an oral small molecule over an injectable peptide, not to mention patient compliance and acceptance advantages. Will the tremendous expansion of synthetic peptide manufacturing be a permanent shift in commonly available pharmaceutical manufacturing technology, or become an interesting historical footnote?
As discussed in a FormBlends report[1]:
Peptides occupy a sweet spot between small molecules and large biologics. They offer target specificity similar to antibodies but with better tissue penetration and lower immunogenicity. They’re cheaper and faster to manufacture than monoclonal antibodies. And unlike many small molecules, they can engage protein-protein interaction surfaces that were previously considered “undruggable.”
Several structural advantages make peptides increasingly attractive to drug developers:
- High potency – Many peptides achieve therapeutic effects at microgram to low milligram doses
- Selectivity – Peptide structure allows precise receptor targeting with minimal off-target effects
- Favorable safety profiles – Peptides typically degrade into natural amino acids, reducing toxicity concerns
- Modular design – Amino acid sequences can be systematically modified to optimize pharmacokinetics
- Scalable synthesis – Modern solid-phase and continuous-flow methods enable commercial-scale production
It is striking that “Scalable synthesis” is cited as an attraction to drug developers. And peptide synthesis is not simply an SPPS platform, as implied above, but manufacturers also have tag-anchored synthesis methods and increasingly sophisticated LPPS and recombinant protein ligation methods which can be employed in combination. Ton-scale production of a synthetic peptide is no longer a daunting prospect.
The first mover in the oral GLP-1 market was Novo with Rybelsus which combined semaglutide with sodium N-(8-[2-hydroxybenzoyl]amino)caprylate (SNAC or Salcaprozate sodium) to protect the peptide from gastric degradation. From a manufacturing perspective, it is remarkable that it is practical to produce the quantities of semaglutide necessary to support a product with a 1% bioavailability. Other developers have taken note and now follow a similar path. Novo is exploring other approaches to provide more bioavailable peptides through their recently announced collaboration with Orbis Medicines.[2]
The synthetic peptide field may only be in its early days now that manufacturing is not a major obstacle to their commercial development. With the potential to use peptides in an oral formulation, the “fork in the road” between peptide and small molecule may be less meaningful.
[1] https://formblends.com/research/reference/peptide-future-pipeline-2025
[2] https://www.orbismedicines.com/news/orbis-medicines-enters-multi-target-drug-discovery-partnership-with-novo-nordisk-worth-up-to-usd-14-billion
