While GLP-1 has been a known target for a long time, the recent explosion in peptide therapeutics was primarily enabled by solving the historical challenge of poor half-life and exposure. Achieving one- or two-week half-lives through techniques like fatty acid acylation was the critical technological unlock for the field.
Related Insights
Breakthrough drugs aren't always driven by novel biological targets. Major successes like Humira or GLP-1s often succeeded through a superior modality (a humanized antibody) or a contrarian bet on a market (obesity). This shows that business and technical execution can be more critical than being the first to discover a biological mechanism.
The GLP-1 drug revolution is moving beyond weekly injections for wealthy markets. Upcoming pill-form versions will eliminate the need for refrigerated supply chains, opening up distribution in developing countries. Combined with expiring patents, this focus on form factor and cost will enable mass global adoption.
The debate isn't about peptides replacing antibodies but about combining them. The future lies in hybrid therapeutics, such as grafting peptides into antibody CDRs or creating fusions that use a peptide for optimal target binding and an antibody scaffold for effector functions, half-life extension, and stability.
The dominance of peptides for GLP-1 therapeutics isn't a failure of antibodies but a success for picking the right tool. Peptides have a natural advantage when the therapeutic strategy involves engineering a natural ligand, making them a better starting point for certain targets like GPCRs.
The FDA defines a peptide as an amino acid chain of 40 or less. Blockbuster drugs like Ozempic and Mounjaro are all exactly 39 amino acids long. This perfect fit suggests potential regulatory shaping or clever drug design to fit an advantageous classification.
Beyond the initial wave of GLP-1s from Novo and Lilly, the next major competitive front in the obesity market will be monthly injectables. Amgen and Pfizer (via its Metsara acquisition) are poised to lead this race, shifting the focus to dosing convenience and long-term adherence.
In a crowded field, GSK's CSO explains their choice of the FGF21 molecule "Effie" was driven by three specific technical advantages: a longer half-life enabling monthly dosing for sicker patients, easier manufacturing via mammalian systems, and the lowest immunogenicity profile compared to competitors.
GLP-1 drugs cause a precipitous drop in inflammation markers within weeks, much faster than the timeline for weight loss. This independent anti-inflammatory mechanism may explain their efficacy in conditions like knee pain and psoriasis.
CEO Jonathan Steckbeck simplifies a complex topic by describing peptides as a "Goldilocks modality." They sit between small molecules (good access, poor specificity) and biologics (poor access, good specificity), ideally offering the best of both worlds for targeted drug delivery.
The mechanism of GLP-1s extends far beyond fat reduction. By increasing insulin sensitivity in every cell—liver, kidney, nerve cells—they effectively help cells process insulin like they did when younger. This positions them as a pervasive longevity product, similar to statins, for pushing back on age-related decline.
