In the United Kingdom around 26% of adults are classified as obese and 38% overweight. By 2040, projections suggest 40% of adults could be classified as obese if current trends continue (Cancer Research UK Obesity Projection 2023). This has led to obesity being classified as a chronic relapsing disease and one of the costliest medical threats of the 21st century. Food craving has both psychological and metabolic roots, with the brain’s reward system strongly linked to metabolic and hormonal signals. Over the past decade the discovery and development of GLP-1 agonists have led to a well validated pharmacological approach to hormonal control and direct suppression of appetite and food craving, leading to clinically significant and sustained reduction in body weight. These molecules mimic the natural hormone by binding to the GLP-1 receptor, triggering glucose lowering signals and appetite-suppression. It’s been estimated that over 100 obesity-related medicines are in active development, many targeting GLP-1 and the incretin pathway. Injectable peptides including Semaglutide (Wygovy) and Tirzepatide (Mounjaro) are among the greatest achievements in modern drug development, with spectacular results in the clinic fuelling unprecedent and relentless demands for drug product. Despite their success, these therapies come with practical challenges: they require injection, careful titration and storage at low temperature. Though not of great concern to patients, Novo Nordisk and Eli Lilly were concerned that patient adherence could be a major problem- most people hate needles and injections- with the only practical solution (if you’ll pardon the pun) being an oral drug.
Developing an oral version of a peptide drug is not a trivial undertaking and is often unsuccessful. Peptides rarely survive the strongly acid conditions in the stomach and are rapidly degraded. Semaglutide peptide is a chain of 31 amino acids and is rapidly digested by stomach acid and gut enzymes. Oral peptides are also difficult to absorb through the gut wall. Despite these challenges an oral version of Semaglutide -Rybelsus- has been developed by leveraging an absorption enhancer SNAC (sodium N-[8-(2-hydroxybenzoyl)amino] caprylate) that protects the peptide from acid and promotes absorption.1 Rybelsus is currently only approved for type-2 diabetes and not weight loss. However, it’s not all good news. The absolute bioavalibility of Rybelsus (the amount of the swallowed dose reaching systemic circulation) is less then 1%! So almost all the drug is degraded. And the peptide is not easy to come by. Semaglutide is made using a three-step process: recombinant expression of a peptide precursor, chemical modification and formulation. This is an expensive and complex undertaking so every gram counts. Injectable Semaglutide on the other hand is 100% bioavalible via subcutaneous absorption. High demand for Semaglutide has been an ongoing challenge for the manufacturer, with global supply chain instability, patent challenges and concomitant price hikes. That said, Novo Nordisk submitted an FDA application in May 2025 for an oral formulation of Semaglutide as a treatment for obesity, with a regulatory decision expected in late 2025.2
The real solution to this challenge is to discover and develop a drug that mimics the biological properties of a large peptide but is a smaller molecule stable enough to survive oral dosing without the challenges described above. Eli Lilly accepted the gauntlet and developed Orforglipron-the first (yet to be approved) small molecule GLP-1 receptor agonist to successfully complete phase 3 clinical trials.
Small molecules are generally easier to manufacture, show greater chemical stability and exhibit higher oral bioavailability (estimated to be 40-60% for Orforglipron). Speaking as someone with a background in drug discovery and development this is truly a holy grail in any drug development programme. Formulation as a once-a-day pill that can be dispensed in standard foil packets, discreetly swallowed (with or without food)- with no needles in sight- is vindication enough. Reduced manufacturing and storage costs will broaden accessibility- another important goal in the fight against obesity. Easier prescribing makes the physicians job much more straightforward too.
Does it work? All the clinical data suggest it does- matching and in some cases outperforming oral Semaglutide and comparing favourably with injected drug. Results from the recently completed obesity trial (ATTAIN-1), show that Orforglipron at its highest dose achieved an average weight loss of ~12.4 % over 72 weeks versus placebo, along with significant improvements in cardiometabolic risk markers. The results exceed expectation and regulatory review is imminent.3
This truly is a new dawn in the fight against obesity. Many more oral anti-obesity drugs will emerge in coming years, with lower therapeutic doses and improved tolerability.4 Searching for new indications and dual modalities is already at an advance stage. Orforglipron represents a milestone in a long journey that can only improve the health and wellbeing of us all.
1) A new era for oral peptides: SNAC and the development of oral semaglutide for the treatment of type 2 diabetes: Reviews in Endocrine and Metabolic Disorders (2022) 23:979–994
2) Novo Nordisk website 1 May 20025
3) Eli Lilly website 17th April, 7th August, 17th September 2025
4) Quarterly view of the GLP-1 pipeline and anticipated indications August 2025.; The expanding benefits of GLP-1 medicines: Cell Reports Medicine 102214, July 2025