Two pills use different molecular strategies to compete in markets established by injected therapies.
In less than four months, the FDA approved two pills built around different approaches to oral drug design. Eli Lilly’s Foundayo activates the GLP-1 receptor with a nonpeptide small molecule. Merck’s Lipfendra delivers a macrocyclic peptide orally to block PCSK9.
Both drugs enter classes whose clinical value was established largely by injected therapies. Peptide GLP-1 receptor agonists and injectable therapies targeting PCSK9 demonstrated the potential of their respective targets. As those classes matured, competition expanded to efficacy, tolerability and how the drugs are administered.
Oral delivery creates distinct chemistry challenges. Digestive enzymes break down peptides, while the intestinal wall prevents most surviving molecules from reaching the bloodstream. Foundayo avoids these barriers with a small molecule. Lipfendra pairs a macrocyclic peptide with an absorption enhancer, lowering LDL cholesterol by more than half despite oral bioavailability of approximately 1%.
These approvals demonstrate innovative ways companies can use new molecular approaches to differentiate products built around validated targets and expand oral treatment options.
Foundayo Replaces the Peptide
Foundayo is a once-daily pill for chronic weight management. It activates the GLP-1 receptor, which helps regulate appetite and blood sugar. Most drugs targeting this receptor are peptide-based injections.
Although Rybelsus and the Wegovy pill have already been approved as oral GLP-1 products, both are peptide-based and contain an absorption enhancer that helps the drug enter the bloodstream. They must be taken on an empty stomach, followed by a 30-minute wait before eating, drinking or taking other oral medications.
Foundayo avoids that delivery problem by replacing the peptide with a small molecule. It is the first approved nonpeptide GLP-1 receptor agonist and can be taken at any time of day without restrictions on food or water.
The FDA approved Foundayo in April for chronic weight management in adults with obesity and adults who are overweight and have at least one related health condition. The approval was supported by ATTAIN-1, a 72-week Phase 3 trial in which participants receiving the highest approved dose lost an average of 11.1% of their body weight, compared with 2.1% among those receiving placebo.
Lipfendra Engineers a Peptide for Oral Delivery
Merck’s Lipfendra is a once-daily pill for adults with high LDL cholesterol. It blocks PCSK9, a protein that limits the liver’s ability to remove LDL cholesterol from the blood.
All other approved PCSK9 inhibitors are delivered by injection. Lipfendra uses a synthetic macrocyclic peptide, meaning its amino-acid chain is closed into a ring. The ring makes the peptide more rigid and resistant to degradation while preserving its ability to bind PCSK9. The tablet also contains sodium caprate to help the peptide cross the intestinal wall.
Even with the absorption enhancer, Lipfendra has oral bioavailability of approximately 1%. The drug must be taken in the morning on an empty stomach, followed by a 30-minute wait before eating or drinking anything other than water, black coffee or plain tea.
The FDA approved Lipfendra in July, making it the first oral PCSK9 inhibitor. In two Phase 3 trials, the drug lowered LDL cholesterol by 56% and 59% relative to placebo after 24 weeks.
From Target Validation to Product Competition
Clinical validation opens the next stage of competition around a drug target. Companies can build on established biology while pursuing greater efficacy, improved tolerability and more convenient administration.
Foundayo and Lipfendra reflect that progression. Foundayo combines oral dosing with freedom from food and water restrictions, while Lipfendra brings the first oral option to the PCSK9 class. One replaces a peptide and the other redesigns one, but both use chemistry to turn validated target biology into differentiated products.
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