From needle to tablet: how peptide drugs learned to survive the gut

Ask a peptide researcher why so many peptide medicines come in syringes and you will usually hear the same answer: the gut is designed to destroy them. Over the past year, though, the FDA has approved several peptide drugs that are taken as daily tablets ⁴⁶⁸. It is the payoff from years of work on a stubborn problem.

Why the gut is hostile to peptides

The gut treats a peptide drug like food protein: something to break down. A 2022 review in Theranostics lays out the obstacle course ¹:

• Acid and enzymes. The stomach is strongly acidic and contains pepsin, while trypsin and chymotrypsin in the intestine chop up peptide chains ¹.
• Mucus. A sticky, negatively charged mucus layer coats the gut lining and slows large molecules down ¹.
• The cell wall itself. Cells lining the intestine are sealed together by tight junctions, and peptides are large, water-loving molecules that cross this layer poorly ¹.

The result is that very little of a swallowed peptide normally reaches the blood. The same review notes, for example, that an oral octreotide capsule reached about 0.7% bioavailability in a phase 1 study ¹.

Strategy one: help the peptide across

Oral semaglutide took the formulation route. Semaglutide tablets pair the peptide with an absorption enhancer called SNAC (salcaprozate sodium) ³. In a 2018 study combining human and dog experiments, researchers found that the tablet releases semaglutide in the stomach, not the intestine, and that absorption happens in a small zone right around the dissolving tablet ². SNAC appeared to buffer the local environment, shielding the peptide from enzymes, and to briefly boost passage through stomach cells, with no evidence that it loosened the junctions between them ².

It is still a low-yield process. The current FDA label estimates that only about 0.4% to 2% of the semaglutide in a tablet is absorbed, depending on the formulation ³. But because semaglutide is so potent and long-lasting, that small fraction is enough to matter. In December 2025 the FDA approved a once-daily semaglutide pill for chronic weight management, which Novo Nordisk described as the first oral GLP-1 medicine for obesity in the US ⁴. In its phase 3 OASIS 4 trial, people who stayed on treatment lost about 16.6% of body weight at 64 weeks, versus 2.7% on placebo ⁴.

Strategy two: redesign the peptide

The newer approach is to build peptides that are tougher from the start. Instead of a floppy linear chain, chemists design macrocyclic peptides: ring-shaped molecules built for stability and tight binding.

Merck's enlicitide is a good example. Its discovery team used mRNA display, a technique that screens enormous libraries of peptides at once, to find starting molecules, then refined them with structure-based design ⁵. The resulting macrocycle binds PCSK9 with very high affinity, blocking its interaction with the LDL receptor and so lowering LDL cholesterol ⁵. In July 2026 the FDA approved it as Lipfendra, which Merck calls the first FDA-approved oral PCSK9 inhibitor shown to lower LDL cholesterol ⁶. In the CORALreef Lipids trial of 2,904 adults, LDL cholesterol fell 56% versus placebo at week 24 ⁶.

Icotrokinra followed a similar path. Jointly discovered and developed by Protagonist Therapeutics and Johnson & Johnson, it is a macrocyclic peptide that blocks the IL-23 receptor, part of an immune pathway involved in psoriasis ⁷⁸. Early work showed oral activity in rat models of gut and skin inflammation (animal data), followed by evidence in healthy volunteers that it blocked the IL-23 pathway throughout the body ⁷. In March 2026 the FDA approved it as Icotyde for moderate-to-severe plaque psoriasis in adults and in children 12 and older who weigh at least 40 kg and are candidates for systemic therapy or phototherapy, based on the phase 3 ICONIC program ⁸. In head-to-head trials against an active comparator, about 70% of patients taking icotrokinra reached clear or almost clear skin at week 16 ⁸.

What the evidence does and doesn't show

These are approved drugs backed by large late-stage trials, a much stronger evidence stage than animal or early human studies. In those trials: adverse reactions with enlicitide were broadly similar to placebo, though diarrhea and dizziness were more common in one trial ⁶, and icotrokinra's label warns about infection risk ⁸. Two fair limits: it is not yet known whether enlicitide reduces heart attacks or deaths, a question its ongoing outcomes trial is designed to answer ⁶, and oral absorption of semaglutide is affected by food and water, which is why tablet peptides come with strict label instructions ³.

The bigger lesson for researchers is that oral peptides are no longer a single trick. Formulation science and ring-shaped molecular design are now both producing approved medicines, and the review literature lists many more approaches in development, from nanoparticles to swallowable microneedle devices, many of which are still in early research or early clinical testing ¹.

What to watch

• Outcome data. The CORALreef Outcomes trial, with more than 14,500 participants enrolled, should show whether enlicitide's LDL lowering translates into fewer cardiovascular events ⁶.
• New targets. Researchers will be watching whether the macrocycle approach that worked for PCSK9 and IL-23 can reach other targets once thought to require injected antibodies.
• Better absorption. Raising oral bioavailability above a few percent could widen the range of peptides that can be swallowed.

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