The Birth of ICOTYDE (4): From PN-235 to FDA, How an Oral Cyclic Peptide Became a Drug

The Birth of ICOTYDE · Part 4

Previous article: At 1898 Da, How Can It Still Be Oral?

The previous article discussed why a cyclic peptide approaching 1900 Da could still potentially become an oral drug. By the time PN-235 was selected as a clinical candidate, the most central medicinal chemistry issues had largely been resolved: this molecule could remain highly stable in the gastrointestinal tract, had extremely high affinity for IL-23R, and, although the fraction absorbed was very low, could still produce systemic exposure.

However, between a well-designed molecule and a real drug, there is still a threshold that cannot be replaced by further chemical optimization: it must prove itself in humans. After PN-235 entered Janssen’s development system, it was named JNJ-77242113, later shortened to JNJ-2113, and ultimately received the generic name icotrokinra. Early human studies first needed to confirm whether the limited oral absorption observed in animal experiments could be reproduced in humans, and whether such exposure would be sufficient to support therapy.

The results showed that this route was feasible. After oral administration of JNJ-77242113, clear systemic drug exposure could be detected in human blood, and exposure increased with dose. This made the earlier design logic valid in humans for the first time: a very large cyclic peptide does not have to cross the intestinal wall as efficiently as a traditional small molecule; as long as gastrointestinal stability is sufficiently strong and target engagement is sufficiently potent, a small amount of intact molecule entering the circulation may also reach an effective concentration. The next step to verify was whether these drugs in the blood could truly produce clinical efficacy.

Why Choose Psoriasis?

Psoriasis is well suited for testing this question. The role of the IL-23 pathway in psoriasis has long been fully validated by multiple biologics, so development of JNJ-77242113 did not need to re-prove whether the target was correct, but could directly test whether an oral cyclic peptide could achieve pathway inhibition that previously relied mainly on injectable biologics. If a new target that had not been fully validated were chosen, it would be difficult to distinguish, in the event of clinical failure, whether the problem lay with the target or with the drug modality; in psoriasis, this layer of uncertainty is much smaller.

The Phase IIb FRONTIER 1 study published in 2024 provided the key answer. After patients with moderate-to-severe plaque psoriasis received different doses of oral JNJ-77242113, efficacy improved with increasing dose, and skin symptoms clearly improved in the higher-dose groups. The significance of this study is not merely that a psoriasis drug achieved positive results; it also provided the first strong proof that an oral cyclic peptide can enter the circulation from the intestine, block IL-23R in tissues distant from the gastrointestinal tract, and translate this into clear clinical efficacy. By this stage, JNJ-77242113 was no longer just an interesting peptide technology, but had begun to possess real drug value.

From Clinical Proof of Concept to Long-Term Treatment

After the success of Phase II, the focus of development changed accordingly. For psoriasis, where multiple highly effective biologics already exist, simply proving “better than placebo” is not enough; a new oral drug must also demonstrate that efficacy can be reproduced consistently, that safety during long-term treatment is acceptable, and that the convenience of daily dosing can create real product value. The subsequently conducted ICONIC Phase III program further validated the efficacy and safety of icotrokinra in moderate-to-severe plaque psoriasis, gradually transforming it from a new oral peptide technology into a product that can be evaluated according to the standards for ordinary chronic disease medications.

This is also a change in the development process that is easily overlooked. For patients, how many non-natural amino acids the molecule contains, and whether its oral bioavailability complies with traditional medicinal chemistry rules, are less important than whether it can continuously control disease in a convenient manner while maintaining acceptable safety. When a complex new technology ultimately becomes an ordinary tablet, the technology itself recedes behind the product.

In 2026, ICOTYDE Is Approved

In March 2026, the FDA approved ICOTYDE (icotrokinra) for eligible patients with moderate-to-severe plaque psoriasis, with a recommended dose of 200 mg orally once daily. From Protagonist’s earliest exploration of IL-23R cyclic peptides, to the selection of PN-235 for clinical development, and then to completion of late-stage development by Janssen and Johnson & Johnson, this route took more than a decade. Setting aside the lengthy development details, what ICOTYDE ultimately proved is that the boundaries between drug modalities are not absolute.

Traditional small molecules are easy to administer orally and enter tissues, but they often struggle when facing large protein–protein interaction interfaces; antibodies can recognize these protein surfaces with extremely high affinity and selectivity, but usually require injection. Peptides sit between the two, with stability and oral absorption long limiting their application. ICOTYDE, a cyclic peptide approaching 1900 Da, uses its relatively large molecular surface to recognize IL-23R with high affinity, and obtains sufficient gastrointestinal stability through cyclization, non-natural amino acids, and long-term medicinal chemistry optimization. Its intestinal permeability remains very low, and the fraction absorbed orally is not high, but extremely strong target engagement, stable yet limited absorption, and an appropriate clinical dose together compensate for these shortcomings.

ICOTYDE did not prove that large-molecule peptides can be absorbed as easily as small molecules, nor did it ever become a typical small-molecule drug. What it demonstrates is that a drug does not have to perform excellently on every traditional metric; as long as different properties can together generate sufficient therapeutic exposure and clinical benefit, a molecule that appears to fall outside convention can likewise become a drug.

From One Drug to a New Possibility

IL-23R is a typical extracellular protein interaction target, a class of targets that in the past was usually the domain where antibodies and other biologics had an advantage. The success of ICOTYDE shows that, for suitable targets, highly engineered cyclic peptides may also acquire similar protein surface recognition capabilities while offering a completely different route of administration. However, this does not mean that all antibody targets can simply be converted into oral cyclic peptides. Whether an appropriate binding site can be found, sufficiently high affinity can be obtained, gastrointestinal degradation can be resisted, and limited absorption can generate effective exposure—each step may determine the success or failure of the program.

Before ICOTYDE, this route was more of a possibility; after ICOTYDE was approved, it became a drug development pathway that can continue to be studied and potentially replicated. For the cyclic peptide field, this may be more important than simply adding another psoriasis drug. The question truly worth watching has shifted from “can a cyclic peptide approaching 1900 Da become an oral drug” to: what will be the next target suitable for conversion from an injectable biologic into an oral cyclic peptide?

End of Series

Scientific Sources

Fourie AM, Cheng X, Chang L, et al. JNJ-77242113, a Highly Potent, Selective Peptide Targeting the IL-23 Receptor, Provides Robust IL-23 Pathway Inhibition upon Oral Dosing in Rats and Humans. Scientific Reports. 2024;14:17515. https://doi.org/10.1038/s41598-024-67371-5

Bissonnette R, et al. An Oral Interleukin-23–Receptor Antagonist Peptide for Plaque Psoriasis. New England Journal of Medicine. 2024;390:510–521. https://doi.org/10.1056/NEJMoa2308713

Bissonnette R, et al. Icotrokinra in Moderate-to-Severe Plaque Psoriasis. New England Journal of Medicine. 2025;393:1784–1795. https://doi.org/10.1056/NEJMoa2504187

Janssen Biotech, Inc.; Protagonist Therapeutics, Inc. Peptide Inhibitors of Interleukin-23 Receptor and Their Use to Treat Inflammatory Diseases. WO2021146441A1. Google Patents