Two Different Paths to Oral Macrocyclic Peptide Drugs: Icotrokinra and Enlicitide

Introduction: Why These Two Oral Cyclic Peptide Drugs Are Worth Comparing

For a long time, although peptide drugs have offered high target selectivity and biological activity, most have still required administration by injection. The reason is that after peptides enter the gastrointestinal tract, they are readily degraded by proteases; moreover, because of their relatively high molecular weight and polarity, they generally have difficulty crossing the intestinal epithelium and entering the bloodstream. How to make peptides orally administrable like conventional small-molecule drugs has long been an important challenge in drug development.

Icotrokinra (formerly known by the development codes JNJ-77242113, JNJ-2113, and PN-235) and Enlicitide (MK-0616) provide two representative answers to this problem. The former was jointly discovered and developed by Protagonist Therapeutics and Janssen/Johnson & Johnson, and directly targets the IL-23 receptor (IL-23R); the latter was developed by Merck and targets PCSK9. They address completely different diseases, yet both attempt to use oral cyclic peptides to achieve therapeutic mechanisms that previously relied mainly on injectable biologics.

As of the publication date of this article, these two approaches are no longer merely clinical proofs of concept. On March 17, 2026, the FDA approved ICOTYDE (icotrokinra) for eligible patients with moderate-to-severe plaque psoriasis; in July 2026, it also approved LIPFENDRA, whose active ingredient is enlicitide decanoate, for lowering LDL-C in adults with hypercholesterolemia. Clinical studies provided evidence of efficacy and safety, while regulatory approval is an independent decision based on a complete submission package; the two should not be conflated.

These two drugs are worth comparing not only because both are cyclic peptides that have been translated into oral products, but also because they demonstrate different molecular discovery evidence, medicinal chemistry priorities, and oral development strategies.

Icotrokinra: Blocking Immune Signaling with an Oral Cyclic Peptide

The target of Icotrokinra is IL-23R. IL-23 is an important cytokine that regulates immune and inflammatory responses and is closely associated with immune-mediated diseases such as psoriasis. Blockade of the IL-23 pathway has long been clinically validated by injectable monoclonal antibodies, whereas Icotrokinra uses a different molecular modality: it is a chemically synthesized macrocyclic peptide that directly binds the extracellular domain of IL-23R with high affinity, prevents IL-23 from activating the receptor, and thereby selectively inhibits downstream signaling.

The challenge in this design is that the interaction between a cytokine and its receptor is a protein–protein interaction, and the binding interface is typically large, making it difficult for conventional small molecules to cover effectively. Cyclic peptides can form relatively fixed three-dimensional conformations and use multiple side chains to contact the protein surface in concert, giving them the potential to balance affinity and selectivity. Published pharmacology studies report that Icotrokinra has a surface plasmon resonance binding constant of 7.1 pM for human IL-23R and can inhibit IL-23-induced cellular signaling without affecting IL-12 signaling.

However, identifying a cyclic peptide that can bind IL-23R is only the first step. Published patents record numerous IL-23R cyclic peptide sequences, structure–activity relationships, and gastrointestinal stability data. Subsequent work continued to adjust amino acid composition, cyclization architecture, terminal groups, and overall molecular properties, ultimately yielding a candidate molecule with extremely high receptor-binding activity, gastrointestinal stability, and sufficient oral exposure. Existing publicly available information does not assign Icotrokinra to a named screening platform that directly corresponds to Enlicitide’s mRNA Display. Therefore, a more accurate statement is that it reflects cyclic peptide discovery around a specific receptor, patent-based structure–activity relationship exploration, and iterative engineering optimization, rather than attributing to it a technology not confirmed by primary sources simply to create a distinction between the routes.

The proportion of orally absorbed Icotrokinra is not high, nor has it become a molecule that follows conventional small-molecule rules of thumb. Its therapeutic feasibility arises from the combined action of multiple properties: maintaining sufficient stability in the gastrointestinal tract, producing reproducible systemic exposure through limited absorption, and occupying IL-23R with extremely high affinity. Phase II and Phase III studies demonstrated its clinical efficacy in plaque psoriasis, and subsequent FDA approval further confirmed that it has been translated from an oral peptide concept into a usable prescription drug. For immune targets that were previously covered mainly by antibodies, this has implications beyond a single product.

Enlicitide: From Cyclic Peptide Screening to an Oral Lipid-Lowering Drug

The target of Enlicitide is PCSK9, a protein that regulates low-density lipoprotein cholesterol (LDL-C) in the blood. After PCSK9 binds to the low-density lipoprotein receptor (LDLR), it promotes LDLR degradation, reducing the liver’s ability to clear LDL-C. Blocking the PCSK9–LDLR interaction can preserve more LDLR and lower LDL-C in the blood; before Enlicitide, this mechanism was achieved mainly by injectable monoclonal antibodies or small interfering RNA drugs.

Merck’s approach has a clearly defined screening technology starting point. Researchers used mRNA Display to obtain PCSK9-binding cyclic peptides from an ultra-large peptide library incorporating cyclization designs and expanded amino acid chemical space, and then combined structural biology, synthetic chemistry, and multiple rounds of medicinal chemistry optimization to gradually convert the screening hit into a candidate molecule with oral pharmacological activity. The original research clearly supports the conclusion that “mRNA Display provided the initial chemical matter,” but it is equally clear that the high-affinity cyclic peptides obtained from screening were not finished oral drugs that could be administered directly.

Subsequent optimization had to address proteolytic and metabolic stability, conformation, solubility, clearance, synthetic scale-up, and intestinal absorption simultaneously. Strategies such as noncanonical amino acids, backbone N-methylation, and multiple cyclizations expanded the range of molecular properties that could be modulated, but they are not universal oral-enabling switches applicable to all cyclic peptides. Enlicitide’s final oral product also uses the permeation enhancer sodium caprate; therefore, its success should be understood as the combined result of molecular engineering, medicinal chemistry, and formulation engineering.

This website has already published five articles that progressively discuss the specific evolution of Enlicitide from an mRNA Display hit to a clinical candidate. This article will not repeat the stepwise structural optimization of Compound 30, Compound 79, Compound 1a, or other numbered compounds, but will retain only the most important summary of this route: large-scale screening identified a starting point capable of covering the PCSK9 protein surface, and sustained multiparameter optimization converted that starting point into an oral drug.

Phase I, Phase IIb, and Phase III studies provided clinical evidence for Enlicitide’s target inhibition, LDL-C reduction, and safety; the subsequent FDA approval of LIPFENDRA means that this highly engineered macrocyclic peptide originating from mRNA Display has completed its translation from a screening hit into an approved oral lipid-lowering drug.

Key Differences Between the Two Drugs

Although Icotrokinra and Enlicitide are both oral macrocyclic peptides, the therapeutic needs they address, their direct targets, and the discovery narratives supported by public evidence are not the same. Icotrokinra is used for immune-inflammatory diseases and blocks cytokine signaling by binding IL-23R; Enlicitide is used for lipid management and maintains LDLR function by blocking the interaction between PCSK9 and LDLR.

Comparison Item	Icotrokinra	Enlicitide
Developer	Protagonist / Janssen / Johnson & Johnson	Merck
Molecular type	Chemically synthesized 13-residue macrocyclic peptide	Highly engineered macrocyclic peptide
Target	IL-23R	PCSK9
Main therapeutic area	Moderate-to-severe plaque psoriasis; other immune-mediated diseases still need to be assessed by specific program	Adult hypercholesterolemia, including heterozygous familial hypercholesterolemia
Mechanism of action	Binds IL-23R and blocks IL-23 receptor signaling	Blocks the PCSK9–LDLR interaction, reduces LDLR degradation, and lowers LDL-C
Discovery and optimization features with direct public support	IL-23R-targeted cyclic peptide discovery, patent-based structure–activity relationship exploration, and iterative engineering optimization; public information does not specify the same mRNA Display starting point as Enlicitide	mRNA Display screening provided the initial hit, followed by structure-guided design, synthetic chemistry, and multiparameter medicinal chemistry optimization
Key points of oral strategy	Oral pharmacological activity achieved through the combined effects of gastrointestinal stability, extremely high target affinity, and limited but effective systemic exposure	Oral delivery achieved through molecular optimization together with a permeation-enhancing formulation containing sodium caprate
U.S. regulatory status as of 2026-10-08	ICOTYDE (icotrokinra) has been approved by the FDA	LIPFENDRA (enlicitide decanoate) has been approved by the FDA

These differences do not mean that the two drugs follow completely different absorption principles. Regardless of which discovery technology produced the initial hit, oral cyclic peptides must strike a balance among target affinity, proteolytic and metabolic stability, solubility, formulation compatibility, and intestinal absorption. Nor do they prove that any cyclic peptide can become orally available simply by introducing noncanonical amino acids; the value of specific residue and structural modifications always depends on the sequence, conformation, target, and the full molecular context.

Why Is High Affinity Especially Important for Oral Cyclic Peptides?

Conventional oral small molecules generally have good intestinal absorption, whereas macrocyclic peptides are limited by factors such as molecular weight, polarity, and hydrogen-bonding networks. Even after optimization, oral bioavailability may still remain low. For such molecules, merely requiring that “absorption can be detected” is far from sufficient; the small amount of drug that enters the circulation must also produce adequate target engagement.

If a cyclic peptide has extremely high affinity for its target and can maintain sufficient effective exposure after entering the bloodstream, then even if only a small proportion of the oral dose is absorbed, it may still achieve the required target occupancy and pharmacological effect. Icotrokinra’s picomolar binding to IL-23R and Enlicitide’s low-picomolar inhibition of PCSK9 illustrate precisely why high affinity is often an important prerequisite for continued optimization in projects of this type.

High affinity also provides a certain “activity budget” for subsequent medicinal chemistry. Researchers can tolerate some loss of binding activity while attempting to improve stability, solubility, clearance, or absorption, without immediately losing pharmacological feasibility. However, this concept cannot be interpreted to mean that affinity can compensate indefinitely for low exposure: whether a drug ultimately succeeds still depends on factors such as free drug concentration, target occupancy, duration of action, dose, interindividual variability, and safety. High affinity is one key condition, not a shortcut around pharmacokinetics.

Oral Cyclic Peptides Are Changing the Boundaries of Peptide Drug Development

In the past, cyclosporine was often regarded as a special case of an orally available macrocyclic peptide. Its molecular structure and conformational features give it unusual membrane permeability, but this property is difficult to generalize directly to other peptides. Therefore, for a long time, oral peptides were more a technical problem to be overcome than a drug modality that could be developed systematically.

The importance of Icotrokinra and Enlicitide lies in the fact that they change this understanding. These two drugs did not arise from serendipitously discovered natural products; instead, starting from clearly defined therapeutic targets, they achieved clinically valuable oral pharmacological activity through the discovery of high-affinity peptide molecules, non-natural amino acid chemistry, and sustained medicinal chemistry and formulation optimization. The specific tools used in the two routes are not the same, and no single technology should be described as a universally applicable solution; what is truly reproducible is the method of continuously solving affinity, stability, exposure, formulation, and manufacturing problems around the same candidate.

More importantly, the IL-23R and PCSK9 targets they address are both targets that conventional small molecules have difficulty handling effectively, while biologics have already validated their therapeutic value. This shows that the potential of cyclic peptides is not only to improve the route of administration for peptide drugs, but also to create a new drug development space between conventional small molecules and antibodies.

Of course, this does not mean that most cyclic peptides can be optimized into oral drugs. Oral absorption remains a stringent molecular selection criterion, and many cyclic peptides with excellent target affinity may ultimately still fail because of inadequate pharmacokinetics, formulation, or safety. However, Icotrokinra and Enlicitide have demonstrated that these difficulties are not insurmountable, nor do they have to rely entirely on rare structural features found in natural products.

The real change marked by these two drugs is that oral cyclic peptides are shifting from a small number of exceptions among natural products into a drug class that can be actively developed through large-scale screening, noncanonical amino acid chemistry, and systematic molecular optimization. For targets that have already been shown by antibodies to have therapeutic value but have long lacked effective oral small molecules, cyclic peptides are providing a new drug discovery and development path that deserves serious investment.

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

U.S. Food and Drug Administration. Drug Trials Snapshots: ICOTYDE. Original approval date: March 17, 2026. https://www.fda.gov/drugs/drug-trials-snapshots/drug-trials-snapshots-icotyde

Alleyne C, Amin RP, Bhatt B, et al. Series of Novel and Highly Potent Cyclic Peptide PCSK9 Inhibitors Derived from an mRNA Display Screen and Optimized via Structure-Based Design. Journal of Medicinal Chemistry. 2020. https://doi.org/10.1021/acs.jmedchem.0c01084

Johns DG, et al. Orally Bioavailable Macrocyclic Peptide That Inhibits Binding of PCSK9 to the Low Density Lipoprotein Receptor. Circulation. 2023;148:144–158. https://doi.org/10.1161/CIRCULATIONAHA.122.062400

Josien H, et al. Discovery Process of Enlicitide, a Highly Engineered Macrocyclic Peptide Therapeutic, through Issue-Driven Fragment-Based Synthetic Assembly and SAR. Journal of Medicinal Chemistry. 2026. https://doi.org/10.1021/acs.jmedchem.6c00661

U.S. Food and Drug Administration. FDA Approves First Oral PCSK9 Inhibitor to Lower LDL Cholesterol in Adults with High Cholesterol. July 17, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-pcsk9-inhibitor-lower-ldl-cholesterol-adults-high-cholesterol