J&J's Oral Peptide Icotrokinra Nears Regulatory Finish Line with NDA Submission for Moderate-to-Severe Plaque Psoriasis
Johnson & Johnson
Medical Device R&D and Manufacturer
Author｜YY
In the minds of most people, peptide drugs are difficult to be compatible with oral dosage forms: they are susceptible to enzymatic degradation in the gastrointestinal tract, have weak membrane permeability, and exhibit unstable systemic exposure. Because of this, the majority of peptide drugs have long relied on injectable administration, such as insulin.GLP-1 To gonadotropin preparations. However, with the breakthroughs in delivery technology and the refined engineering of molecular structures, successful cases of orally administered peptide drugs coming to market are constantly emerging.The most representative case in the near term is undoubtedly Johnson & Johnson andProtagonistCo-developed oralIL-23RAntagonistic PeptideIcotrokinra。
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Icotrokinra
Breakthrough in Oral Cyclic Peptides
Icotrokinra （Figure1) is a first-of-its-kind (first-in-class) A targeted oral peptide drug that selectively blocksIL-23 Receptor inhibitionIL-23Signal pathway, exerting immunomodulatory effects.IL-23 It is a key inflammatory factor in various autoimmune diseases such as psoriasis, and its pathway has long been primarily addressed by injectable biologics (e.g.,ustekinumab、guselkumab) Undertake the suppression task.Icotrokinra The structure is based on a cyclic peptide backbone, designed to integrate dual optimizations for gastrointestinal stability and receptor affinity, demonstrating performance in vitro.picomolar LevelIL-23R Combined capabilities demonstrate superior selectivity and functional inhibition efficiency. Traditionally,IL-23The pathway is a target for many biologics, andicotrokinra The advantage lies in that it is an oral polypeptide drug, offering a more convenient treatment method compared to existing subcutaneous or intravenous injection drugs.
In preclinical studies,Icotrokinra Exhibited in rats and monkeys0.1–0.3%The oral bioavailability, although not high in value, still achieves clear systemic pharmacological activity without the use of absorption enhancers, indicating that its oral design is practically effective. The compound exhibits high stability in plasma, gastrointestinal contents, and hepatocytes across multiple species, with a low protein binding rate (approximately in human plasma).50%), and can be widely distributed to target tissues such as skin, joints, and the gastrointestinal tract.
The drug is mainly excreted through feces, with low metabolic levels in the body (individual metabolites in plasma and excreta are both below2%), the system circulation is mainly in the form of the parent drug.Icotrokinra Not with typical drug transport proteins or CYP450 Enzyme interactions, suggesting its drug interactions (DDI) The risk is extremely low. In the first human trial, the drug showed25–1000mg Linear pharmacokinetic characteristics within the dose range were observed, no serious adverse events were reported, and the only detectable drug-related component in plasma was the unchanged parent drug.
Comprehensive ADME Characteristics, Tissue Distribution, and Clinical Safety,Icotrokinra Exhibiting pharmacokinetic properties consistent with typical small peptides, supporting its stability and low...DDIThe Development Potential of Oral Immunomodulatory Drugs with Risk.
Figure1. IcotrokinraChemical Structure
2025Year7Month, Johnson & Johnson has officially submitted toFDASubmitIcotrokinraThe new drug marketing application, indicated for adult patients with moderate to severe plaque psoriasis.12Adolescents over the age of. This application is based onICONICSeries Four ItemsIIIFull data from the clinical phase, covering placebo anddeucravacitinibA direct comparison, supplemented by additional evidence targeting refractory-area psoriasis, adolescent subgroups, and long-term follow-up. In terms of efficacy, safety, and breadth of indications, this submission is widely regarded as the most disruptive oral drug launch attempt in the field of psoriasis treatment in recent years.Icotrokinra TheIII The Phase Clinical Project is led by Johnson & Johnson, collectively referred to asICONIC Plan, covering four key registration studies (ICONIC-LEAD、ICONIC-TOTAL、ICONIC-ADVANCE 1&2). This series of trials not only fully achieved the primary endpoint, but also inICONIC-ADVANCE 1&2 It clearly shows its superior efficacy in psoriasis compared to oral small molecules.TYK2 Inhibitordeucravacitinib。According to reports,7Month31Day,IcotrokinraAlready inSubmission in ChinaIND。
ICONIC-LEAD Up to49.5% of patients at the24 Zhou Reached an AgreementPASI 100(Complete clearance of skin lesions), while the incidence of adverse events (49.1%) and the placebo group (51.9%) are almost the same, with reassuring safety. Additionally, in psoriasis patients involving "difficult-to-treat areas" such as the scalp, genitals, and hands and feet,ICONIC-TOTAL In the study,Icotrokinra Also demonstrated excellent local control capabilities.
Johnson & Johnson has already2025 Year of LaunchICONIC-ASCEND Research, Intentions with Own Biologicsustekinumab Engage in a direct comparison, and if we secure another victory,IcotrokinraIt will achieve a rare dual advantage between efficacy and convenience, with the potential to disrupt the current first-line treatment pattern for psoriasis dominated by biologics. This striking head-to-head study between peptide and monoclonal antibody will be a direct challenge to whether oral peptides can replace biologics and a critical demonstration of oral peptide formulations.
From an industrial perspective,IcotrokinraThe listing is expected to create new market space for peptide oral drugs as alternatives to biologics.Globally about1.25Among hundreds of millions of psoriasis patients, it is estimated that more than3000Ten thousand patients meet the moderate to severe criteria, and a significant proportion of them have not yet received systematic treatment, mainly due to poor injection compliance and difficulty in accessing medication. For these patients, a once-daily regimen that does not require a cold chain or injection training is ideal.Icotrokinra, undoubtedly possesses broad market penetration potential.
Although Johnson & Johnson has not disclosed formal sales forecasts, some analysts conservatively predict that ifIcotrokinraIn2026Approved in the year, its annual sales peak may reach30–50billion dollars, and became the world's first orally administered form to be launched on the market.IL-23RInhibitor. More importantly,It will pave the way for a series of cyclic peptides, non-natural amino acid peptides, and even peptides.PROTAC...and other complex molecules establish path dependence, propelling peptide drugs from the "injection era" into the "systemic delivery era."
IcotrokinraExpected to become the first approved oralIL-23Receptor inhibitors, which are revolutionary in the treatment of psoriasis.Currently, many potent treatment options on the market, such as adalimumab (Humira) and Etanercept (Enbrel) All require subcutaneous injection or intravenous injection, which may affect patient compliance.IcotrokinraThrough oral administration, it provides a more convenient treatment option compared to these injectable drugs, significantly improving patients' quality of life. Johnson & Johnson also plans toicotrokinraExtended to the treatment of other immune diseases, such as Ulcerative Colitis and Crohn's Disease, further verifying its wide application potential in the field of immune regulation.。
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IcotrokinraStructural Highlights
PenicillamineStrategy
In the structural design of peptide drugs, the introduction of disulfide bonds is a conventional strategy to enhance molecular conformational stability, improve target affinity, and increase enzymatic resistance. However, traditional disulfide bonds are primarily formed by two cysteines (Cys) residues, which have limited resistance to gastrointestinal enzymatic degradation, making them insufficient to meet the stringent requirements of oral formulations.
Icotrokinra One of the breakthroughs lies in the adoption of two elements in its cyclic peptide structure.L-penicillamine（Pen, Penicillamine) residue, constructing a highly rigid and sterically hindered atypical disulfide bond structure, achieving a dual breakthrough in stability and oral adaptability.
Figure2. Penicillamine(Left) andcysteine(Right) Chemical Structure Comparison
Penicillamine Is a β-A cysteine analog with two methyl groups attached (Figure2), commonly known as“3,3-Dimethylcysteine." This disubstituted structure brings three major advantages:
● Enhanced Conformational Rigidity:Pen–Pen The ring structure formed by disulfide bonds is more rigid, and the spatial locking of the peptide chain is more stable, effectively enhancing molecular integrity under oral conditions.
● Improved Metabolic Stability:Its hydrophobic methyl groups shield the contact sites with intestinal proteases, reducing the risk of hydrolysis.
● Conducive to transmembrane absorption:A more hydrophobic surface facilitates membrane permeation in intestinal epithelial cells, enhancing oral absorption efficiency.
DespiteL-(R)-penicillamine May interfere with vitamins in a free stateB6 Function and bring toxicity, but inIcotrokinra In the cyclic peptide configuration, this component is in a stable binding state, with no toxicological signals or safety warnings observed. In fact,Penicillamine Itself has long been regarded asFDA Approved drugs (such asCuprimine) Used to treat Wilson's disease, heavy metal poisoning, and rheumatoid arthritis, its pharmacological predictability is extremely high.
PenWith the expanding application scope of oral peptide formulations,Marks the leap from sequence optimization to precise conformational engineering in the design of oral peptides.In recent years, an increasing number of candidate peptides have been introduced.Pen SubstituteCys To enhance stability,Penicillamine Or is becoming one of the key structural units in the platformization of oral peptides.
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IcotrokinraWhether it hasPIPAttribute
DespiteIcotrokinra Currently focused on psoriasis, but its immune modulation mechanism suggests its potential indications may extend far beyond this. Inflammation and immune diseases, particularly autoimmune diseases, have already given rise to numerous treatments represented by Humira.PIP（pipeline-in-a-pill, with its own pipeline) drug.
“Pipeline-in-a-pill”（PIP) concept, originally referring to a drug's ability to demonstrate efficacy across multiple indications, forming a pipeline-level horizontal expansion capability rather than being limited to the treatment of a single disease. In recent years, this concept has been widely used to evaluate biologics or targeted drugs with multi-target indications, mechanism versatility, and development scalability. ForIcotrokinra Speaking of which, although only the psoriasis indication has been submitted for marketing approval so far, its target mechanism, clinical layout, and structural platform capabilities have already begun to show the雏形of "drug as pipeline."
First,From a mechanistic perspective,IcotrokinraTargetedIL-23Receptors are highly conserved inflammatory regulatory nodes in a variety of immune-related diseases.IL-23Pathways play a critical role in diseases such as plaque psoriasis, psoriatic arthritis, ulcerative colitis, Crohn's disease, and even uveitis. Currently mainstream injectable biologics, such asustekinumabAndguselkumab, which also represents a horizontal expansion across different indications. This means that,IcotrokinraIt has clear indications for extension at the mechanism level, and is not just a drug specifically for psoriasis.
Secondly,From a clinical strategy perspective, Johnson & Johnson andProtagonistHas been systematically advancing this extended path.In PsoriasisNDAAt the same time of submission, its two items in psoriatic arthritisIIIPhase Research (ICONIC-PsA 1/2) has been synchronized, ulcerative colitisIIbPhase Research (ANTHEM-UC) is also underway. It can be seen that,IcotrokinraIs attempting to build its own multi-indication landscape through the path of "from skin to joints, from skin to intestines", a layout that echoesDupixent"The path of asthma expanding to skin and rhinitis is extremely similar."
More importantly,IcotrokinraAs a cyclic oral polypeptide,The molecular structure it adoptspenicillamineThe constructed atypical disulfide bond design not only imparts the drug with good gastrointestinal stability and membrane permeability but also lays the foundation for further structural expansion.Its molecular framework, characterized by "high rigidity, low metabolism, and high targeting," holds promise for being transplanted and replicated onto other inflammatory targets in the future, evolving into a platform-based design template for orally administrable mid-sized drugs. Compared to the exorbitant treatment costs of traditional injectable antibodies, which often reach tens of thousands of dollars, as well as the global accessibility issues posed by cold chain logistics,IcotrokinraThe oral structural platform it represents undoubtedly has greater global promotion potential and adaptability to a wider population.
Therefore, in terms of target universality, clinical extensibility, and the replicability of a structured platform,IcotrokinraHas initially possessed the capability to become "pipeline-in-a-pill"The key characteristics." Although its future in indications beyond psoriasis still requires moreIIIThe validation period has not yet arrived, but the design logic and development strategy demonstrated by this drug are breaking through the single-line thinking of indications, constructing a new generation of drug development paradigm that is "mechanism-driven and maps to multiple indications." If injectable antibodies have built a broad-spectrum era for biologics over the past decade, thenIcotrokinraThe direction it represents, or will push oral peptides into its ownPIPGeneration.
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IcotrokinraCan a new era for oral peptides be pioneered?
Icotrokinra If approved for marketing, it would not only provide a new option for the treatment of psoriasis but also signify a profound transformation in the treatment model. For a long time, the standard treatment regimen for moderate to severe psoriasis has mainly relied on injectable biologics, especially targetedTNF、IL-17AndIL-23Monoclonal antibodies for pathways, such asAdalimumab（Humira）、Secukinumab（Cosentyx) andUstekinumab（Stelara). These antibody-based drugs have shown significant efficacy and clear targets, but issues such as injection frequency, reliance on cold chain logistics, and high dependence on medical resources continue to limit their penetration rate among a broader population. This is particularly evident in younger patients, those in remote areas, and individuals with low adherence.
Icotrokinra It is in this context that it has emerged. It not only targets the sameIL-23Pathway, still in multipleIIIIn the clinical phase, it demonstrated non-inferior or even superior efficacy, especially in terms of complete clearance rate of skin lesions (PASI 100) has approached or even surpassed the historical data of some biologics. More importantly, its characteristics of once-daily oral administration, no injections, and no reliance on cold chain transportation will provide an optimized dosing regimen for many patients with autoimmune diseases. This shift in formulation not only liberates patients but may also reshape the decision-making pathways of prescribing physicians, promoting the expansion of treatment strategies from specialized management to broader prescription practices.
At a deeper level,Icotrokinra The arrival also challenged the long-standing dominance of monoclonal antibody drugs in the field of chronic diseases.In the past, injectable antibodies were considered the ultimate weapon, especially in the field of immunology, where they were almost irreplaceable. However, the rise of oral peptides has proven that highly specific, potent, and controllable immune intervention can also be achieved through meticulous molecular structure design and target matching. This combination of equivalent efficacy and superior formulation will force biologics to face renewed competition in terms of price, convenience, and market acceptance.
Johnson & Johnson inIcotrokinraThe active investment also indicates,Large pharmaceutical companies are no longer hesitant about the "needle-to-pill" trend.. Just as oral small-molecule drugs replaced intravenous chemotherapy drugs in those years,Icotrokinra It could be the tipping point for a new revolution in drug delivery methods. Its anticipated launch not only provides a more flexible and precise solution for psoriasis treatment but also signals the approach of an era of biologics without the need for injectors.
Ref.
Buntz, B. J&J bets on nipocalimab and oral peptides in immunology. Drug Discovery & Development. 23. 07. 2025.
Knight, B. et al. Translational Pharmacokinetics of Icotrokinra, a Targeted Oral Peptide that Selectively Blocks Interleukin-23 Receptor and Inhibits Signaling. Dermatol Ther (Heidelb). Jul. 8. Doi: 10.1007/s13555-025-01454-7.
Peptide Technology: Cysteine AnaloguespenicillamineApplications in Peptide Drug Development and Synthesis. Zhong肽 Biochemical,2025Year5Month16Day.
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