Icotrokinra (JNJ2113): A stable and orally bioavailable peptide as a first-in-class selective antagonist of Interleukin-23 Receptor
We are pleased to review a recently published article in Dermatology and Therapy for our August Journal Club. Beverly Knight and colleagues report the translational pharmacokinetics of Icotrokinra (JNJ-2113), a first-in-class investigational targeted oral peptide that selectively antagonizes the IL-23 receptor.
Icotrokinra demonstrated remarkable stability across species in a range of biological matrixes including plasma, gastrointestinal (GI) content, and hepatocytes. Notably, the peptide exhibited in vitro stability with a mean half-life exceeding 24 hours in fecal and GI mucosal matrices from rat, monkey and human, as well as in simulated gastric fluid (SGF) and purified GI enzyme solutions.
Despite its low monolayer cell permeability, Icotrokinra achieved oral bioavailability of 0.1-0.3% in rat and monkey without the use of absorption enhancer.
Peptide therapeutics have traditionally been viewed as injectable due to their low stability in the GI tract and low permeability. However recent advancements have enabled the successful development of orally available peptide drugs as Rybelsus® (semaglutide) by Novo Nordisk and Mycapssa® (octreotide) from Chiasma, as well as late investigational candidate MK0616, an oral PCSK9 inhibitor from Merck, and Icotrokinra (JNJ2113) from Johnson & Johnson. These successes demonstrate that the long-held perception of peptide as unsuitable for oral delivery can be overcome. With their inherent advantages of high target specificity and low off-target effects, peptide therapeutics have now the potential to offer patients safe, effective and convenient oral treatment options.
Open Access article: https://doi.org/10.1007/s13555-025-01454-7
Beverly Knight, Brinda Tammara, Nishit B. Modi, Shannon Dallas, Saro Mardirosian, Jianyao Wang, Aline Laenen, Laurent Leclercq, Karen DiLoreto, Lieve Adriaenssen, Darren Moss, David Polidori, Siladitya Ray Chaudhuri, Seonghee Park, Carlo Sensenhauser, Anthony Ndifor, Siddharth Sukumaran, Tristan Baguet, Yifan Shi, Shefali Patel, Brian Geist, Anne Fourie, Raymond Patch, Chengzao Sun, Stephanie A. Barros, Sandeep Somani, Mario Monshouwer, Translational Pharmacokinetics of Icotrokinra, a Targeted Oral Peptide that Selectively Blocks Interleukin-23 Receptor and Inhibits Signaling, Dermatology and Therapy, 2025.
Chengzao Sun
Member, BPF Scientific Advisory Board
Co-founder and CSO, Pinnacle Medicines
linkedin.com/in/chengzao-sun-17aa6513/
Read previous editions of the BPF Journal Club series: https://www.boulderpeptide.org/journal-club