PII-056 - ADME PROFILING OF TARGETED ORAL PEPTIDE JNJ-77242113

B. Knight¹, S. Dallas², S. Mardirosian², J. Wang², A. Laenen³, L. Leclercq³, D. Moss³, K. DiLoreto², S. Park², D. Polidori⁴, C. Sensenhauser², A. Ndifor⁴, Y. Shi², S. Patel², A. Fourie⁵, R. Patch⁶, C. Sun⁷, M. Monshouwer³; ¹Johnson & Johnson Innovative Medicine, San Diego, CA, USA, ²Johnson & Johnson Innovative Medicine, Spring House, PA, United States, ³Johnson & Johnson Innovative Medicine, Beerse, Antwerpen, Belgium, ⁴Johnson & Johnson Innovative Medicine, San Diego, CA, United States, ⁵Johnson & Johnson Innovative Medicine (retired), San Diego, CA, United States, ⁶Johnson & Johnson Innovative Medicine (retired), Spring House, PA, United States, ⁷Pinnacle Medicines, Warrington, PA, United States.

Background: JNJ-77242113, a very potent targeted oral peptide that selectively inhibits IL-23 receptor signaling, was profiled in vitro and in vivo to elucidate its absorption, distribution, metabolism, and excretion (ADME) properties, as well as its drug-drug interaction potential.

Methods: Standard industry-accepted in vitro assays were used to characterize the permeability and metabolic turnover of JNJ-77242113, as well as its potential for interaction with standard drug transporters and metabolic enzymes. The pharmacokinetic properties of the compound, including oral bioavailability, distribution, metabolism, and excretion, were characterized in vivo in rat and monkey (the species used for safety studies), following dosing with cold and [14C]-radiolabeled drug. Exploratory metabolite profiling was also conducted using plasma samples from the Phase 1 study.

Results: The ADME properties of JNJ-77242113 are consistent with the typical PK behaviors of small peptides (low permeability, clearance via renal filtration and catabolic degradation). Oral bioavailability was < 1% in animals, but exposures were sufficient for systemic activity. The compound was stable across species in plasma and GI matrices (>24 hours) as well as hepatocytes (indicating a lack of hepatic metabolic clearance). The drug showed low protein binding across species (~50%) and was freely distributed to tissues, including skin, joints, and gastrointestinal tissues. Unchanged drug was the main circulating component in rat, monkey, and human plasma. Metabolites were observed at low levels in rat and monkey plasma and excreta (confirming coverage in toxicology species), whereas only unchanged drug was detected in human plasma. Fecal excretion of unabsorbed drug was the main route of elimination following oral dosing (96.8% of the dose in rat; 67.0% in monkey), while renal excretion contributed to clearance of systemic JNJ-77242113 (0.2% of the dose in rat, 1.0% in monkey). JNJ-77242113 was not a substrate or inhibitor of prototypical drug transporters or cytochrome P450 enzymes at relevant clinical concentrations ( < 10 ng/mL).

Conclusion: The ADME characterization of JNJ-77242113 revealed a drug profile that is consistent with typical small peptides, except for its high stability. No drug-drug interaction risk was found.