060: Pharmacokinetic Modeling of the IRF5 Antisense Oligonucleotide JNJ-66525433 & IRF5 mRNA Expression in Healthy Individuals

Statement of Purpose, Innovation or Hypothesis: JNJ-66525433 is an antisense oligonucleotide (ASO) that targets interferon regulatory factor 5 (IRF5) messenger ribonucleic acid (mRNA), leading to its degradation. IRF5 has been implicated as key contributor to the pathogenesis of several immune-mediated diseases including inflammatory bowel diseases. The present study evaluated the pharmacokinetic and pharmacodynamic (PK/PD) relationship of JNJ-66525433 after oral administration in healthy individuals. Because JNJ-66525433 was developed to be locally acting with limited systemic distribution, both the systemic and mucosal colon tissue concentrations of JNJ-66525433 were evaluated.

Description of Methods & Materials: JNJ-66525433 was investigated in a Phase 1, first-in-human, randomized, double-blind, placebo-controlled study in healthy individuals. In the single ascending-dose part, individuals received a single oral dose ranging from 120 mg to 1200 mg under fasted conditions. In the multiple ascending-dose part, individuals received oral JNJ-66525433 once daily for 14 consecutive days at doses ranging from 120 mg to 720 mg. A series of blood samples were collected to determine plasma JNJ-66525433 concentrations. Colon biopsy samples were also collected 24 hours post last dose on Day 14 after multiple dose treatment. JNJ-66525433 colon concentrations and IRF5 mRNA levels were determined. PK modeling analysis, including both JNJ-66525433 plasma and colon concentrations was conducted using NONMEM (version 7.4, GloboMax LLC, Hanover, MD).

Data & Results: The plasma concentrations of JNJ-66525433 after both single and multiple doses were described using a 2-compartment linear model with transit compartments to describe absorption. Rectum and sigmoid colon tissue concentrations were linked to the central compartment by the respective partition coefficient. The PK parameter from the final model for the absorption rate constant, volume distribution of central and peripheral compartments, and intercompartment distribution for JNJ-66525433 were estimated. Clearance was fixed as a majority of concentrations in the elimination phase of the PK profiles were below the lower limit of quantification. The partition coefficients were estimated as 4860 and 8610 for rectum and sigmoid colon, respectively, indicating that drug exposure was significantly higher in the local region than that in the systemic circulation. All parameters were estimated reasonably well with relative standard errors < 40% and goodness-of-fit plots suggested the model adequately described both the plasma and colonic tissue concentrations. Simulations were performed with the assumption of a JNJ-66525433 tissue half-life of 5.5-22 days (internal preclinical data) after several dosing scenarios. The model simulation suggested that more than 90% of individuals following dose regimens of either 2 weeks on 720 mg daily dose and 10 weeks off, or 6 weeks on 720 mg daily dose and 6 weeks off would achieve colonic tissue concentrations above the IC50 values of IRF5 knockdown. Additionally, correlations between average colon concentrations of JNJ-66525433 and IRF5 mRNA expression were assessed. No apparent correlations were identified between colon concentrations of JNJ-66525433 and the mRNA expression decreases.

Interpretation, Conclusion or Significance: A fit-for-purpose PK model showed the planned dose regimens achieved targeted tissue concentration levels with no apparent correlation between colon concentrations and IRF5 mRNA expression.

Disclosures: JS, ZX, AV, SD, BF, AH and VS are employees of Janssen Research & Development, LLC and own stock/stock options.

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Additional Information/Authors: No