063: Preclinical & Clinical Pharmacokinetics of JNJ-75220795, A siRNA Therapeutic Targeting PNPLA3, for Metabolic-associated Steatohepatitis

Statement of Purpose, Innovation or Hypothesis: Metabolic-associated steatohepatitis (MASH) is a progressive disease type of  metabolic-associated fatty liver disease (MAFLD) characterized by liver steatosis with inflammation and hepatocellular injury with or without fibrosis. Genome wide studies demonstrated that a loss-of-function I148M mutation in the PNPLA3 gene is a major risk factor for NASH and development of cirrhosis and hepatocellular carcinoma. JNJ-75220795 or also known as ARO-PNPLA3 is an investigational N-acetyl-D-galactosamine- or GalNAc-conjugated small interfering ribonucleic acids (siRNA) therapeutic targeting the PNPLA3 gene developed for NASH. In this study, we characterized preclinical and clinical single-dose pharmacokinetics and immunogenicity of subcutaneous JNJ-75220795.
 

Description of Methods & Materials: For preclinical PK, subcutaneous and intravenous injections of JNJ-75220795 were administered to Sprague-Dawley rats and Cynomolgus monkeys, and plasma and tissue samples were collected at various timepoints. For clinical PK, two phase 1 studies were conducted in the US and in Japan for the first-in-human (FIH) and first-in-Japanese (FIJ) studies, respectively, which enrolled a total of 64 participants with homozygous or heterozygous PNPLA3 I148M mutation. The FIH study was a single ascending dose study with placebo or subcutaneous JNJ-75220795 at escalating doses of 10, 25, 75, 200, and 400mg. The FIJ study was a single-dose study with placebo or 75 mg of subcutaneous JNJ-75220795. Noncompartmental PK parameters were determined from individual concentration-time data using Phoenix WinNonlin, version 8.1.1 (Certara, Princeton, NJ). 

Data & Results: JNJ-75220795 was rapidly absorbed and eliminated from plasma with half-life of 0.7-3.3h in rats and non-human primates (NHP). AUC in the liver was approximately 2800-fold greater compared to that of plasma after a single SC dose in rats. In NHPs, JNJ-75220795 was still detectable at high levels in the liver on day 14 after dosing. In humans, the median Tmax was reached between 3 to 9 hours after dosing, and the terminal half-life ranged from 3 to 6 hours. Cmax values ranged from 36.8 to 1883 ng/mL and AUClast values ranged from 356 to 26978 ng*h/mL across all doses in approximately dose-proportional manner. No apparent differences in mean concentrations were observed between homozygous vs heterozygous mutant subjects and between Japanese vs non-Japanese participants within the same dose cohorts. Total urinary recovery per dose administered (Ae[% dose]total) ranged from 8.6 to 26.3% with renal clearance of 3.4 to 10.5 L/h across all doses. There were two cases (5.1%) of treatment-emergent anti-drug antibodies (ADA) against JNJ-75220795 in the FIH study, and none in the FIJ stud
 

Interpretation, Conclusion or Significance: JNJ-75220795 had a rapid systemic absorption and elimination and exhibited linear kinetics in plasma. The renal clearance rate was high however, urinary excretion was considered a minor pathway for systemic elimination of JNJ-75220795. Distribution to hepatocytes via ASGPR-mediated endocytosis was considered a major pathway of systemic elimination. Overall incidence of ADA against JNJ-75220795 was low. Both preclinical and clinical data suggest that JNJ-75220795 predominantly distributes to the liver, which is consistent with other GalNAc-conjugated siRNAs. Overall, JNJ-75220795 showed favorable single dose preclinical and clinical PK profile with prolonged localization in the target organ, the liver. Appropriate dosing regimen of JNJ-75220795 under repeated dose settings should be further evaluated.
 

Disclosures: These studies were funded by Janssen Research and development

Citations/References:

Additional Information/Authors: We thank Arrowhead Pharmaceutical for executing the preclinical studies

Complete list of authors:

Jae Yoon Jeon1, Vivaswath S. Ayyar2, Shohei Ouchi3, Elisa Fabbrini1, Anastasiya Koshkina1, Wenying Jian2, Lijuan Kang2, Korin Cofsky2, Brian Rady2, Ryo Tamamura3, Yuki Saito3, Aimi Yamashita3, Susan Wendel1, Hideo Makimura1, Dénes Csonka4, Navin Goyal1

1Janssen Research & Development, LLC, Raritan, NJ, USA; 2Janssen Research & Development, LLC, Spring House, PA, USA; 3Janssen Pharmaceutical K.K., Tokyo, Japan; 4Actelion Pharmaceuticals Ltd, Allschwil, Switzerland