QSP Model of modRNA to Treat Crigler-Najjar Syndrome Type 1

Collaboration with Alexion Pharmaceuticals - Published in CPT: Pharmacometrics & Systems Pharmacology


Crigler‐Najjar syndrome type 1 (CN1) is an autosomal recessive disease caused by a marked decrease in uridine‐diphosphate‐glucuronosyltransferase (UGT1A1) enzyme activity. Delivery of hUGT1A1‐modRNA (a modified messenger RNA encoding for UGT1A1) as a lipid nanoparticle is anticipated to restore hepatic expression of UGT1A1, allowing normal glucuronidation and clearance of bilirubin in patients. To support translation from preclinical to clinical studies, and first‐in‐human studies, a quantitative systems pharmacology (QSP) model was developed. The QSP model was calibrated to plasma and liver mRNA, and total serum bilirubin in Gunn rats, an animal model of CN1. This QSP model adequately captured the observed plasma and liver biomarker behavior across a range of doses and dose regimens in Gunn rats. First‐in‐human dose projections made using the translated model indicated that 0.5 mg/kg Q4W dose should provide a clinically meaningful and sustained reduction of >5 mg/dL in total bilirubin levels.


Joshua F. Apgar , Jian-Ping Tang, Pratap Singh, Nanda Balasubramanian, John Burke, Michael R. Hodges, Melissa A. Lasaro, Lin Lin, Bjorn L. Miliard, Kristi Moore, Lucy S. Jun, Susan Sobolov, Anna Katharina Wilkins and Xiang Gao (2018). 

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