Open AccessLeveraging Quantitative Systems Pharmacology Approach into Development of Human Recombinant Follistatin Fusion Protein for Duchenne Muscular Dystrophy
Author(s) -
Nguyen Hoa Q.,
Iskenderian Andrea,
Ehmann David,
Jasper Paul,
Zhang Zhiwei,
Rong Haojing,
Welty Devin,
Narayanan Rangaraj
Publication year - 2020
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12518
Subject(s) - follistatin , duchenne muscular dystrophy , myostatin , drug development , recombinant dna , pharmacology , pharmacokinetics , medicine , dosing , muscular dystrophy , pharmacodynamics , drug , bioinformatics , drug discovery , computational biology , skeletal muscle , endocrinology , biology , genetics , gene
Quantitative understanding about the dynamics of drug–target interactions in biological systems is essential, especially in rare disease programs with small patient populations. Follistatin, by antagonism of myostatin and activin, which are negative regulators of skeletal muscle and inflammatory response, is a promising therapeutic target for Duchenne Muscular Dystrophy. In this study, we constructed a quantitative systems pharmacology model for FS‐EEE‐Fc, a follistatin recombinant protein to investigate its efficacy from dual target binding, and, subsequently, to project its human efficacious dose. Based on model simulations, with an assumed efficacy threshold of 7–10% muscle volume increase, 3–5 mg/kg weekly dosing of FS‐EEE‐Fc is predicted to achieve meaningful clinical outcome. In conclusion, the study demonstrated an application of mechanism driven approach at early stage of a rare disease drug development to support lead compound optimization, enable human dose, pharmacokinetics, and efficacy predictions.