Leveraging Quantitative Systems Pharmacology Approach into Development of Human Recombinant Follistatin Fusion Protein for Duchenne Muscular Dystrophy.
Activin Receptors, Type II
/ antagonists & inhibitors
Animals
Drug Dosage Calculations
Follistatin
/ administration & dosage
Humans
Ligands
Models, Biological
Muscle, Skeletal
/ drug effects
Muscular Dystrophy, Duchenne
/ drug therapy
Myostatin
/ antagonists & inhibitors
Neuromuscular Agents
/ administration & dosage
Recombinant Fusion Proteins
/ administration & dosage
Signal Transduction
Systems Biology
Journal
CPT: pharmacometrics & systems pharmacology
ISSN: 2163-8306
Titre abrégé: CPT Pharmacometrics Syst Pharmacol
Pays: United States
ID NLM: 101580011
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
07
01
2020
accepted:
13
04
2020
pubmed:
19
5
2020
medline:
24
8
2021
entrez:
19
5
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32419339
doi: 10.1002/psp4.12518
pmc: PMC7306616
doi:
Substances chimiques
FST protein, human
0
Follistatin
0
Ligands
0
MSTN protein, human
0
Myostatin
0
Neuromuscular Agents
0
Recombinant Fusion Proteins
0
ACVR2B protein, human
EC 2.7.11.30
Activin Receptors, Type II
EC 2.7.11.30
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
342-352Informations de copyright
© 2020 Shire HGT Inc. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.
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