Leveraging Quantitative Systems Pharmacology Approach into Development of Human Recombinant Follistatin Fusion Protein for Duchenne Muscular Dystrophy

Figures

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  Figure 1. Structure of quantitative systems pharmacology model for FS‐EEE‐Fc and other myostatin/activin inhibitors. Disposition of the drug and different molecular entities was described in relevant physiological compartments, including muscle, pituitary, plasma, and other organ tissues. In the molecular level of model, myostatin and activin interact with activin type IIB receptor (ActRIIB), leading to inhibition of muscle growth. Myostatin and activin also bind to FS‐EEE‐Fc or other myostatin/activin inhibitors that act as ligand traps to block the interaction of these ligands with ActRIIB.

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  Figure 2. Model calibrations to clinical pharmacokinetic (upper panel) and muscle growth data (lower panel) of anti‐myostatin adnectin. Data points represent clinical observations that were used for parameter estimation. Lines represent fitted curves and 95% confidence interval for the model predictions that were generated using the estimated parameters by Gaussian method. With fit results obtained from parameter estimation, the function in MatLab computes the Gaussian confidence intervals for each estimated model response at every time step.

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  Figure 3. Model calibrations to clinical pharmacokinetic (left panel) and pharmacodynamic of follicle‐stimulating hormone levels (right panel) of ACE‐031. Data points represent clinical observations that were used for parameter estimation. Lines represent fitted curves and 95% confidence interval for the model predictions that were generated using the estimated parameters by Gaussian method. With fit results obtained from parameter estimation, the function in MatLab computes the Gaussian confidence intervals for each estimated model response at every time step.

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  Figure 4. Model was applied for FS‐EEE‐Fc to demonstrate potential efficacy of dual target antagonist (a), to explore optimal binding affinities (b), and to project human pharmacokinetic (c), and efficacious dose (d).