Human FGF21 mRNA

Fibroblast growth factor 21 (FGF21) is a promising therapeutic agent for type 2 diabetes (T2D) and nonalcoholic steatohepatitis (NASH). Researchers have demonstrated that subcutaneous (s.c.) injections of mRNA encoding the human FGF21 protein can achieve therapeutic levels of FGF21. Efficacy of the mRNA was assessed after repeated s.c. administration over two weeks in diet-induced obese (DIO) mice, which showed significant reductions in body weight, plasma insulin levels, and hepatic steatosis. Pharmacokinetic/pharmacodynamic (PK/PD) modelling of several studies in both lean and DIO mice showed that mRNA encoding human proteins provided improved therapeutic coverage over recombinant dosed proteins in vivo. This study is the first subcutaneous mRNA therapy to demonstrate preclinical efficacy in disease-relevant models, demonstrating its potential for the treatment of chronic diseases including type 2 diabetes and NASH.

Here, the researchers studied the half-life and bioavailability of recombinant human FGF21 (recFGF21) and recFc-FGF21 proteins in lean mice. After subcutaneous injection of recFGF21, the terminal half-life was short, only 1.5 hours, and the systemic bioavailability reached complete release (Figure 1A). After subcutaneous injection of recFc-FGF21, the terminal half-life was about 9 hours and the systemic bioavailability was 40% (Figure 1B). This is consistent with previous literature reports that recFGF21 is rapidly cleared after in vivo administration, while binding to the Fc domain (recFc-FGF21) can prolong the half-life of FGF21.

Next, the researchers explored whether the administration of FGF21 mRNA could increase the exposure level and duration of FGF21 and Fc-FGF21. As shown in Figure 1C, after subcutaneous injection, the expression of recFGF21 mRNA was significantly increased, and the expression of FGF21 mRNA (mFGF21) was significantly decreased. Administration of mFGF21 resulted in delayed peak concentrations and a longer terminal half-life of recFGF21 compared to recFGF21. Administration of mFGF21 resulted in a 26-fold higher net production of FGF21 protein than the corresponding molar dose of recFGF21. The combination of the prolonged plasma concentration-time profile and high net protein production resulting from mFGF21 delivery allowed the researchers to reduce the dosing frequency of mFGF21 to once daily, rather than twice daily as required for recFGF21, to achieve similar mean FGF21 exposures over the dosing interval. Using a pharmacokinetic (PK) model of single-dose exposure in lean mice, the exposure profiles of recFGF21 and mFGF21-expressed proteins were also simulated in DIO mice after repeated dosing for 14 days (Figure 1D). The plasma recFGF21 or mFGF21 expression protein levels measured after 14 days were consistent with the predicted concentrations, indicating that the PK properties of FGF21 protein and mRNA delivery in lean and DIO mice were similar.

Figure 1. Plasma concentration-time profiles of FGF21 and Fc-FGF21 administered as recombinant protein or expressed by mRNA. (Bartesaghi S, et al., 2022)