Development of Zalfermin, a Long-Acting Proteolytically Stabilized FGF21 Analog

Area of Science:

• Biochemistry
• Pharmacology
• Endocrinology

Background:

• The natural fibroblast growth factor 21 (FGF21) hormone possesses inherent druggability challenges.
• These limitations hinder its therapeutic potential for metabolic diseases.

Purpose of the Study:

• To develop zalfermin, an FGF21 analog designed for enhanced stability and efficacy.
• To address the limitations of native FGF21 for therapeutic applications.

Main Methods:

• Protein engineering techniques were employed to resolve issues like deamidation (Asp121 to Gln) and oxidation (Met168 to Leu).
• N-terminal degradation was prevented via alanine elongation, and C-terminal metabolism was inhibited.
• A C18 fatty diacid was conjugated to enhance half-life (t1/2) by reversible albumin binding.

Main Results:

• Zalfermin demonstrated improved stability and pharmacokinetics (53 h t1/2 in cynomolgus monkeys).
• The modified analog retained potent activation of the FGF-receptor complex with selectivity.
• Significant body weight loss was observed in diet-induced obese mice.

Conclusions:

• Zalfermin represents a successfully engineered FGF21 analog with enhanced druggability and therapeutic potential.
• The developed analog shows promise for treating metabolic dysfunction-associated steatohepatitis and related conditions.