Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Long-Acting FGF21 Analog Zalfermin

Abstract

This first-in-human study investigated the safety, pharmacokinetics, and pharmacodynamics of the long-acting fibroblast growth factor 21 (FGF21) analog zalfermin. Healthy male participants (n = 56) with body mass index 25.0-34.9 kg/m² were randomized to single ascending doses (2, 6, 12, 24, 48, 96, and 180 mg) of subcutaneous zalfermin or placebo. In a second study, a single dose of 12, 30, or 96 mg was administered to Japanese (n = 24) and non-Asian (n = 18) healthy males to confirm a consistent safety and pharmacokinetic profile across ethnicity. Overall, 98 participants were enrolled across both studies and followed for 36 days. Blood samples were obtained for safety and for pharmacokinetic and pharmacodynamic assessments. The primary endpoint for both studies was the number of adverse events from treatment initiation to the end of follow-up, which was greater in the highest zalfermin dose cohorts in both studies. Adverse events were non-serious, mainly gastrointestinal-related, and mostly mild to moderate in severity; no deaths occurred. In both studies, dose proportionality was established for maximum serum concentration and area under the curve from time 0 to infinity. Time to maximum serum concentration ranged from 24 to 54 h. The serum half-life of zalfermin was ~120 h in both studies, compatible with once-weekly dosing. Significant improvements in plasma lipids were observed. Zalfermin had an acceptable safety profile across all single ascending doses, consistent with the FGF21 class. Further investigations into multiple ascending doses of zalfermin and treatment duration are warranted to assess the potential treatment of steatohepatitis and cardiometabolic disease. Trial Registration: ClinicalTrials.gov (NCT03015207 and NCT04722653).

Keywords: adverse drug reactions; adverse events; ethnicity; liver; metabolism; obesity; pharmacodynamics; pharmacokinetics; pharmacology; phase I.

FIGURE 1

Mean serum concentrations of zalfermin after a single dose in healthy male participants (study 1; 2–180 mg, N = 6 per group) (A, B) and in healthy Japanese and non‐Asian male participants (study 2; 12, 30, and 96 mg, N = 6 per group) (C, D). Values below the LLQ are imputed. LLQ, lower limit of quantification.

FIGURE 2

Change from baseline in serum lipids after a single dose of zalfermin in healthy male participants (study 1; 2–180 mg, N = 6 per group) (A), and in healthy Japanese and non‐Asian male participants (study 2; 12, 30, and 96 mg, N = 6 per group) (B). All data are geometric mean. HDL‐C, high‐density lipoprotein cholesterol; JP, Japanese; LDL‐C, low‐density lipoprotein cholesterol; NA, non‐Asian; VLDL‐C, very low‐density lipoprotein.