Another Kid on the Block: Long-acting FGF21 Analogue to Treat Dyslipidemia and Fatty Liver.

Fibroblast growth factor 21 (FGF21) is a metabolic hormone critically involved in the regulation of energy balance, glucose, and lipid homeostasis with its therapeutic potential to treat hyperglycemia and dyslipidemia being described in 2005 (1). Subsequently, a large number of preclinical and clinical studies have been conducted to explore FGF21 pharmacological prospects in various obesity-related conditions, such as type 2 diabetes mellitus, dyslipidemia, nonalcoholic fatty liver disease, and cardiac abnormalities (2). While this protein delivered multiple therapeutic benefits in animals and humans, it soon became clear that the native form of human FGF21 is unlikely to become a successful therapeutic. This was largely because of its poor biopharmaceutical properties: short half-life, propensity for aggregation in soluble formulations, and proteolytic instability.

To address these issues, various engineering approaches have been sought to develop FGF21 analogues with improved biophysical, pharmacokinetic, and pharmacodynamic properties. Introduction of an additional disulfide bond in LY2405319 resulted in substantial biopharmaceutical refinements eventually allowing early tests for FGF21 bioactivity in humans (3). While in that clinical trial LY compound was administered once-daily, the next line of FGF21 analogues were geared toward longer duration of action. BMS-986036 and BIO89-100 are now the molecular examples of polyethylene glycol–driven time-action extension that show potent efficacy in treating nonalcoholic steatohepatitis (NASH) after once-weekly/once-biweekly administration (4, 5). Fc domain-fusion, another method to extend half-life, was introduced to efruxifermin (EFX) that demonstrated substantial benefits in NASH patients during a recent phase 2 study, simultaneously reducing fatty liver, hepatic fibrosis, dyslipidemia, and providing better glycemic control with once-weekly administration (6). To date, however, no FGF21-based molecules have been approved for clinical use.

In the recent issue of The Journal of Clinical Endocrinology & Metabolism, Rader et al (7) reported the therapeutic effects of a novel long-acting FGF21 variant in obese individuals. This engineered analogue, LLF580, also contains an additional disulfide bond but at an unspecified location, and an Fc domain fused to the N-terminus of the FGF21 backbone with no other structural or biophysical characteristics shared. The clinical study with LLF580 was double-blinded and comprised 61 obese participants (mean ± SD: age 45 ± 11 years, BMI 36.1 ± 3.8), 30 of whom were treated with LLF580 at a 300-mg dose via once-monthly subcutaneous injections for 3 months with another 31 individuals receiving placebo. Compared to control, LLF580 treatment led to sizable improvements in lipid profiles, such as a 54% (P < .001) decrease in serum triglycerides, a 7% (P = .002) lowering of total cholesterol, a 12% (P < .001) decrease in low-density lipoprotein cholesterol, and a 36% (P < .001) increase in high-density lipoprotein cholesterol, with this efficacy being similar to the clinical effects of other FGF21 analogues (3). In addition, liver fat fraction was reduced by 52% (P < .001) in the LLF580 vs placebo group, which is comparable to the activity of BIO89-100 (5). These therapeutic benefits of LLF580 were accompanied by significant reductions in other markers of liver injury, including 17% (P < .001), 10% (P < .001), and 6% (P = .017) decreases in aspartate transaminase, alanine transaminase, and alkaline phosphatase, respectively. Nevertheless, no significant effect of LLF580 over placebo on liver fibrosis was observed in this study, suggestive of its potential therapeutic limitations in comparison with other FGF21 analogues currently in development (4-6). Furthermore, while LLF580 treatment led to lowering of insulin, C-peptide, homeostatic model assessment of insulin resistance, and increases in adiponectin levels, no change in fasting glucose, glycated hemoglobin A1c, or body weight was demonstrated. To note, EFX, another Fc-fusion protein, was potent in correcting obesity and hyperglycemia (6). Taken together, the observations by Rader and colleagues (7) provide clear evidence for the substantial efficacy of LLF580 to improve lipid profiles, fatty liver, and hepatic function, but lack effects on liver fibrosis, glycemic control, and body weight.

Several FGF21-based drug candidates in development such as BMS-986036, EFX, and CovX-FGF21 that are structurally improved for prolonged time action (3) are suited for once-weekly administration. While the pharmacokinetic properties of LLF580 to benchmark with other analogues have not been communicated, Rader et al (7) indicate that this molecule can provide metabolic benefits on once-monthly clinical dosing, suggestive of an extended half-life. Such frequency of administration delivers additional patient convenience with LLF580 over the competition yet this durable pharmacology was reached only at a single and very high 300-mg dose. This number compares unfavorably with other FGF21-based molecules whose effective clinical levels lie within the 20- to 700-mg dose range for once-weekly or as in case of BIO89-100 for once-biweekly administration. It remains to be seen if the superior duration of action of LLF580 can also be achieved in patients at a substantially lower and thus more cost-effective dose.

As for safety profile, LLF580 was generally well tolerated in obese individuals over 12 weeks of treatment. Even though 2 serious adverse events were reported in the Rader and colleagues trial, neither were deemed to be related to the compound action. Similar to the previous studies with FGF21-based compounds, a higher incidence of mild to moderate gastrointestinal adverse events was also noted, as well as changes in bone formation biomarkers in the LLF580 group. The latter warrants further clinical investigations on the interplay between FGF21 mode of action and bone quality.

In conclusion, the therapeutic benefits of LLF580, a novel long-acting variant of FGF21 described by Rader et al (7), add more clinical evidence for the effectiveness of the FGF21 mechanism to treat metabolic complications in humans. However, this molecule, now called BOS-580 since its recent offload from Novartis pipeline to Boston Pharmaceuticals (8), needs to be studied in greater detail. In particular, a detailed pharmacokinetic evaluation is critically needed, in part to determine the minimum effective dose of LLF580 for once-monthly administration in humans. Further studies with a larger sample size are also warranted to grasp the full spectrum of the clinical benefits that can be delivered by this compound. Whether the remarkable improvements in dyslipidemia with LLF580 use are translatable into long-term cardiovascular outcomes should be evaluated as well.