031: No Increase in the Risk of Liver or Muscle Toxicity in Pegozafermin-treated Patients With Metabolic Dysfunction-Associated Steatohepatitis on Statin Background Therapy

Statement of Purpose, Innovation or Hypothesis: Pegozafermin is a specifically engineered, long-acting glycoPEGylated analogue of fibroblast growth factor 21 (FGF21) in development for the treatment of metabolic dysfunction-associated steatohepatitis (MASH/NASH) and severe hypertriglyceridemia (SHTG). It has previously been suggested that non-alcoholic fatty liver disease (NAFLD) is associated with reduced CYP3A drug metabolism activity in vivo and hepatic CYP3A4 expression in humans (Reference). Statins, many of which are CYP3A4 substrates, are commonly used in patients with MASH and SHTG, raising a potential concern about increased statin exposure and toxicity, including liver or muscle toxicity. The purpose of this post-hoc analysis from the Phase 2b ENLIVEN study in patients with MASH was to assess for the presence of liver or muscle toxicity in pegozafermin-treated patients who were on background statin therapy as a potential manifestation of this putative Drug-Drug-Interaction (DDI).

Description of Methods & Materials: Changes in creatine kinase (CK), alanine transaminase (ALT), aspartate transferase (AST), low-density lipoprotein cholesterol (LDL-c), and triglycerides from the Phase 2b study (placebo, 15 mg QW, 30 mg QW and 44 mg Q2W) at Week 8 compared to baseline were assessed in pegozafermin-treated and placebo patients on background treatment with statins that are metabolized by the hepatic isoenzyme CYP3A4 (atorvastatin, simvastatin, and lovastatin). The analysis included only patients who were on statins continuously from baseline to at least Week 6. Adverse events (AEs) related to the liver or muscle toxicity were evaluated in all patients.

Data & Results: Treatment with pegozafermin across doses led to significant decrease in liver transaminases and metabolic parameters at Week 8. There was no significant change in CK levels from baseline to Week 8 in placebo (n=18) or in patients treated with the highest pegozafermin dose (30 mg QW, n=19) with statin background therapy (Figure 1). A comparable observation was made for the other dose groups. Aligned with these findings, there was no difference in the AE profile of pegozafermin-treated patients with or without background statin therapy, including liver and muscle-related AEs. Two unrelated grade 1 myalgia AEs, 1 each in placebo and in the 30 mg QW pegozafermin group, were reported in patients who were on background statin therapy. One patient in the lowest 15 mg QW pegozafermin cohort had ongoing chronic rhabdomyolysis prior to randomization. In this subject, baseline CK levels were 840 U/L, slightly increased at Week 4 to 990 U/L and subsequently decreased to 570 U/L at Week 8; no additional AEs suggestive of muscle toxicity were reported in this subject.

Interpretation, Conclusion or Significance: In this post-hoc analysis from the Phase 2b study in MASH, there was no evidence of liver-related or muscle toxicity in pegozafermin-treated subjects on background statin therapy. These findings are reassuring, as they may indicate the absence of a clinically meaningful DDI between statins and pegozafermin that could result from putative decrease in CYP3A4 metabolism. Consequently, pegozafermin patients can continue their statin regimen in the absence of notable concerns about experiencing increased statin toxicity.

Disclosures:

Citations/References: Woolsey, S. J., S. E. Mansell, R. B. Kim, R. G. Tirona and M. D. Beaton (2015). "CYP3A Activity and Expression in Nonalcoholic Fatty Liver Disease." Drug Metab Dispos 43(10): 1484-1490.

Additional Information/Authors: Figure 1 footnotes: PGZ, pegozafermin; QW, weekly.
Note: Symbols with lines are individual observations; symbols with error bars represent mean and standard deviation for each respective group.