Introduction and methods

The efficacy and safety of evinacumab in HoFH patients with little to no low-density lipoprotein receptor activity

Presented at the virtual EAS 2020 by Frederick Raal (University of Witwatersrand, Johannesburg, South Africa)

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder caused by mutations in the LDL receptor. HoFH is characterized by elevated LDL-c levels, which results in early accelerated atherosclerosis. Affected individuals respond less to standard lipid-lowering therapy (LLT), such as PCSK9 inhibition which relies on functional activity of the LDL receptor. Evinacumab is a monoclonal antibody that binds to angiopoietin-like 3 (ANGPTL3) and reduces LDL-c levels independent of LDL receptor function.

This study assessed the LDL-c lowering efficacy and safety of evinacumab in HoFH patients with little to no LDL receptor activity.

In the ELIPSE homozygous FH study, after a run-in period of 8 weeks, HoFH patients (≥12 years) on stable maximally tolerated LLT and LDL-c levels ≥ 1.8 mmol/L were randomized (2:1) to receive either 15 mg/kg evinacumab (n=43) or placebo (n=22) every 4 weeks intravenously. The double- blind treatment period lasted 24 weeks. The primary endpoint was the percent change in calculated LDL-c levels from baseline to 24 weeks during this treatment period. The study was continued by an open extension period of 24 weeks, where all patients received 15 mg/kg evinacumab every 4 weeks.

This post-hoc analysis included 10 HoFH patients with <2% functional LDL receptor activity (8 received evinacumab and 2 placebo). Diagnosis of FH was made genotypically or based on clinical criteria: documented pathogenic mutation in both LDLR alleles, homozygous or compound heterozygous mutations in APOB or PCSK9, double heterozygous or homozygous LDLRAP1 mutations, or patients had untreated total cholesterol levels > 12.9 mmol/L and triglycerides <3.4 mmol/L, and a family history of both parents with documented total cholesterol levels of >6.5 mmol/L or xanthoma before the age of 10.

Main results

• In the 10 HoFH patients with less than 2% LDL receptor activity, evinacumab resulted in a 53.5% (SE: 11.4) reduction in LDL-c compared to increased LDL-c levels of 18.8% (SE:21.9) in the placebo group. The treatment difference for LDL-c was -72.3% (SE: 24.7) when corrected for placebo (P=0.005).
• Evinacumab was generally well tolerated (short-term safety).

Conclusion

Evinacumab treatment reduced LDL-c levels significantly in HoFH patients with <2% LDL receptor activity. These findings suggest that evinacumab may be a potential treatment option for HoFH patients with little to no LDL receptor activity. Evinacumab appeared to be safe, but safety is further evaluated in the extended 24 week open-label period of this study.

Our reporting is based upon the information provided at the EAS 2020 congress

Watch a video about this study by prof. Raal