Pushing limits in dyslipidemia management: Novel drug Evinacumab gives promising results
mechanism of action: Evinacumab
A new drug target is emerging for the treatment of patients in whom the LDL cholesterol level remains too high despite treatment with existing therapies. Angiopoietin-like 3 (ANGPTL3), an inhibitor of lipoprotein lipase and endothelial lipase, has been implicated in lipid metabolism and cardiovascular disease in various genetic investigations.
Evinacumab, a fully human monoclonal antibody against ANGPTL3 (Figure), was shown to lower the LDL cholesterol level by 49% in patients with homozygous familial hypercholesterolemia. In the current issue of NEJM, Rosenson et al. provide more evidence on evinacumab in drug-refractory heterozygous familial hypercholesterolemia.
The investigators conducted a randomized, controlled, phase 2 trial involving 272 patients with refractory hypercholesterolemia. Overall, 73% of the patients had heterozygous familial hypercholesterolemia, 60% were women, and 90% were White. Refractory hypercholesterolemia was defined as an LDL cholesterol level of 70 mg/dl or higher with atherosclerotic cardiovascular disease or a level of 100 mg/dl or higher without atherosclerotic cardiovascular disease, despite background therapy at maximum tolerated doses.
At baseline, nearly all the patients were receiving a PCSK9 inhibitor, 70% were receiving statin therapy (with 46% receiving a high-intensity statin), and 33% were receiving ezetimibe. Yet, the mean LDL cholesterol level at baseline was approximately 150 mg/dl which suggests that many patients had untreated levels of 300 to 500 mg/dl.
Three subcutaneous doses of evinacumab (administered weekly or every 2 weeks) and two intravenous doses (administered every 4 weeks) were evaluated for their effect on the primary outcome of the change from baseline in the LDL cholesterol level at 16 weeks. The use of evinacumab reduced the LDL cholesterol level by more than 50% at the maximum dose. Evinacumab also reduced the apolipoprotein B level and all atherogenic lipoprotein levels, and the drug was associated with few high-grade adverse effects.
This trial marks an important milestone in the development of evinacumab. For cases of refractory hypercholesterolemia that are difficult to treat, evinacumab could become an important option for patients and clinicians.
A decade ago, the field of lipid therapeutics had its sights set beyond statin therapy. Now, the field is embarking on a frontier beyond PCSK9 monoclonal antibodies, with genetic studies providing a map and patients with familial hypercholesterolemia leading the way.
Source: Rosenson RS, Burgess LJ, Ebenbichler CF, et al. Evinacumab in patients with refractory hypercholesterolemia. N Engl J Med 2020; 383: 2307-19.
Full article available at: https://www.nejm.org/doi/full/10.1056/NEJMoa2031049
