Evinacumab shows benefit in certain patients with severe hypertriglyceridemia
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In a phase 2 study, evinacumab reduced triglyceride levels in patients with severe hypertriglyceridemia but not familial chylomicronemia syndrome, a speaker reported at the American College of Cardiology Scientific Session.
The reductions after treatment with evinacumab (Evkeeza, Regeneron) were evident in certain patients from two cohorts of multifactorial chylomicronemia syndrome, but not in patients from a cohort of familial chylomicronemia syndrome, Robert S. Rosenson, MD, director of cardiometabolic disorders at The Mount Sinai Hospital and professor of medicine at Icahn School of Medicine at Mount Sinai, said during the presentation.
“We investigated individuals with triglyceride levels greater than 1,000 mg/dL who were hospitalized for acute pancreatitis,” Rosenson told Healio. “These are individuals who are at extremely high risk for recurrent acute pancreatitis. In individuals who have had one or more episodes, the risk [for recurrent acute pancreatitis] increases dramatically to about 20% within 1 year, and for people who had had two or more episodes, the incidence of recurrent acute pancreatitis is about 40%. These are individuals who struggle to lower their triglycerides because they often have mutations that don’t respond to the conventional therapies. Individuals with severe hypertriglyceridemia will worsen with fat, both dietary fat and supplemental fat such as that found in fish oil capsules, a therapy often used for lowering triglycerides. There is a tremendous unmet need.”
Phase 2 results
Evinacumab is a human monoclonal antibody that binds to and blocks angiopoietin-like 3 (ANGPTL3). Evinacumab is approved by the FDA for use in homozygous familial hypercholesterolemia but not for patients with familial or multifactorial chylomicronemia syndrome.
The current study included 51 patients (53% men) with severe hypertriglyceridemia and at least one hospitalization for acute pancreatitis who were divided into three cohorts:
- those with familial chylomicronemia syndrome who had bi-allelic loss-of-function mutations in APOA5, APOC2, GPIHBP1, LMF1, or LPL (cohort 1);
- those with multifactorial chylomicronemia syndrome who had heterozygous loss-of-function mutations in APOA5, APOC2, GPIHBP1, LMF1, or LPL (cohort 2); and
- those with multifactorial chylomicronemia syndrome but no lipoprotein lipase pathway mutations (cohort 3).
“Familial chylomicronemia syndrome is rare, about 1 in 1 million, but the other conditions are about 1 in 5,000,” Rosenson told Healio.
Patients were randomly assigned on a 2:1 basis to evinacumab 15 mg/kg or placebo every 4 weeks for 12 weeks (double-blind treatment period), followed by evinacumab for all patients every 4 weeks for 12 weeks (single-blind treatment period), followed by a 20-week safety follow-up period.
The primary endpoint was intra-patient change in serum triglyceride levels between baseline and 12 weeks (after the double-blind period for those assigned evinacumab and after the single-blind period for those assigned placebo) in cohort 3. In that cohort, the least squares mean reduction in triglycerides from baseline to 12 weeks was –27.1% (standard error, 37.4; 95% CI, –71.2 to 84.6) and the median reduction was –68.8% (95% CI, –84.1 to –38.8), Rosenson said.
Median change in triglycerides during the double-blind period was –64.8% in the evinacumab group and 9.4% in the placebo group in cohort 2 (P = .0076) and –80.9% in the evinacumab group and 80.9% in cohort 3 (P = .0418), he said. There was no difference in median change in triglycerides in cohort 1 (P = .9495).
“Disinhibiting the activity of an enzyme that’s non-functioning isn’t going to do anything,” Rosenson said. “But in the other groups, evinacumab was very effective at lowering triglycerides.”
Treatment-emergent adverse events were similar in the evinacumab and placebo groups, Rosenson said. In the double-blind treatment period, 8.6% of the evinacumab group and 12.5% of the placebo group had acute pancreatitis events.
‘Important breakthrough’
“We learned something different from the studies of evinacumab in patients with hypercholesterolemia,” Rosenson told Healio. “In this study, at 4 weeks, not everybody had detectable levels of evinacumab. Thus, the triglyceride levels went up in those individuals and they had recurrent acute pancreatitis. What the study is telling us is that in patients with severe hypertriglyceridemia, a higher dose of evinacumab will be needed to maintain the drug levels over a 4-week period of time.”
Therefore, he said in an interview, a phase 2b study of evinacumab 20 mg/kg every 4 weeks for reduction of acute pancreatitis is being launched.
He noted most patients from the multifactorial chylomicronemia syndrome cohorts had CHD in addition to severe hypertriglyceridemia, and evinacumab “is working on both risks, and I think that is a very important breakthrough for these patients.”
Perspective
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Michael H. Davidson, MD, FACC, FACP, FNLA
Severe refractory hypertriglyceridemia and the resulting complications of acute pancreatitis, eruptive xanthomas, chronic abdominal pain and cognitive impairment results in a substantial reduction in the quality of life for these patients. Despite fibrates and prescription omega-3 fatty acids, these patients continue to suffer and have recurrent bouts of pancreatitis. Therefore, there is a significant unmet medical need to find a novel effective and safe medication to lower triglycerides in patients with this disorder.
However, severe refractory hypertriglyceridemia is a heterogeneous genetic disorder in which some patients have loss of function of lipoprotein lipase (LPL) activity due to either homozygous (very rare) or compound heterozygous monogenic mutations, others have a mixed picture of heterozygous for a single mutation but have other more common polymorphisms associated with hypertriglyceridemia and another patient cohort (probably most common) had multiple common polymorphisms associated with elevated triglyceride levels but do not have a monogenic mutations in the LPL pathway.
Evinacumab, an anti-ANGPLT3 monoclonal antibody, was studied in an early proof-of-concept phase 2 trial. ANGPTL3 is an inhibitor of LPL, and therefore blocking this protein will increase LPL activity.
Unfortunately, patients with at least two monogenic mutations causing the most profound loss of LPL activity had no significant reductions in triglycerides, but in the other cohorts of patients, there was a 60% to 70% reduction in median triglyceride levels. Therefore, it appears that for evinacumab to be effective, there must be some residual LPL activity that can be increased in response to ANGPTL-3 inhibition.
These results speak to the promise of precision medicine with genetic testing to identify the most appropriate patients with severe refractory hypertriglyceridemia to receive a therapy such as evinacumab. The investigators and the sponsor should be applauded for understanding the complex nature of refractory hypertriglyceridemia and differentiating the patients based on genetic testing prospectively.
Of concern, however, is the relatively high rate of pancreatitis in the trial, even for patients on evinacumab (though numerically better than placebo). In addition, there were seven cases (in five patients) of pancreatitis in the 12-week single-blind phase in which every patient was on evinacumab, but many of the cases occurred when the patient came off the drug. This means the rebound in triglyceride levels occurs relatively quickly off therapy and needs to be considered in how best to evaluate this therapy in longer-term trials. As a lipidologist with many patients with familial chylomicronemia syndrome and multifactorial chylomicronemia syndrome, I know there is clearly an unmet need to help these patients who suffer severely from this devastating disease. My hope is that evinacumab can move forward in clinical development to address this unmet medical need.
Perspective
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Michael Honigberg, MD, MPP
The key take-home message from this phase 2 clinical trial is that evinacumab, a monoclonal antibody against ANGPTL3, lowered triglycerides in individuals with severe hypertriglyceridemia without familial chylomicronemia syndrome. This finding is important and implies that evinacumab may represent an effective therapy for triglyceride lowering and reduction of pancreatitis risk in such individuals. A larger phase 2b trial of evinacumab is planned in individuals with severe hypertriglyceridemia without familial chylomicronemia syndrome. In addition, this study highlights the importance of finding other effective therapies for individuals with familial chylomicronemia syndrome.
Compared with placebo, evinacumab led to large reductions in fasting triglyceride levels compared with placebo in individuals without familial chylomicronemia syndrome. There was no evidence of benefit in those with familial chylomicronemia syndrome, who had the highest baseline triglyceride levels. In individuals without identified LPL pathway gene mutations, the median change in triglycerides after 12 weeks of evinacumab therapy was -68.8%, corresponding to a median reduction in triglycerides by 905 mg/dL. Rates of adverse events were similar between groups.
Based on recent clinical trials, evinacumab is emerging as a promising therapy for the management of individuals with elevated LDL who do not demonstrate adequate response to other LDL-lowering therapies such as statins, ezetimibe, bempedoic acid and PCSK9 inhibitors. Evinacumab may have a particular role in the treatment of homozygous familial hypercholesterolemia, a genetic condition characterized by markedly elevated LDL cholesterol levels and very premature atherosclerotic CVD. Affected individuals often respond poorly to other LDL-lowering therapies owing to their lack of fully functional LDL receptors.
The results of the present study additionally suggest a potential role for evinacumab in the management of severe hypertriglyceridemia without familial chylomicronemia syndrome. The presentation hinted that triglyceride response to evinacumab therapy may differ by the presence of specific underlying gene mutations, although these results were not presented; I will be looking out for these analyses in the manuscript when it is published, and such data may be useful for identifying individuals most likely to benefit from evinacumab therapy.
Severe hypertriglyceridemia (elevated circulating triglyceride levels) represents an important risk factor for acute pancreatitis. Current treatment options for severe hypertriglyceridemia include dietary modification; weight loss; abstinence from alcohol; withdrawal of medications that may elevate triglyceride levels; and prescription of statins, fibrates and omega-3 fatty acids. However, hypertriglyceridemia, particularly when driven by an underlying genetic cause, may be very difficult to treat.
For individuals with familial chylomicronemia syndrome, who carry mutations in both copies of a key gene in the LPL pathway, the APPROACH trial tested volanesorsen (Waylivra, Akcea), an antisense oligonucleotide targeting apoC-III mRNA. Volanesorsen led to large reductions in triglycerides but unexpected high rates of thrombocytopenia and thus was not approved by the FDA. A modified form of this therapy designed to avoid thrombocytopenia is currently under study.
ANGPTL3 is a liver-derived protein hormone that inhibits lipoprotein lipase and endothelial lipase. Human genetic studies and, subsequently, animal and human clinical studies have shown that inhibition of ANGPTL3 leads to lower circulating LDL, high-density HDL and triglycerides. Recent human clinical trials studying individuals with elevated LDL, including those with homozygous and heterozygous familial hypercholesterolemia, demonstrated that evinacumab led to ≥ 50% reduction in LDL compared with placebo on top of currently available lipid-lowering therapies. These studies also suggested that evinacumab substantially lowers triglycerides.
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Rosenson RS, et al. Joint American College of Cardiology/Journal of the American Medical Association Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; May 15-17, 2021 (virtual meeting).
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