FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Two different approaches to shutting down the function of a human liver protein that inhibits lipoprotein lipase showed preliminary evidence of safely producing favorable lipid changes in healthy volunteers in two separate, phase 1 studies.
These findings, coupled with promising observational data from people who carry loss-of-function mutations in the gene for this protein, angiopoietin-like 3 (ANGPTL3), have raised hopes that interventions that interfere with the function of the ANGPTL3 protein may provide new and effective ways to improve lipid levels and cut the incidence of cardiovascular disease events.
“There is now a growing body of epidemiologic, genetic, and genomewide association studies supporting the hypothesis that lowering levels of ANGPTL3 in plasma by inhibiting hepatic ANGPTL3 synthesis will be beneficial in terms of reducing plasma levels of atherogenic apolipoprotein B and in improving metabolic measures associated with dyslipidemia,” wrote Mark J. Graham and his associates in a recently published article ( N Engl J Med. 2017 Jul 20;377:222-32 ).
The phase 1 study results reported by this group came from 44 healthy adults aged 18-65 years who received varying doses of a commercially developed antisense drug, ANGPTL3-LRX, as either single or serial subcutaneous injections. ANGPTL3-LRX is an oligonucleotide designed to inhibit production of messenger RNA for the ANGPTL3 protein.
Six people received the highest ANGPTL3-LRX dosage administered, 60 mg given as a weekly injection for 6 weeks, and after this regimen they showed an average 50% cut in triglycerides levels, compared with baseline, and an average 33% drop in their low LDL cholesterol levels from baseline. None of the 33 people treated with ANGPTL3-LRX in the trial had a documented serious adverse event, and the only treatment dropout was a patient who was lost to follow-up during the treatment phase, reported Mr. Graham, a researcher at Ionis Pharmaceuticals, the sponsor of the study and the company developing the antisense drug, and his associates.
The second phase 1 study examined a different way to block ANGPTL3 activity, with a human monoclonal antibody to this protein. The study involved 83 healthy adults aged 18-65 years with fasting triglyceride levels of 150-450 mg/dL and fasting LDL cholesterol levels of at least 100 mg/dL. Each participant received a single subcutaneous injection or intravenous dose of the antibody, evinacumab, at varying amounts or placebo. The maximum observed lipid changes seen was a drop in triglycerides of 76% and a fall in LDL cholesterol by 23%. Treatment also produced a maximum drop in HDL cholesterol of 18%. No person left the study because of an adverse event. The most common adverse event was headache, in seven people (11% of evinacumab recipients), reported Frederick E. Dewey, MD, a researcher at Regeneron Pharmaceuticals, the company developing evinacumab, and his associates ( N Engl J Med. 2017 Jul 20;377:211-21 ).
The Regeneron report also included results from population studies they ran. They reported performing genome sequencing on specimens from 58,335 adults enrolled in the DiscovEHR study, and identified 13 distinct loss-of-function variants in the ANGPTL3 genes that occurred individually in a small number of these people.
They then ran analyses of lipid levels and coronary artery disease prevalence rates in people who carry one of these 13 loss-of-function genetic signatures in one of their ANGTPL3 genes. Among 45,226 of the people in DiscovEHR those with a variant had on average a 27% lower triglyceride level, a 9% lower LDL cholesterol level, and a 4% lower HDL cholesterol level than noncarriers, after adjustment for covariates. Analysis of coronary artery disease prevalence showed that, after adjusting for age, sex, and ancestry, carrying a loss-of-function variant was linked with a statistically significant 41% lower prevalence of all coronary artery disease, and a 34% lower prevalence of myocardial infarction that fell short of statistical significance.
A second population study looked at links between loss-of-function variants and coronary artery disease in more than 130,000 Danish people. This showed a nonsignificant 37% lower prevalence of coronary artery disease in people with a variant. Two different types of meta-analyses of the data from both the DiscovEHR and Danish studies showed coronary disease rates reduced by either 31% or 39% in variant carriers depending on which meta-analysis approach the researchers used, both statistically significant reductions.
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