BOSTON, MA — Blocking the effects of a gene that promotes raised triglycerides and lipoproteins can sharply reduce their levels in humans, which, based on animal models, is associated with slowed or reversed progression of atherosclerosis, suggest two new published reports from separate studies that may provide the best validation yet for the promising line of research[1][2].
The new studies looked at the genetic basis, effects on atherosclerosis in mice, and lipid-altering effects in people for two agents that take distinct approaches to blocking effects of the protein coded by the gene ANGPTL3, which, among other functions, inhibits lipoprotein lipase.
That the two studies, published in tandem May 4, 2017 in the New England Journal of Medicine, reached similar findings for drugs targeting the same biochemical pathway shows how solid the approach is and its potential for producing new drugs for dyslipidemia, according to Dr Christie M Ballantyne (Houston Methodist DeBakey Heart & Vascular Center, Houston, TX).
“This stuff’s really exciting,” Ballantyne, who isn’t connected with the studies, told
heartwire
from Medscape in an interview. “It looks very promising, but there’s still a lot of work ahead.”
The lead author on one of the published reports agreed that the two studies substantiate and support each other. “We were quite reassured to see that targeting the same gene or gene products led to the same reduction in lipid levels, which in our study was also associated, by genetic means or in the preclinical models, with a reduction in atherosclerotic burden,” said Dr Frederick E Dewey (Regeneron Genetics Center, Tarrytown, NY) when interviewed.
His group’s research correlated ANGPTL3 loss-of-function variants with significantly reduced lipid levels and CHD prevalence in several huge cohorts, and saw administration of evinacumab (Regeneron), a monoclonal antibody against ANGPTL3 protein, change lipid markers in mice and people[1].
The antibody-based treatment contrasts with the agent highlighted in the other report[2], an antisense oligonucleotide (ASO) (IONIS-ANGPTL3-LRx, Ionis Pharmaceuticals) targeting ANGPTL3 messenger RNA that blocks hepatic production of ANGPTL3 protein.
Together, the reports “provide some additional evidence for modulating of lipid levels via this pathway, via either antisense oligonucleotide inhibition, or antibody inhibition, as being favorable,” said Dewey, whose conversation with heartwire
was monitored by a Regeneron communications officer.
Most authors on both of the reports were employees of the two companies that developed the agents and funded and ran the studies, Regeneron and Ionis.
Who Would These Agents Be For?
Dewey said the experience with the anti-ANGPTL3 antibody has been “very encouraging” for seeing its potential in people with homozygous familial hypercholesterolemia (FH), who have few effective treatment options.
“Where I see this fitting in is in individuals who have really not met expectations on the traditional LDL-reducing therapies,” especially those that work via LDL receptors, “and also in individuals potentially with more mixed dyslipidemia.”
Possible uses for the antisense agent might be somewhat broader, Dr Sotirios Tsimikas (Ionis Pharmaceuticals and the University of California San Diego, La Jolla), senior author on his report, speculated for heartwire
in an interview.
Certainly people with FH are good potential candidates, especially those with homozygous FH, “a population that theoretically you could get off apheresis, if you have a very potent effect.” But also it might work for the large proportion of patients with acute coronary syndromes who have elevated remnant lipoprotein levels, which the drug can lower but which aren’t addressed by the PCSK9 inhibitors.
Also, according to Tsimikas, in animal models the treatment improves hepatic steatosis and measures of insulin sensitivity. “So a group of patients that would be attractive to study would be diabetic patients with elevated remnant cholesterol, where you can address several of the metabolic parameters,” he said.
“And, if you improve insulin sensitivity along with lowering the atherogenic lipoproteins, you could really get a bang for your buck, so to speak, in terms of addressing more than one metabolic parameter that’s triggering cardiovascular risk.”
Monoclonal Antibody Against ANGPTL3 Protein
As Dewey and his colleagues reported, administration of evinacumab in a mouse model of dyslipidemia was associated with decreases in several characteristics of atherosclerotic plaque, including a 39% reduction in lesion size (P<0.001) and, in more severe lesions, a 45% reduction in necrotic content (P=0.001).
Included in the same report were partial results of a three-center, phase 1 randomized evinacumab dose-escalation study with 83 patients with “mildly to moderately” elevated triglycerides or LDL-C. The group showed steep dose-dependent declines in triglycerides (P<0.0001 after 4 days), LDL-C (P=0.0047 after 15 days), and HDL-C (P =0.0049 after 15 days).
There was also a comparison of coronary disease cases and controls in five large cohorts, totaling >180,000 persons, in which those who were heterozygous for a ANGPTL3 loss-of-function mutation showed 27% lower levels of triglyceride and lesser reductions in LDL-C and HDL-C, all significant. Carriers of the variant also showed a 41% lower prevalence of coronary artery disease (P=0.004).
His group’s study, “demonstrates pretty convincingly, either by genetic means or by pharmacological means, that reducing the action of ANGPTL3 is cardioprotective,” Dewey said.
“I think it provides a robust suite of evidence in which really all of the preclinical data and human genetic findings line up in a very encouraging way with respect to product development in humans.”
Ballantyne cautioned that while antibody treatments tend to be effective, safe, and fairly clean in terms of side effects, neutralizing anti-antibody responses can be an issue, as they were for the PCSK9 inhibitor bococizumab (Pfizer). The company subsequently abandoned clinical development of the monoclonal antibody.
Dewey said no such autoimmune response has been observed with evinacumab.
Also, what seemed the most effective evinacumab dosage in the dose-escalation part of the study was 20 mg/kg IV, which in an 80 kg individual, for example, would amount to 1600 mg, Ballantyne pointed out. “That’s a lot of monoclonal, and they’re expensive. That’s not a trivial issue.”
Targeting ANGPTL3 Messenger RNA
Although a reaction with neutralizing antibodies is theoretically possible with the mRNA-blocking ASO agent, so far none have been observed with any antisense drugs used in clinical trials, according to Tsimikas.
In that agent’s publication, with lead author Mark J Graham (Ionis Pharmaceuticals, Carlsbad, CA), mice of several varieties, including some with LDL-receptor knockout or diet-induced obesity, were given the mRNA-blocking ASO agent.
In all models, hepatic expression of ANGPTL3 mRNA dropped precipitously followed by, variously in the different mouse models, reductions in levels of triglycerides, LDL-C, HDL-C, and other lipoproteins, and increases in lipoprotein lipase expression and measures of insulin resistance, among other potentially favorable metabolic changes.
LDL-receptor knockout mice given the ASO, compared with controls not getting the agent, showed significant reductions in atherosclerosis progression, by 52% at a 50 mg/kg/week dosage (P=0.002) and by 37% (P=0.048) at one-quarter that dosage.
In addition, 44 volunteer subjects were randomized to receive either single or multiple doses of agent or placebo; 33 of them received the active agent.
Those who received a single dose didn’t show significant changes in ANGPTL3 protein, triglycerides, total cholesterol, or non-HDL-C. But by day 43 in the multiple-dose group, active therapy was associated with significant reductions in ANGPTL3 protein ranging from 46.6% at the lowest of four dosages (P=0.001) to 84.5% at the highest dosage (P=0.001).
There were also consistent reductions vs placebo in a range of lipid and lipoprotein markers at all dosage levels except the lowest, at P <0.01 and P<0.05 levels of significance. Those markers were triglycerides, LDL-C, very-LDL-C, non-HDL-C, apolipoprotein B, and apolipoprotein C-III.
How Different Are These Agents?
Tsimikas pointed out that evinacumab works in the circulation whereas the antisense ASO works in the liver, where it seems to have a broader range of effects that theoretically could be clinically useful; the effects on insulin sensitivity and liver fat accumulation are possible examples.
But in terms of modifying lipoprotein levels, “most likely what you’ll see is a very similar effect,” depending on dosing, he said. With either agent, “if you can get a 70% reduction in triglycerides and LDL, particularly with a mechanism that doesn’t involve the traditional LDL-receptor pathways, it may be a very nice approach to meet the unmet need in these patients that continue to have elevated triglycerides and LDL despite what we currently can offer them.”
The study of evinacumab and cohorts with ANGPTL3 loss-of-function variants was funded by Regeneron Pharmaceuticals, of whom Dewey is an employee. Disclosures for the other authors are at nejm.org. The study of the ASO targeting ANGPTL3 mRNA was funded by Ionis Pharmaceuticals. Tsimikas said he is an employee of both Ionis and the University of California San Diego; disclosures for the other authors are at nejm.org. Ballantyne discloses consulting for Regeneron and serving as an investigator for Ionis for a different agent in development, and has been involved in studies of multiple lipid-modifying agents including PCSK9 inhibitors, ezetimibe, statins, anacetrapib, and eicosapentaenoic acid ethyl ester.
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