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An RNA interference therapy, targeting ANGPTL3 in the liver, drastically reduced fasting triglycerides in people with mixed hyperlipidemia, the ARCHES-2 trial showed.

Used atop usual statins and other medications, zodasiran at various doses conferred large reductions in fasting triglyceride level from baseline to week 24 -- ranging from 51 percentage points at the 50 mg to 63 percentage points at 200 mg after adjusting for placebo (P<0.001 for all tested doses).

Administered by subcutaneous injections on day 1 and week 12 in the study, zodasiran also lowered non-HDL cholesterol, apolipoprotein B, and LDL cholesterol, reported a group led by Robert Rosenson, MD, of Icahn School of Medicine at Mount Sinai in New York City.

"Reductions across all lipid and lipoprotein end points with zodasiran were durable through 36 weeks, findings consistent with prolonged silencing of ANGPTL3 mRNA and decreases in plasma ANGPTL3 levels," the investigators wrote in the . The study findings were also presented at the European Atherosclerosis Society Congress.

As for safety, adverse events were mostly balanced between zodasiran and placebo groups in the trial. There were no liver-related adverse events associated with zodasiran.

However, there was a transient elevation in glycated hemoglobin levels in patients with preexisting diabetes who received the highest dose of zodasiran. With the 200-mg zodasiran dose, increases in glycated hemoglobin levels were estimated at 0.38% from baseline to week 24 in people with diabetes and 0.12% during that period in patients without diabetes.

"Whether dysglycemia with therapeutic inhibition of ANGPTL3 is related to alterations in the supply of free fatty acids to the liver remains unclear. Perhaps increased substrate delivery to the liver and a subsequent increase in hepatic gluconeogenesis due to enhanced metabolism of triglyceride-rich lipoproteins with zodasiran contributed to this observed effect," Rosenson's team suggested.

In any case, the group said that lifestyle changes and antiglycemic therapy would address any mild dysglycemia with zodasiran.

Zodasiran is being developed to address an unmet need in people with mixed hyperlipidemia, or concomitant elevated LDL cholesterol and triglyceride levels. Despite the effectiveness of existing medications for lowering LDL cholesterol, affected patients still have a residual cardiovascular risk attributed to remnant cholesterol in triglyceride-rich lipoproteins.

In ARCHES-2, remnant cholesterol fell by 34.4 mg/dL with the highest dose of zodasiran relative to placebo -- which can be expected to translate to a 20% reduction in major adverse cardiac events based on available modeling data, Rosenson and colleagues asserted.

Dose-dependent ANGPTL3 reductions with zodasiran ranged from 54 percentage points with the 50-mg dose to 74 percentage points with the 200-mg dose (P<0.001 for all tested doses).

Study authors contrasted this agent with other ANGPTL3 blockers, namely the human monoclonal antibody evinacumab (Evkeeza) and second-generation antisense oligonucleotide vupanorsen.

"Our study represents one of the first trials of an RNA inhibitor of ANGPTL3 with advantages like durable gene silencing and infrequent dosing," Rosenson said .

"It's our contention," Rosenson added, "that based on these promising results, further studies are warranted to determine the potential of zodasiran, an investigational drug has the potential to reduce the risk of cardiovascular events in a broad range of patients through a single therapy that targets all the lipoprotein fractions."

Zodasiran 200 mg has been selected for a three-group cardiovascular outcomes trial that will also test plozasiran 25 mg with matching placebo.

Also developed by Arrowhead Pharmaceuticals, plozasiran recently showed "nearly equivalent" reductions in levels of triglycerides and remnant cholesterol as zodasiran, similar safety, and additional HDL cholesterol-raising effects to boot, the ARCHES-2 authors wrote.

Their phase IIb double-blind trial had been conducted at 25 sites in four countries.

Investigators enrolled people with mixed hyperlipidemia, namely fasting triglycerides 150-499 mg/dL and either an LDL cholesterol level of ≥70 mg/dL or a non-HDL cholesterol level of ≥100 mg/dL. Participants were eligible if they maintained a stable diet for at least 2 weeks, stayed on a maximally-tolerable statin for at least 4 weeks, and were receiving background medications at stable doses.

There were 204 individuals randomly assigned in a 3:1 ratio to receive subcutaneous injections of zodasiran (50, 100, or 200 mg) or placebo on day 1 and week 12.

Participants had a mean age of 61 years, with over half men. Average BMI was 33, with 42% having type 2 diabetes. Mean plasma triglyceride level was 246 mg/dL, LDL cholesterol 97 mg/dL, non-HDL cholesterol 146 mg/dL, and remnant cholesterol 48 mg/dL.

Statins were used at baseline by 96% of people. Less common were therapies such as PCSK9 inhibitors (1%), fibrates (21%), and GLP-1 receptor agonists (6%).

At week 24, normalization of fasting triglyceride levels (<150 mg per deciliter) was achieved in 88% of the zodasiran 200 mg group.

This high dose was associated with a 12% incidence of urinary tract infections (vs 4% with placebo and 6% with the lower zodasiran doses) that occurred exclusively in people with a history of diabetes at baseline. "Some of the UTIs were reported before the administration of zodasiran or placebo, so the causal relationship is unclear," Rosenson's group cautioned.

Limitations of ARCHES-2 include its short duration and having patients get zodasiran just twice during the study.

For longer follow-up data, the investigators pointed to the ongoing 2-year open-label extension study.

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