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RNA Therapeutics From Ionis Pharmaceuticals, Eli Lilly Take Aim at Triglycerides

American College of Cardiology's 2024 scientific meeting

ATLANTA – An antisense oligonucleotide in late-stage clinical development as a treatment for patients with familial chylomicronemia syndrome has shown promise at reducing triglyceride levels and acute pancreatitis events, according to Phase III results presented at the American College of Cardiology's annual scientific meeting on Sunday.

Ionis Pharmaceuticals is developing the ligand-conjugated ASO, olezarsen, as a treatment for patients with familial chylomicronemia syndrome (FCS) who have highly elevated triglyceride levels in their blood. FCS is a rare genetic disorder in which patients cannot break down fats due to a deficiency in the activity of lipoprotein lipase, an enzyme that typically degrades triglycerides.

Olezarsen is designed to inhibit production of Apolipoprotein C-III, a protein that regulates triglyceride metabolism, by targeting APOC3 mRNA.

Patients with FCS have "severely elevated triglyceride levels — think about 10 to 100 times the normal levels we see in cardiology patients," Erik Stroes, a professor in the vascular medicine department at the Amsterdam University Medical Center in the Netherlands, said during a presentation at ACC. Elevated triglycerides in the blood can lead to various health problems, including increased risk of cardiovascular disease and acute pancreatitis.

Ionis has previously said it plans to file a new drug application with the US Food and Drug Administration this year for olezarsen in FCS, which, if approved, would be the company's first independently commercialized product.

Last year, Ionis completed a randomized-controlled Phase III study, dubbed BALANCE, in which investigators enrolled 66 patients with genetically confirmed FCS, including pathogenic variants in the LPL, APOA5, GPIHBP1, LMF1, and APOC2 genes, as well as high triglyceride levels of at least 880 milligrams per deciliter at screening and a history of pancreatitis. Patients received one of two doses of olezarsen or a placebo, administered subcutaneously every four weeks for 53 weeks. All patients were also recommended to follow a low-fat diet and continued to receive other therapies such as statins, fibrates, and omega-3 fatty acids.

Study results from the Phase III trial were published simultaneously on Sunday in the New England Journal of Medicine.

Investigators observed a 43.5 percent average reduction in fasting triglyceride levels six months after starting treatment among patients in the high-dose treatment group, a statistically significant difference compared to patients in the placebo arm. Patients sustained lower triglyceride levels through 12 months. While patients in the low-dose group experienced a 22.4 percent average reduction in triglyceride levels after six months compared to the placebo arm, the difference was not statistically significant.

Patients in both treatment groups experienced a decrease in apoC-III compared to placebo after six months. After 53 weeks, patients in the placebo arm reported 11 acute pancreatitis episodes across seven patients, whereas there was only one episode reported in each of the two treatment groups. In the low-dose group, that episode took place more than 100 days after beginning treatment, and in the high-dose group, the episode happened after more than 350 days.

"It's nice to talk about triglycerides," Stroes said, but from a patient's perspective, they're concerned about clinical outcomes. For patients, "the real thing [that matters] is pancreatitis risk."

Olezarsen had a favorable safety and tolerability profile at both doses, Stroes said. There were no serious treatment-emergent adverse events related to the ASO.

There were two patients who discontinued treatment due to adverse events in the high-dose group, one of whom reported diarrhea, vomiting, flushing, and chest discomfort, and another who reported chills, myalgia, and trismus. One patient in the low-dose treatment group died, however, the investigators determined it was unrelated to olezarsen.

In other ongoing Phase III trials, Ionis is also evaluating olezarsen as a treatment for a broader population of patients with hypertriglyceridemia, or highly elevated triglyceride levels. Brian Bergmark, an investigator in the Thrombolysis in Myocardial Infarction Study Group at Brigham and Women's Hospital, on Sunday presented data from a randomized-controlled Phase IIb trial, BRIDGE-TIMI 73a, involving 154 patients who either had severe hypertriglyceridemia or had moderate hypertriglyceridemia and other cardiovascular risk factors. 

Patients received the same dosage options as in the BALANCE study: one of two doses of olezarsen or a placebo administered every four weeks for about a year. In this study, investigators found that olezarsen cut patients' triglyceride levels by about half at both dose levels compared to the placebo group after six months. Patients in the low-dose group also experienced about a 64 percent average reduction in apoC-III levels, while the high-dose group experienced an average reduction of 74 percent.

Also on Sunday, Stephen Nicholls, program director of Monash Health's Victorian Heart Hospital in Australia, presented safety data from a randomized-controlled Phase I trial of solbinsiran, an siRNA that Eli Lilly is developing as a treatment for patients with mixed dyslipidemia, or elevated levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides, which increases risk of cardiovascular disease. Solbinsiran aims to reduce expression of the ANGPTL3 gene, which regulates lipoprotein metabolism.

In the Phase I trial, 56 patients received either a single dose or repeat doses of solbinsiran or placebo, administered subcutaneously, with the patients in the treatment group given solbinsiran at one of multiple dose levels. Investigators observed treatment-emergent adverse events in 17 percent to 67 percent of those on solbinsiran and in 20 percent to 50 percent of those on placebo. All adverse events related to the drug were mild. Twelve of 42 patients who received the drug reported injection-site reactions compared to one of 14 patients who received placebo. In terms of pharmacodynamics, investigators observed dose-dependent reductions in ANGPTL3 by 86 percent to 89 percent, in triglycerides by 70 percent to 73 percent, in non-high-density lipoprotein cholesterol by 41 percent to 46 percent, and in apolipoprotein B by 30 percent to 36 percent.

Outside of the Phase I study, which has completed, the siRNA is currently being tested in a Phase IIb trial that's expected to be completed this year.

With a growing number of biologics in clinical development targeting different lipoproteins, Nicholls expects these types of drugs will become part of standard cardiovascular care in the future. "The prevention landscape is evolving right before our eyes," he said. "For many people who are considered to have some significant cardiovascular risk, [treatment is] probably going to include at least one injectable."