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Antisense Drug Slashes High Triglycerides

— Two trials show promise in moderate and extreme elevations

MedpageToday

ATLANTA -- A novel antisense mRNA drug slashed triglycerides in higher risk or moderate hypertriglyceridemia patients and in those with extremely elevated levels from familial chylomicronemia syndrome, two randomized phase IIb trials showed.

Olezarsen, administered subcutaneously once a month, reduced plasma triglyceride levels by 49.3 and 53.1 percentage points with the two tested doses as compared with placebo (50 and 80 mg, respectively, both P<0.001) among a cohort with predominantly moderate hypertriglyceridemia at elevated cardiovascular risk, reported Brian A. Bergmark, MD, of the Brigham and Women's Hospital and Harvard ľֱ School in Boston.

"This triglyceride effect was greater than is possible with currently available treatments," he said in reporting the phase IIb trial at the American College of Cardiology (ACC) annual meeting.

In a phase III trial among familial chylomicronemia syndrome patients, the higher dose reduced triglycerides by 43.5 percentage points more than did placebo (P<0.001), although the lower dose was ineffective. A secondary endpoint showed a reduction in pancreatitis for the pooled olezarsen groups compared with placebo, with a mean rate ratio of 0.12 at week 53 (95% CI 0.02-0.66).

No major safety concerns emerged in either trial, both of which were simultaneously published in The New England Journal of Medicine.

Olezarsen is an antisense oligonucleotide targeting messenger RNA for apolipoprotein C-III (APOC3), which keeps triglyceride-rich lipoproteins from binding to receptors in the liver for elimination, resulting in high circulating levels of triglycerides, noted Gerald F. Watts, DSc, MD, PhD, of Royal Perth Hospital and the University of Western Australia in Perth, Australia.

"Olezarsen is essentially similar to volanesorsen, a second-generation antisense oligonucleotide," he wrote in an NEJM explaining the science. However, an important difference is olezarsen's conjugation to a factor that targets it to the liver, which "markedly increase[s] the efficiency and safety of olezarsen as compared with volanesorsen, permitting use of a lower dose, injection volume, and frequency of administration. Liver-specific targeting also decreases the chances of off-target effects."

ACC study discussant Neha Pagidipati, MD, MPH, of Duke University in Durham, North Carolina, noted the unmet clinical need for these patients.

"As somebody who takes care of patients in a lipid clinic, this is one of the toughest patient populations that we have to take care of," she said at a press conference. "They are very high risk and there's very little out there that we can treat them with. And so to see two trials addressing this patient population this morning was a really welcome thing."

Watts agreed that "current therapies for severely elevated levels of triglycerides are ineffective, with a continuing risk of life-threatening acute pancreatitis, a gap that will probably be closed by olezarsen, which has recently been granted fast-track designation by the Food and Drug Administration for the treatment of the familial chylomicronemia syndrome."

However, some clinicians questioned the outcomes studied.

"With respect to acute pancreatitis risk, it's the triglyceride lowering that seems to be the thing that can really help those patients the most," said ACC session study discussant Daniel Soffer, MD, president of the National Lipid Association. But for atherosclerotic cardiovascular disease (ASCVD) risk, "it's not the triglyceride level, it's the non-HDL cholesterol and ApoB level." Those should have been the primary endpoint in the moderate hypertriglyceridemia trial, he suggested.

For the moderate patients, Dave Dixon, PharmD, of Virginia Commonwealth University in Richmond, agreed that triglyceride lowering has not panned out as a mechanism to reduce cardiovascular risk in clinical trials.

"Even if you look at the REDUCE-IT trial with icosapent ethyl [Vascepa], the benefit there was not necessarily related to the reduction in triglycerides," he told ľֱ. "But I do think that there's a greater potential that these medications may actually reduce ApoB more so, which then might translate to some reduction in risk."

All agreed that cardiovascular outcomes data will be key. Bergmark pointed to a "large amount of upcoming data" from the Essence-TIMI 73b trial in moderate hypertriglyceridemia patients, which also has a coronary CT angiography substudy to look for atherosclerotic regression, as well as two CORE-TIMI 73 trials in the severe hypertriglyceridemia population with open-label extension.

While Watts noted potential advantages to an injectable like olezarsen in that it is "more potent and longer acting than oral agents, addressing issues with adherence to treatment," he added that "robust implementation will require demonstration of long-term effectiveness and safety, a favorable cost-benefit ratio, and unfettered access to therapy."

Moderate Hypertriglyceridemia Trial Details

The phase IIb Bridge-TIMI 73a trial included 154 adults (median age 62) at 24 sites in North America who either had moderate hypertriglyceridemia (150-499 mg/dL) and elevated cardiovascular risk or who had severe hypertriglyceridemia (≥500 mg/dL). They were randomly assigned 1:1 to a 50- or 80-mg cohort and then randomized 3:1 to monthly subcutaneous olezarsen or matching placebo within each of those dose groups.

Both doses led to rapid and sustained reduction from the median baseline triglyceride level of 241.5 mg/dL, Bergmark said, which was consistent across key subgroups.

Triglycerides dropped from baseline by an average 7.8% (95% CI 0.2-15.3) in the placebo group but by 57.1% (95% CI 50.9-63.2) with 50-mg olezarsen and by 60.9% (95% CI 54.7-67.1) in the 80-mg group.

The drug also reduced levels of the target APOC3 by 64-73 percentage points, non-HDL cholesterol by around 24 percentage points, and ApoB by around 18 percentage points more than with placebo. No significant change emerged in LDL, and only a nominal difference from placebo for total cholesterol.

Treatment-emergent adverse events (AEs) showed more low level elevations in liver enzymes but significant increases were uncommon and not more frequent than with placebo. No serious AEs occurred in any group.

A reduction in platelet count to below 100,000/μL occurred in one placebo-treated patient (3%), none in the olezarsen 50-mg group, and three 50-mg olezarsen patients (5%, P=0.64 vs placebo). None dropped below 75,000 platelets/μL.

That was "one of the things we were all looking for," said Pagidipati, "because a prior APOC3 agent, volanesorsen, showed an impact in thrombocytopenia."

Dixon added: "I still always want to see more long-term safety data as well. I think if you look back at pemafibrate, another triglyceride lowering agent, that in the large clinical outcomes trial, there were some signals of issues related to safety. It's important to make sure we have a balanced approach to looking at the safety aspects as well as efficacy."

Severe Hypertriglyceridemia Trial Details

Erik Stroes, MD, PhD, of Amsterdam University Medical Center, reported the at ACC. It included 66 patients with genetically identified familial chylomicronemia syndrome. They were randomly assigned to receive 50- or 80-mg olezarsen or placebo subcutaneously every 4 weeks for 53 weeks.

Baseline triglycerides averaged 2,630 mg/dL, and 71% of participants had a history of acute pancreatitis within the prior decade.

Acute pancreatitis occurred by 53 weeks with 11 episodes in the placebo group and one in each olezarsen group.

AEs of moderate severity deemed treatment related occurred only in four patients in the 80-mg olezarsen group.

"The safety analysis showed no imbalance among the three trial groups with respect to liver, renal, or platelet laboratory variables; mild injection- site reactions were more common with olezarsen than with placebo," Stroes and colleagues wrote in NEJM.

Limitations included the small sample size in this rare genetic condition as well as uncertainty about adherence to dietary restrictions, "which could have affected the degree of triglyceride lowering and incidence of acute pancreatitis," the group added. The largely White cohort was "partially owing to genetic founder effects in European populations."

"Additional trials in larger and more diverse populations are needed to confirm our findings. The efficacy and safety results of the Balance trial support further clinical testing of olezarsen to prevent the clinical sequelae of familial chylomicronemia syndrome," they concluded.

Disclosures

Bridge-TIMI 73a and Balance were funded by Ionis Pharmaceuticals.

Bergmark disclosed relationships with Abbott Vascular, Abiomed, Bain Life Sciences, Bolt, Cardiovascular Systems, Endovascular Engineering, Philips, Shockwave Medical, and SpectraWave.

Stroes disclosed relationships with Amgen, AstraZeneca, Daiichi-Sankyo, Ionis, Merck, Novartis, Novo Nordisk, and Sanofi Pasteur.

Watts disclosed relationships with Amgen, Arrowhead Pharmaceuticals, Novartis, and Silence Pharmaceuticals.

Dixon disclosed relationships with Boehringer Ingelheim.

Primary Source

New England Journal of Medicine

Bergmark BA, et al "Olezarsen for hypertriglyceridemia in patients at high cardiovascular risk" N Engl J Med 2024; DOI: 10.1056/NEJMoa2402309.

Secondary Source

New England Journal of Medicine

Watts GF "Science behind the study: Shooting the messenger to treat hypertriglyceridemia" N Engl J Med 2024; DOI: 10.1056/NEJMe2402653.

Additional Source

New England Journal of Medicine

Stroes ESG, et al "Olezarsen, acute pancreatitis, and familial chylomicronemia syndrome" N Engl J Med 2024; DOI: 10.1056/NEJMoa2400201.