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Patients with the genetic recessive disorder persistent chylomicronemia who received the investigational drug plozasiran had significantly lower triglyceride levels and a reduced risk of acute pancreatitis compared with a placebo group, a phase III randomized trial showed.

Among 75 patients, the median change in fasting triglyceride levels from baseline to 10 months was 80% lower in patients receiving 25-mg plozasiran, 78% lower in patients receiving 50-mg plozasiran, and 17% lower in those receiving placebo (P<0.001), reported Gerald F. Watts, DSc, MD, PhD, of the University of Western Australia and Royal Perth Hospital in Perth, and colleagues in the .

Patients receiving plozasiran also had a reduced incidence of acute pancreatitis (OR 0.17, 95% CI 0.03-0.94, P=0.03), a key secondary endpoint since both genetic and multifactorial chylomicronemia are linked to risk of recurrent acute pancreatitis.

For other key secondary endpoints, including the percent change in the fasting triglyceride level from baseline to the mean of values at 10 months and 12 months and changes in the fasting apolipoprotein C-III level from baseline to 10 months and 12 months, patients in the plozasiran groups had better results compared with the placebo group.

"Our findings underpin the rapid development of plozasiran for the treatment of extreme hypertriglyceridemia to prevent acute pancreatitis in patients with [familial chylomicronemia syndrome] or other causes of persistent chylomicronemia with a history of pancreatitis," Watts and team wrote.

Study results were also presented at the European Society of Cardiology meeting in London.

B. Gisella Carranza Leon, MD, of Vanderbilt University Medical Center in Nashville, told 木瓜直播 that "as a lipidologist, it is exciting to see that new therapies for treatment of severe hypertriglyceridemia are under development."

"In the U.S., we do not have FDA-approved treatment for familial chylomicronemia syndrome," she said. "Studies that focus on drug development for rare diseases like this one give us hope that in the future, we will be able to offer a pharmacologic treatment for this condition."

Watts and colleagues noted that the "risk of acute pancreatitis is directly and causally related to triglyceride levels in chylomicrons, especially when such levels are persistently elevated above 880 mg per deciliter." Pancreatitis due to triglyceride levels also tends to have a worse prognosis than other forms, they added.

Standard triglyceride-lowering treatments, such as statins, fibrates, and fish oils, do not reduce risk of acute pancreatitis, offering little benefit to patients with persistent chylomicronemia, they wrote.

Carranza Leon pointed out that "the reason this disease is so debilitating is because of the recurrent pancreatitis episodes."

She said the recommended lifestyle intervention -- reducing fat intake to below 10-20% of total calories -- is difficult for patients to maintain, "especially long-term," and it also only partially lowers chylomicronemia and triglyceride levels.

Plozasiran is a hepatically targeted small interfering RNA that reduces the production and secretion of hepatic apolipoprotein C-III, a small glycoprotein mostly made by the liver that largely determines triglyceride levels. that suggested that plozasiran substantially reduced apolipoprotein C-III levels, with a median reduction in triglyceride levels of -86%, led Watts and colleagues to conduct this trial for patients with extreme and persistent chylomicronemia, including those with genetically defined disease, they explained.

For this study conducted from January 2022 to April 2024, the authors randomized 75 patients with persistent chylomicronemia with or without a genetic diagnosis from 58 centers in 21 countries to either 25 or 50 mg of subcutaneous plozasiran or placebo every 3 months for a year. Mean age was 43-48, 44-54% were women, and 71-76% were white. At baseline, the median triglyceride level was 2,044 mg/dL.

"We did not insist on genetic confirmation of familial chylomicronemia syndrome before randomization on the basis of findings that patients who meet published criteria for symptomatic persistent chylomicronemia with recurrent pancreatitis also have complications associated with substantial morbidity and mortality," the authors noted, but they did confirm biallelic or digenic pathogenic variants in the relevant genes of 44 patients (59%).

Incidence of adverse events was similar across the treatment groups, and most commonly included abdominal pain, nasopharyngitis, headache, nausea, upper respiratory tract infection, and diarrhea. Severe and serious adverse events occurred more often in the placebo group.

Acute pancreatitis occurred in 4% of patients receiving plozasiran and in 20% of those receiving placebo.

"This study was conducted on a small number of patients, and there is a possibility that when the medication is given to a larger group of patients, new and unknown side effects may appear," Carranza Leon noted.

Another study limitation, the authors added, was that they did not assess participants' quality of life or plozasiran's effect on postprandial lipemia, which is presumed to drive pancreatitis risk. "We cannot exclude the possibility that nonadherence to diet and physical activity might have contributed to larger variations in triglyceride levels and widening in the confidence intervals of the effects of plozasiran," they wrote.

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