Plozasiran lowers APOC3, triglycerides, other lipids in high-risk populations
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Key takeaways:
- Plozasiran demonstrated durable improvement in triglycerides, APOC3 and other lipid parameters for patients with very high triglycerides.
- The drug also showed benefit in familial chylomicronemia syndrome.
In patients with severe hypertriglyceridemia, plozasiran, a novel RNA interference agent, lowered apolipoprotein C-III and triglycerides and improved other lipid parameters, according to the final results of the phase 2b SHASTA-2 trial.
In addition, Arrowhead Pharmaceuticals, the sponsor of plozasiran, announced the top-line results of the phase 3 PALISADE trial, in which plozasiran reduced APOC3 and triglycerides for patients with genetically confirmed or clinically diagnosed familial chylomicronemia syndrome, and lowered risk for acute pancreatitis in that population.
SHASTA-2
SHASTA-2 included 226 patients with severe hypertriglyceridemia, defined as triglycerides of more than 500 mg/dL, who were randomly assigned to plozasiran 10 mg, 25 mg or 50 mg or placebo, Christie M. Ballantyne, MD, FACC, FACP, FAHA, FNLA, chief of the section of cardiovascular research and professor of medicine at Baylor College of Medicine, said during a presentation at the National Lipid Association (NLA) Scientific Sessions. The presentation included results from the main analysis at 48 weeks and the first 15 months of the open-label extension study, in which all patients received plozasiran once every 3 months after the 48 weeks of the trial.
“These are metabolic syndrome-type patients,” Ballantyne, who became president of the NLA during the sessions, said during the presentation. “We see lots of obesity and lots of diabetes. They have high levels of triglycerides, in the 800 mg/dL to 900 mg/dL range. Non-HDL cholesterol and ApoB are also elevated. Remnant cholesterol is quite high.”
At 24 weeks, plozasiran lowered APOC3 as much as –78% (placebo-subtracted, –48%) and triglycerides as much as –74% (placebo-subtracted, –58%) at 24 weeks (P < .001 for all), with results sustained out to 48 weeks and through the open-label extension study, Ballantyne said.
In addition, plozasiran lowered remnant cholesterol as much as –62% (placebo-subtracted, –45%) and raised HDL as much as 68% (placebo-subtracted, 38%; P < .001 for all), he said.
“The non-HDL cholesterol goes down, but the LDL cholesterol goes up, so the reduction in non-HDL cholesterol is due to the reduction in remnant cholesterol,” Ballantyne said.
Serious adverse events were similar in the treatment and placebo groups, he said.
“The majority of patients, over 90%, got to triglycerides under 500 mg/dL,” he said. “That is the zone where we feel you are not going to get pancreatitis. If you’re under 500 mg/dL, even with a bad couple of days, you’re not going to get into that range of 1,500 mg/dL to 3,000 mg/dL where we see lots of pancreatitis. If you’re over 1,000 mg/dL, it’s very easy for someone to get into extremely high levels from just a couple of days of poor diet. Half the patients got to under 150 mg/dL, which we consider to be the healthy region. In the open-label extension, there was sustained efficacy. Based upon this information, a large phase 3 program is now underway.”
PALISADE
In the phase 3 PALISADE trial of plozasiran in patients with familial chylomicronemia syndrome, the median reduction in triglyceride level at 10 months was –80% for patients taking plozasiran 25 mg every 3 months and –78% for those taking plozasiran 50 mg every 3 months, compared with –17% for patients assigned placebo (P < .001), according to a press release from Arrowhead.
The 10-month reductions in APOC3 were –88% and –94% in the 25 mg and 50 mg plozasiran groups, respectively, according to the release.
The number of treatment-emergent adverse events was similar between the plozasiran and placebo groups, whereas severe and serious adverse events, including acute pancreatitis, occurred less often in the plozasiran groups than in the placebo group, the company stated in the release.
“We see plozasiran data as best in class and with the potential to address multiple cardiometabolic diseases with substantial unmet need,” Christopher Anzalone, PhD, president and CEO of Arrowhead, said in the release. “We will now communicate the results to the FDA and discuss filing a new drug application for [familial chylomicronemia syndrome]. We will also continue to advance multiple additional phase 3 studies for other patient populations. It is gratifying to see one of our investigational RNA [interference]-based medicines get potentially closer to the patients who need it most.”
The full data from PALISADE will be presented at upcoming medical conferences, according to the release.
Reference:
- Arrowhead Pharmaceuticals reports successful topline results for plozasiran from the pivotal phase 3 PALISADE study in patients with familial chylomicronemia syndrome. https://www.businesswire.com/news/home/20240603389820/en/Arrowhead-Pharmaceuticals-Reports-Successful-Topline-Results-for-Plozasiran-from-the-Pivotal-Phase-3-PALISADE-Study-in-Patients-with-Familial-Chylomicronemia-Syndrome. Published June 3, 2024. Accessed June 3, 2024.
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Ballantyne CM, et al. Late breakers. Presented at: National Lipid Association Scientific Sessions; May 30-June 2, 2024; Las Vegas (hybrid meeting).
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