In patients with severely elevated triglyceride levels who are at risk for acute pancreatitis, the investigational drug plozasiran brought about substantial reductions in triglyceride levels in the phase 2 SHASTA-2 study.
Most patients receiving plozasiran showed a fall in triglyceride levels to < 500 mg/dL threshold of acute pancreatitis risk.
The safety profile of the drug was generally favorable, but it was associated with an increase in low-density lipoprotein cholesterol (LDL-C) and a transient decline in glycemic control in patients with diabetes in the study.
“Plozasiran produced significant reductions in triglyceride levels below the threshold associated with elevated risk for pancreatitis,” concluded lead investigator Daniel Gaudet, MD, PhD, professor of medicine at the University of Montreal, Canada.
“These data support the initiation of pivotal studies of plozasiran for the treatment of severe hypertriglyceridemia,” he added.
“Severe hypertriglyceridemia is a challenging condition for which few effective treatments are currently available,” Gaudet noted. “From the patients’ standpoint, the possibility that in the near future there could be an agent that safely and effectively lowers severely elevated triglyceride levels and reduces or eliminates the risk of developing pancreatitis is extraordinary.”
Gaudet presented the SHASTA-2 study on April 7 at the American College of Cardiology’s Annual Scientific Session, held in Atlanta, Georgia. The results were simultaneously published online in JAMA Cardiology.
An estimated 1 in 5 US adults — and more than 2 in 5 of adults aged 60 years or older — have elevated triglycerides, defined as > 150 mg/dL, which contributes to coronary artery disease. Severe hypertriglyceridemia, defined as triglyceride levels > 500 mg/dL, can also cause pancreatitis.
Plozasiran is an investigational RNA interference therapeutic that targets the apolipoprotein C-III (ApoC-III) protein, which inhibits the liver’s ability to clear triglycerides out of the body. It works by reducing the production of ApoC-III, thereby enabling the liver to increase triglyceride clearance.
The SHASTA-2 trial included 229 patients with severe hypertriglyceridemia. Their average triglyceride level at baseline was 900 mg/dL. Most participants also had at least three of these risk factors: elevated risk for or history of cardiovascular disease, diabetes, low high-density lipoprotein cholesterol (HDL-C), and high body mass index.
Patients were randomly assigned to one of four groups. Three groups received two injections of plozasiran at one of three doses (10 mg, 25 mg, or 50 mg); the fourth group received two injections of placebo. The first injection was given on day 1 and the second at week 12.
The study’s primary endpoint was the change in fasting triglyceride levels from study entry to 24 weeks. This was reduced by 74% in plozasiran-treated patients compared with 17% in patients who received placebo.
At 48 weeks, the average reduction was 58% in patients who received the highest doses of plozasiran compared with 7% for those on placebo.
The average reduction in ApoC-III was 78% for plozasiran-treated patients vs 1% for the placebo group at 24 weeks. At 48 weeks, ApoC-III levels were reduced by 48% on average among patients receiving the highest doses of plozasiran, whereas ApoC-III levels increased 4% in the placebo group.
At 24 weeks, over 90% of patients who received the higher doses (25 mg or 50 mg) of plozasiran saw their triglyceride levels fall to < 500 mg/dL. At 48 weeks, 77% of these patients still had triglyceride levels < 500 mg/dL.
More than 50% of patients on higher doses achieved triglyceride levels of below 150 mg/dL (the normal range) at 24 weeks.
“Significant and durable dose-dependent reductions in ApoC-III and triglycerides persisted through week 48, or 36 weeks after patients received their second dose of plozasiran,” Gaudet noted.
In terms of other lipid parameters, dose-dependent and significant increases in HDL-C level were observed at week 24 with plozasiran, which remained significant to week 48. But the drug was also associated with dose-dependent increases in LDL-C level, which peaked after the second dose. In those receiving the highest dose (50 mg), the placebo-adjusted increase in LDL-C was 60%. LDL-C steadily declined after 24 weeks and was not significantly different from placebo values at week 48.
A phase 3 trial is now planned with the 25-mg dose.
Discussant of the study at the ACC late-breaking clinical trials session, Pradeep Natarajan, MD, MMSc, director of preventive cardiology at Massachusetts General Hospital, Boston, noted that Apo C-III loss of function mutations are associated with lowered triglycerides and reduced coronary artery disease risk without substantial changes in LDL-C levels, so he wondered why LDL-C was increased with plozasiran.
He also questioned why the drug was associated with an adverse effect on glycemic control.
Gaudet replied that LDL-C increase may be expected as part of the mechanism of action of plozasiran but that could be treated with statins or PCSK9 inhibitors.
He also suggested that the increases in LDL-C level may be offset by the attendant decreases in levels of triglycerides, remnant cholesterol and non–HDL-C, and the lack of increase in ApoB level seen with the drug.
On the glycemic status, Gaudet pointed out that ApoC-III has a deleterious effect on glycemic control, so ApoC-III inhibition should not cause a decline in glycemic control. “We do not see a long-term deleterious effect on glycemic control with this drug and carriers of the ApoC-III gene variants do not have problems with glycemic control,” he added.
LDL-C Increase?
Discussing the SHASTA-2 study at an ACC press conference, Neha Pagidipati, MD, MPH, associate professor of medicine at the Duke Clinical Research Institute, Durham, North Carolina, said: ” When I look at the overall results of this study, obviously a 50% lowering of triglycerides at 48 weeks is certainly very exciting.”
But she expressed concern over the LDL-C increase, adding that understanding the mechanism of that and the potential implications will be very important.
“Going forward, this is a very exciting time for this patient population who have long been underserved and under treated and I look forward to seeing outcomes data and more safety data on this agent,” she concluded.
Pagidipati pointed out that plozasiran is one of two new agents for hypertriglyceridemia that were the subject of late-breaking clinical trials at the ACC meeting.
The other agent, olezarsen, also targets the production of ApoC-III, but plozasiran is an RNA interfering molecule, whereas olezarsen is an antisense oligonucleotide.
She also noted that the patient populations were different in the two studies. Though all patients in SHASTA-2 had very elevated triglyceride levels, all > 500 dL/mg, in the olezarsen trial, only a small minority of patients had triglyceride levels that high, making them more of a high-risk moderate-hypertriglyceridemia population.
The SHASTA-2 study was funded by Arrowhead Pharmaceuticals, the manufacturer of plozasiran. Gaudet reports receiving grants and personal fees from Arrowhead.
