Novel antisense drug shows promise in hypertriglyceridemia, diabetes, NAFLD
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Vupanorsen, an investigational antisense therapy, reduced triglyceride levels at 6 months and demonstrated benefit on additional lipid parameters compared with placebo in patients with hypertriglyceridemia, diabetes and hepatic steatosis.
Vupanorsen (AKCEA-ANGPTL3-LRX, Akcea Therapeutics) is an antisense oligonucleotide therapy that reduces production of angiopoietin-like 3 (ANGPTL3) protein, which is a key regulator of triglyceride and cholesterol metabolism, in the liver
“ANGPTL3 is one of the most exciting lipid targets because it covers a wide spectrum of disorders and lipoproteins. It is effective in difficult-to-treat triglyceride levels and cholesterol levels,” Daniel Gaudet, MD, PhD, professor of medicine at Université de Montréal, told Healio.
Gaudet reported data at the virtual European Society of Cardiology Congress from a phase 2, randomized, double-blind, dose-ranging study that compared vupanorsen with placebo. The study enrolled 105 patients with fasting triglyceride levels greater than 150 mg/dL, type 2 diabetes and hepatic steatosis. The mean age was 54 years, 47% were women and median triglyceride level at baseline was 252 mg/dL.
Patients were randomly assigned vupanorsen or placebo (n = 27). The vupanorsen group received 40 mg every 4 weeks (n = 26), 80 mg every 4 weeks (n = 26) or 20 mg weekly (n = 26). All assigned treatments were administered subcutaneously for 6 months.
Mean treatment duration was 134 days in the vupanorsen group and 150 days in the placebo group. Mean compliance was high overall, at 96%. Eighty-seven percent of patients completed treatment.
The primary efficacy endpoint was percent change in fasting triglycerides from baseline to 6 months. At 6 months, researchers observed triglyceride reductions of 36% in patients assigned 40 mg vupanorsen (P = .03), 53% in those assigned 80 mg vupanorsen (P < .0001) and 47% in those assigned 20 mg vupanorsen (P = .0009), compared with 16% with placebo.
The researchers also reported reductions in ANGPTL3: 41% with 40 mg vupanorsen, 59% with 80 mg vupanorsen and 56% with 20 mg vupanorsen, compared with 8% with placebo (P for all < .0001).
Compared with placebo, 80 mg vupanorsen every 4 weeks reduced several key secondary endpoints including remnant cholesterol (38%), apolipoprotein C-III (58%), non-HDL (18%), total cholesterol (19%), apolipoprotein B (9%) and HDL (24%).
The researchers observed no improvement in hepatic fat fraction or glycemic parameters. In addition, vupanorsen did not result in clinically significant changes in platelet counts, as no patients attained a platelet level lower than 100,000/mm3. There were also no time-dependent or dose-dependent effects on platelet counts, according to the researchers.
Adverse events were mild to moderate and occurred in 83% of patients assigned vupanorsen vs. 59% assigned placebo. The most common events among those assigned vupanorsen were injection-site erythema (12%) and injection-site pruritus (14%).
“We will have to wait until the results once the phase 3 trials are conducted to draw a final conclusion, but at this stage, what we can say is that it’s promising and exciting,” Gaudet told Healio.
The phase 2 data were simultaneously published in the European Heart Journal.
“We are very encouraged by the demonstrated efficacy, safety and tolerability profile of vupanorsen,” Damien McDevitt, PhD, chief executive officer for Akcea, said in a company press release. “There are millions of patients worldwide living with dyslipidemia that puts them at risk of cardiovascular events. By reducing ANGPTL3, vupanorsen has the potential to reduce the risk of cardiovascular events caused by dyslipidemia in many of these patients, thereby addressing a major area of continued unmet medical need.”
Reference:
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Gaudet D. Late-Breaking Science in Lipids. Presented at: European Society of Cardiology Congress; Aug. 29-Sept. 1, 2020 (virtual meeting).
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