Focus – Plozasiran: a novel APOC3 siRNA in mixed hyperlipidemia
August 2024
Plozasiran, a first-in-class hepatocyte-targeted APOC3 small interfering RNA therapeutic,
substantially reduced triglyceride levels in patients with mixed hyperlipidemia.
Ballantyne CM, Vasas S, Azizad M, et al. Plozasiran, an RNA interference agent targeting APOC3, for
mixed hyperlipidemia. N Engl J Med 2024; doi: 10.1056/NEJMoa2404143
STUDY SUMMARY
| Objective: | To investigate the safety and efficacy of plozasiran in patients with mixed hyperlipidemia. |
| Study design: | A phase 2b, double-blind, randomized, placebo-controlled trial of 48 weeks duration. The trial was conducted at 36 centres in the U.S., Europe, New Zealand, Australia, and Canada. |
| Study population: | Patients with mixed hyperlipidemia, defined as a triglyceride (TG) level of 150 to 499 mg/dL and either low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL or non-high-density lipoprotein cholesterol (HDL-C) ≥100 mg/dL. At entry, patients had maintained a stable diet for at least 2 weeks, had received a stable maximal tolerated dose of a statin (unless unable or unwilling to receive statins) for at least 4 weeks, and had been receiving background medication at a stable dose. |
| Main study variables: | Primary: The primary end point was the least squares (LS) mean percent change in fasting TGs from baseline to week 24. |
| Methods: | Randomized patients were assigned in a 3:1 ratio to receive plozasiran or placebo within each of 4 cohorts. In the first 3 cohorts, patients received a subcutaneous injection of plozasiran (10 mg, 25 mg, or 50 mg) or placebo on day 1 and at week 12 (quarterly doses). In the fourth cohort, participants received 50 mg of plozasiran or placebo on day 1 and at week 24 (half- yearly dose). Data from patients who received placebo were pooled. Efficacy and safety analyses were based on all patients who received at least one dose of study treatment. |
RESULTS
Overall, 353 patients (mean age 61 years, mean body mass index [BMI] 32 kg/m 2 ) were
randomized to study treatment, of whom 324 (91.8%) completed the study. Overall, 53-65% of
patients were male. At baseline, mean lipid levels were 244 mg/dL for TGs, 103 mg/dL for LDL-
C, 151 mg/dL for non-HDL-C and 47 mg/dL for remnant cholesterol. Overall, 18% of patients
had an LDL-C <70 mg/dL and 92% were receiving statin treatment (54% high-intensity statin).
The least squares (LS) mean percent change in TG levels from baseline to week 24 are
summarized in Table 1. Treatment with plozasiran resulted in significant reduction in TG levels
versus placebo (p<0.001). The effect on TG level was evident at 4 weeks after the initiation of
treatment. In addition, plozasiran resulted in significant reduction in APOC3 with versus
placebo: LS mean percent change -57.3% (95% CI, −66.6 to −48.1) with the 10-mg-quarterly
dose, −72.5% (95% CI, −81.7 to −63.3) with the 25-mg-quarterly dose, and −78.5% (95% CI,
−87.8 to −69.3) with the 50-mg-quarterly dose, with strong, positive correlations with the
change in the TG level. There were also reductions in non-HDL-C (by −24.2% with the 50-mg-
quarterly dose), driven largely by reduction in the remnant cholesterol level (by 47.5%, 95% CI
61.4 to 33.7, with the 50-mg-quarterly dose).
At week 24, a fasting TG level <150 mg/dL was achieved by 79% of patients in the 10-mg-
quarterly group, 92% in the 25-mg-quarterly group, 92% in the 50-mg-quarterly group, and 77%
in the 50-mg-half-yearly group.
Table 1. TG level at baseline and change at week 24.
| Pooled placebo |
Plozasiran, 10 mg Quarterly |
Plozasiran, 25 mg Quarterly |
Plozasiran, 50 mg Quarterly |
Plozasiran, 50 mg Half- Yearly |
|
| N | 87 | 67 | 67 | 66 | 66 |
| Lipids (mg/dL) TG at baseline |
237.2±76.2 | 253.2±81.4 | 234.1±72.7 | 250.3±81.3 | 248.0±80.6 |
| LS mean percent change (95% CI) vs. placebo |
−49.8 (−59.0, −40.6) |
−56.0 (−65.1, −46.8) |
−62.4 (−71.5, -53.2) |
−44.2 (−53.4, −35.0) |
Worsening glycemic control was observed in 10% of patients on placebo, 12% in the 10-mg-
quarterly dose group, 7% in the 25-mg-quarterly dose group, 20% in the 50-mg-quarterly dose
group, and 21% in the 50-mg-half-yearly dose group.
| Authors’ conclusion: | In this randomized, controlled trial involving participants with mixed hyperlipidemia, plozasiran, as compared with placebo, significantly reduced TG levels at 24 weeks. A clinical outcomes trial is warranted. |
COMMENT
Mixed hyperlipidemia, characterized by elevated TGs and LDL-C, is increasingly common as the
prevalence of obesity and type 2 diabetes mellitus increases. An elevated TG level is a surrogate for
TG-rich lipoproteins and their remnants, which have been shown to carry up to 4 times as much
cholesterol per particle as LDL (1). Evidence from mechanistic studies show that elevated levels of
TG-rich lipoproteins promote atherogenesis (2), and in humans, have been associated with an
increased risk of atherosclerotic cardiovascular disease (1,3). These findings underscore the need to
treat both elevated TGs and LDL-C associated with mixed hyperlipidemia.
Despite highly efficacious treatment for LDL-C, however, individuals with persistent elevated TGs
remain at high residual risk of cardiovascular events (1, 4-6). This has therefore prompted novel
therapeutic approaches directed to different targets of TG-rich metabolism. One of these targets is
apolipoprotein C3 (APOC3), a key regulator of TG-rich lipoprotein metabolism. Such an approach is
supported by studies showing that individuals carrying APOC3 loss-of-function variants had lower TG
levels and were at reduced risk of cardiovascular events (7-9).
SiRNA-approaches to reduce APOC3 expression have attracted much interest, given their high
specificity, potency, and reversibility. Plozasiran is an N-acetylgalactosamine–conjugated siRNA
which reduces APOC3 expression in the liver. In a previous trial, plozasiran was shown to produce
dose-dependent reductions in APOC3 and TG levels in healthy volunteers and in patients with
hypertriglyceridemia (10).
The current study shows that treatment with plozasiran resulted in substantial and durable
reduction in TG levels in individuals with mixed hyperlipidemia, with most patients attaining TG
levels <150 mg/dL at 24 weeks. Moreover, extended follow-up showed that the effects of plozasiran
were sustained 36 weeks after administration of the last dose. Increases in the glycated hemoglobin
level in the quarterly and half-yearly 50-mg dose may be related to postprandial glycemia. Similar
findings of worsening glycemic control have been reported with volanesorsen, an APOC3 antisense
oligonucleotide in patients with familial chylomicronemia syndrome, although there were no long-
term adverse effects on glucose homeostasis (11).
Taken together, encouraging results from this phase 2 trial support further clinical development of
plozasiran, including a cardiovascular outcomes study to investigate whether lowering TG levels with
this treatment is associated with reduction in residual cardiovascular risk.
| References | 1. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res 2016;118:547-563. 2. Ginsberg HN, Packard CJ, Chapman MJ, et al. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies — a consensus statement from the European Atherosclerosis Society. Eur Heart J 2021;42:4791-806. 3. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014;384:626-635. 4. Langsted A, Madsen CM, Nordestgaard BG. Contribution of remnant cholesterol to cardiovascular risk. J Intern Med 2020;288:116-127. 5. Varbo A, Benn M, Tybjærg-Hansen A, et al. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427-436. 6. Schwartz GG, Abt M, Bao W, et al. Fasting triglycerides predict recurrent ischemic events in patients with acute coronary syndrome treated with statins. J Am Coll Cardiol 2015;65:2267-2275. 7. Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med 2014;371:32-41. 8. TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med 2014;371:22-31. 9. Wulff AB, Nordestgaard BG, Tybjærg-Hansen A. APOC3 loss-of-function mutations, remnant cholesterol, low-density lipoprotein cholesterol, and cardiovascular risk: mediation- and meta- analyses of 137895 individuals. Arterioscler Thromb Vasc Biol 2018;38:660-668. 10. Gaudet D, Clifton P, Sullivan D, et al. RNA interference therapy targeting apolipoprotein C-III in hypertriglyceridemia. NEJM Evid 2023;2(12):EVIDoa2200325. 11. Jones A, Peers K, Wierzbicki AS, et al. Long-term effects of volanesorsen on triglycerides and pancreatitis in patients with familial chylomicronaemia syndrome (FCS) in the UK Early Access to Medicines Scheme (EAMS). Atherosclerosis 2023;375:67-74. |
| Key words | Key words: apolipoprotein C3; plozasiran; triglyceride-rich lipoproteins; remnant cholesterol; residual cardiovascular risk |
