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STUDY SUMMARY | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Objective: | To evaluate the safety, tolerability, and efficacy of single and multiple subcutaneous doses of a GalNAc3-modified antisense oligonucleotide to apolipoprotein (apo) C-III (AKCEAAPOCIII-LRx) in healthy individuals with modest elevations of plasma triglycerides (TG). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Study design: | Double-blind, placebo-controlled, dose-escalation Phase I/IIa study | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Study population: | Healthy volunteers (aged 18–65 years) with TG levels >90 mg/dL or >200 mg/dL. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Main study variables: |
· Efficacy: Apolipoprotein (apo) C-III and TG; secondary variables were total cholesterol (total C), apo B, non-high-density lipoprotein cholesterol (HDL-C), very low-density lipoprotein cholesterol (VLDL-C) · Safety: treatment-emergent adverse events; urinalysis, chemistry, haematology, vital signs and electrocardiogram findings. |
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Methods: | The study comprised single and multiple dose components. In the single-dose study there were five cohorts (N = 8 per cohort, total randomized 6 active:2 placebo), using doses of 10, 30, 60, 90, and 120 mg. Subjects were required to have a fasting TG level >90 mg/dL for the 10, 30, and 60 mg dose cohorts and >200 mg/dL for the 90 and 120 mg cohorts. The multiple-dose study included subjects with a fasting TG level >200 mg/dL. The doses were 15 and 30 mg weekly for 6 weeks (N = 8 per cohort, total randomized 6 active: 2 placebo) and 60 mg every 4 weeks for 6 months (N= 10, total randomized 6 active:4 placebo). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Results: |
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Authors’ conclusion: | Treatment of hypertriglyceridemic subjects with AKCEA-APOCIII-LRx results in a broad improvement in the atherogenic lipid profile with a favourable safety and tolerability profile. |
COMMENT
Accumulating data support the causality of TG-rich lipoproteins/remnant cholesterol in atherosclerotic cardiovascular disease.1-3 The available therapeutic options, however, have limitations, and with the exception of the REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) with the omega-3 fatty acid eicosapentaenoic acid,4 have failed to show definitive clinical benefit.
Consequently, novel therapeutic approaches have been directed to alternative targets. Apo C-III is a key regulator of TG metabolism.5 Genetic studies have shown that loss-of function mutations in APOC3, the gene encoding apo C-III, are associated with reduced levels of apo C-III and TG and a reduced risk of coronary artery disease.6,7 By contrast, elevated apo C-III levels are associated with increases in TG and TG-rich lipoproteins/remnant cholesterol and inflammation, and higher cardiovascular risk.8 These findings provide a rationale for investigating therapeutic approaches inhibiting apo C-III in individuals with high TG levels. This hepatocyte-targeted antisense oligonucleotide is one approach in current development.
The results of this study are encouraging. Subcutaneous administration of this novel treatment (either as a single dose or with a multiple ascending dose approach) resulted in dose-dependent significant reduction in plasma apo C-III and TG levels, with reductions in TG of about 70% when administered weekly or every 4 weeks. TG-lowering effects persisted up to 4 months after dosing with the 4-weekly dosing regimen. Treatment was also well tolerated, with no evidence to suggest adverse effects, as previously seen with another APOC3 antisense oligonucleotide, volanesorsen.9
In summary, the results of this trial provide support for continued development of this novel therapeutic approach to lowering elevated TG levels.
References |
1. Laufs U, Parhofer KG, Ginsberg HN, Hegele RA. Clinical review on triglycerides. Eur Heart J 2020;41:99-109c. 2. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014;384:626-35. 3. Sandesara PB, Virani SS, Fazio S, Shapiro MD. The forgotten lipids: triglycerides, remnant cholesterol, and atherosclerotic cardiovascular disease risk. Endocr Rev 2019;40:537-57. 4. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11–22. 5. Taskinen MR, Borén J. Why is apolipoprotein CIII emerging as a novel therapeutic target to reduce the burden of cardiovascular disease? Curr Atheroscler Rep 2016;18:59. 6. Crosby J, Peloso GM, Auer PL et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med 2014;371:22–31. 7. Jorgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjaerg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med 2014;371:32–41. 8. Qamar A, Khetarpal SA, Khera AV et al. Plasma apolipoprotein C-III levels, triglycerides, and coronary artery calcification in type 2 diabetics. Arterioscler Thromb Vasc Biol 2015;35:1880–8. 9. Levin AA. Treating disease at the RNA level with oligonucleotides. N Engl J Med 2019;380:57–70. |
Key words | apolipoprotein C-III, triglycerides, antisense oligonucleotide; dose-dependent |