Antisense Oligonucleotide Inhibition of Apolipoprotein C-III Reduces Plasma Triglycerides in Rodents, Nonhuman Primates, and Humans
Elevated plasma triglyceride levels have been recognized as a risk factor for the development of coronary heart disease. Apolipoprotein C-III (apoC-III) represents both an independent risk factor and a key regulatory factor of plasma triglyceride concentrations. Furthermore, elevated apoC-III levels have been associated with metabolic syndrome and type 2 diabetes mellitus. To date, no selective apoC-III therapeutic agent has been evaluated in the clinic.
To test the hypothesis that selective inhibition of apoC-III with antisense drugs in preclinical models and in healthy volunteers would reduce plasma apoC-III and triglyceride levels.
Methods and results:
Rodent- and human-specific second-generation antisense oligonucleotides were identified and evaluated in preclinical models, including rats, mice, human apoC-III transgenic mice, and nonhuman primates. We demonstrated the selective reduction of both apoC-III and triglyceride in all preclinical pharmacological evaluations. We also showed that inhibition of apoC-III was well tolerated and not associated with increased liver triglyceride deposition or hepatotoxicity. A double-blind, placebo-controlled, phase I clinical study was performed in healthy subjects. Administration of the human apoC-III antisense drug resulted in dose-dependent reductions in plasma apoC-III, concomitant lowering of triglyceride levels, and produced no clinically meaningful signals in the safety evaluations.
Antisense inhibition of apoC-III in preclinical models and in a phase I clinical trial with healthy subjects produced potent, selective reductions in plasma apoC-III and triglyceride, 2 known risk factors for cardiovascular disease. This compelling pharmacological profile supports further clinical investigations in hypertriglyceridemic subjects.
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- "This provides strong human validation of APOC3 as a therapeutic target. A phase 1 trial of an antisense oligonucleotide against APOC3 has been reported showing dose-dependent reductions in TG with small increases in HDL-C . One small study of three patients with homozygous or compound heterozygous mutations in the LPL gene demonstrated that antisense inhibition of APOC3 lowered TGs by 50-80% , providing evidence that APOC3 also participates in an LPL-independent pathway of TG removal. "
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- "As observed in preclinical studies, administration of ISIS 308401 led to significant dose-dependent reductions in apoC-III protein with concomitant reductions in plasma TG (−50 %) relative to baseline at the highest administered dose. Reductions in plasma apoC-III protein and TG were seen as early as 8 days after the initial dose . ISIS 308401 was generally well tolerated with no serious adverse events or early dosing terminations. "
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