Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia

Mychal Outlaw, Mercer University College of Pharmacy

According to the Journal of the American Board of Family Medicine, apolipoproteins are proteins associated with lipids that assist with their assembly, transport, and metabolism1.

An article in the Journal of Proteomics and Bioinformatics describes apolipoprotein C-III (APOC3) as a component of very-low-density lipoprotein (VLDL) that inhibits lipoprotein lipase and blocks hepatic metabolism of lipoproteins. The journal also states that an increase in APOC3 is related to the development of hypertriglyceridemia2.

According the Methods of Molecular Medicine, the mechanism of antisense inhibition is targeting RNA of any protein leading to altered gene expression and diminished translation and production of that specific protein. The journal states that the majority of antisense studies aim to reduce undesired disease-associated proteins3.

Design Randomized, double-blinded, placebo-controlled, phase 2 study; N = 85
Objective To evaluate the pharmacodynamic effects of ISIS 304801 on fasting APOC3 levels
Study Groups This study included two groups: patients receiving active or placebo ISIS 304801 as monotherapy (n = 57) and patients receiving active or placebo ISIS 304801 along with fibrates (n = 28).
Methods The study included patients with severe or uncontrolled hypertriglyceridemia.  Patients were assigned to the ISIS 304801 monotherapy cohort were randomly assigned in a 1:1:1 ratio to receive a dose of 100, 200, or 300 mg; the patients in these dose groups were then randomly assigned in a 3:1 ratio to receive active agent or placebo. Patients assigned to the ISIS 304801–fibrate cohort were randomly assigned in a 1:1 ratio to receive a dose of 200 or 300 mg; patients in these dose groups were then randomly assigned in a 2:1 ratio to receive active agent or placebo. The study drug was administered as a single subcutaneous injection once a week for 13 weeks as monotherapy or as an add-on to fibrate.
Duration February 2012- January 2014
Primary Outcome Measure The percentage change in fasting total APOC3 levels from baseline (level at day 8) to the end of treatment (mean of the levels at day 85 and day 92)
Baseline Characteristics Adult patients with severe or uncontrolled hypertriglyceridemia
Results ISIS 304801 Monotherapy Cohort:

The difference between this group and the placebo group in the percentage change from baseline was a decrease of 79.6% vs. an increase of 4.2% (P<0.001).

ISIS 304801- Fibrate Cohort:

The mean percentage change in APOC3 levels from baseline to the end of treatment was a reduction of 70.9% in the 300-mg dose group, as compared with a reduction of 2.2% in the placebo group (P<0.001).

Adverse Events Common Adverse Events: Injection site reactions
Serious Adverse Events: Serum- sickness like reactions
Percentage that Discontinued due to Adverse Events: 10%
Study Author Conclusions This study found that treatment with ISIS 304801 resulted in dose-dependent lowering of triglyceride levels among patients with a broad range of baseline levels. Selective antisense inhibition of APOC3 synthesis provides evidence for a causal relationship between APOC3 and triglyceride metabolism.   The results of our study support the continued development of ISIS 304801 for the treatment of patients who remain at risk for cardiovascular events along with other conditions because of very high triglyceride levels.

Elevated levels of APOC3 in plasma have been associated with impaired lipolysis and impaired clearance of triglyceride-rich lipoproteins from the circulation. ISIS 304801 (volanesorsen) is an antisense oligonucleotide that is designed to reduce levels of APOC3 messenger RNA4. It was developed by Isis Pharmaceuticals Inc. to treat hypertriglyceridemia and is currently undergoing clinical trials to evaluate its safety and efficacy5.

ISIS 304801’s inhibition of APOC3 synthesis produced dose-dependent reductions of 80% in APOC3 levels and of 71% in triglyceride levels when used for treatment of hypertriglyceridemia. A similar response in APOC3 and triglyceride levels was shown when ISIS 304801 was added to fibrate therapy. Both groups also experienced an increase in HDL cholesterol levels and a decrease in VLDL cholesterol levels. The reduction in APOC3 levels shown in this study after treatment with ISIS 304801 suggests clinical relevance. Limitations of this study include small population size, minimal diversity among subjects of the study and short duration of the study4.

References

  1. The Journal of the American Board of Family Medicine. 2006;19(3):310.
  2. VS Rao, Sussant KD, VJ Rao (2008) Functional Protein Analysis of Hypertriglyceridemia: A Bioinformatic Approach. J Proteomics Bioinform 1: 098-103. doi:4172/jpb.1000015
  3. Zhang, Y. Clare, Taylor, M, Willis, K, Phillips, M. Antisense Inhibition; Methods of Molecular Medicine. Available at: http://link.springer.com/protocol/10.1385/1-59259-854-4:011#. Accessed August 14, 2015.
  4. Gaudet D, Alexander VJ, Baker BF, et al. Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia. N Engl J Med. 2015;373(5):438-447.
  5. Available at: http://apociii.com/. Accessed August 14, 2015.
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