Volanesorsen, an experimental drug, substantially reduces triglycerides in patients with a range of high baseline levels, according to a small, placebo-controlled study published in the July 30, 2015, issue of the New England Journal of Medicine. The antisense agent, which blocks the synthesis of apolipoprotein C-III (APOC3), showed dose-dependent efficacy both alone and in combination with fibrate therapy. 

Previous studies have linked genetic variants that result in attenuation of APOC3 to reduced risk of cardiovascular disease, say John J.P. Kastelein, MD, PhD, of Academic Medical Center (Amsterdam, the Netherlands), and colleagues. “However, whether targeted reduction of APOC3 will confer such a benefit in patients at high risk for cardiovascular disease, including patients with type 2 diabetes, remains to be determined.” 

Volanesorsen (formerly designated ISIS 304801; Isis Pharmaceuticals; Carlsbad, CA) binds to messenger RNA for APOC3, leading to its degradation and, in turn, inhibition of APOC3 synthesis. APOC3 is “a key regulator of lipoprotein metabolism and plays a pivotal role in regulating plasma triglyceride levels,” the authors explain.

Various Doses Pitted Against Placebo

Investigators of the 7-center trial enrolled 57 untreated patients with triglyceride levels between 350 mg/dL and 2,000 mg/dL. Patients were randomized to 1 of 3 arms testing 100 mg, 200 mg, or 300 mg of volanesorsen. Then, within each of the 3 dose groups, patients were randomly assigned to receive the active agent (n = 41) or placebo (n = 16).

Similarly, 28 patients already on fibrates who had triglyceride levels between 225 mg/dL and 2,000 mg/dL were randomized to 200 mg or 300 mg of volanesorsen before being randomly assigned to the active agent (n = 20) or placebo (n = 8).

The study drug was given as a single subcutaneous injection once a week for 13 weeks.

Mean age ranged from 48.6 to 58.9 years; 97% of patients were white and 71% were men. Mean body mass index indicated borderline obesity. More than one-third (36%) of patients were on a stable statin regimen. Mean baseline APOC3 levels were elevated in the volanesorsen monotherapy (22.8 mg/dL) and volanesorsen-fibrate (17.6 mg/dL) groups compared with normal values of 10-15 mg/dL. The corresponding mean baseline triglyceride levels were 581 mg/dL and 376 mg/dL. In addition, 24% of patients carried loss-of-function mutations in the gene encoding lipoprotein lipase.

Across-the-Board Decreases

Volanesorsen resulted in substantial dose-dependent decreases in APOC3 (primary endpoint) and triglycerides from baseline to the end of treatment in both treatment groups, while placebo slightly increased these lipid parameters. Meanwhile, HDL levels increased in a dose-dependent manner (table 1).

Table 1. Mean Percent Change in Lipid Parameters: End of Treatment vs Baseline

In addition, there were dose-dependent reductions in very-low-density lipoprotein (VLDL) cholesterol and VLDL APOC3 as well as substantial decreases in VLDL apolipoprotein B (apoB; a marker of VLDL particle number) with the 300-mg dose in both treatment groups. 

The large decreases in triglyceride levels were accompanied by dose-dependent increases in LDL cholesterol, LDL apoB concentration, and LDL particle size with volanesorsen monotherapy. However, non-HDL cholesterol and total apoB levels remained relatively unchanged and similar to the placebo group. 

Local cutaneous reactions at the injection site were seen in a mean of 13% of volanesorsen injections in the monotherapy cohort and 15% of injections in the combined-therapy cohort. However, these reactions were typically mild and resolved spontaneously. Ten percent of volanesorsen-treated patients discontinued treatment due to adverse events; there was no apparent connection with dosage.

There was no significant effect of volanesorsen treatment on renal or hepatic function and no evidence of drug-drug interactions in patients receiving concomitant medications, such as statins and glucose-lowering drugs.  

Potential for Clinical Impact

The observed reduction in APOC3 “could have clinical relevance,” the authors say, noting that “increased APOC3 levels are an independent risk factor for coronary heart disease and are implicated in atherogenesis.” Furthermore, the fact that volansorsen treatment consistently resulted in reductions in total plasma triglyceride levels supports a direct relationship between the apolipoprotein and circulating triglyceride, they add.

A recent analysis showed that lowering triglycerides in patients with baseline levels above 500 mg/dL was associated with a reduction of pancreatitis episodes and cardiovascular events, with the greatest benefit seen in patients whose levels dropped below 200 mg/dL, the investigators report. In the current study, approximately 80% of patients who received the higher doses of volanesorsen had achieved those levels by 13 weeks, they note.

The basis for the dose-dependent increase in LDL cholesterol in the monotherapy group is likely multifactorial, the investigators say, but the rise may potentially be offset by treatment with statins or fibrates, since LDL rises were less pronounced in the combination group. 

Despite its small size and other limitations, the study provides results that “support the continued development of [volanesorsen] for the treatment of patients who remain at risk for cardiovascular events and pancreatitis because of very high triglyceride levels,” the researchers conclude.

Source: 
Gaudet D, Alexander VJ, Baker BF, et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N Engl J Med. 2015;373:438-447.

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