Last month, our team presented data showing apolipoprotein C-III (apoC-III) inhibition with a RNA-targeted antisense therapy called volanesorsen effectively lowered triglycerides in patients with hypertriglyceridemia by 70%. This data was presented today at the National Lipid Association annual meeting in Philadelphia.
Volanesorsen is designed to reduce the production of apoC-III, a protein produced in the liver that plays a central role in the regulation of plasma triglyceride (TG) levels. Elevated TG levels are associated with increased risk of pancreatitis and cardiovascular events. Presented data also showed a statistically significant reduction (p=0.01) in pancreatitis events during treatment with volanesorsen.
Apolipoprotein C-III (apoC-III) is a key regulator of plasma triglyceride (TG) levels. It has been shown that loss of function mutations in apoC-III are associated with lower TG levels and a reduction in cardiovascular risk. Conversely, elevated TG levels are associated with increased risk of both cardiovascular events and pancreatitis. In recent years, there has been an effort to develop strategies to reduce levels of apoC-III in order to reduce elevated triglyceride levels. In 2016, our team led a pivotal study in patients with severe hypertriglyceridemia, defined as triglycerides ≥ 500 mg/dL, with volanesorsen, a second-generation antisense oligonucleotide that inhibits apoC-III synthesis.
The COMPASS Study
The COMPASS clinical trial was a randomized, multi-center, double-blind, placebo-controlled, 26-week, phase 3 study to evaluate the effect of apoC-III reduction with volanesorsen on fasting TG levels in patients with hypertriglyceridemia. The COMPASS study was a supportive study used to further validate findings from a randomized, double-blind, placebo-controlled, Phase 3 study of volanesorsen in the treatment of patients with the familial chylomicronemia syndrome (FCS), known as the APPROACH Study. In the COMPASS trial, we studied patients with fasting TG ≥ 500 mg/dL, (n=113, mean ±SD, TG level 1261 ±955mg/dL). The patients were randomized 2:1 to receive 300 mg volanesorsen subcutaneously (SC) once a week or placebo, respectively for 26 weeks.
We found that that patients treated with volanesorsen experienced significant reductions in triglyceride levels:
- For the primary endpoint of the study, volanesorsen-treated patients (n=75) achieved a statistically significant (p<0.0001) mean reduction in triglycerides of 71.2% from baseline after 13 weeks of treatment, compared with a mean reduction of 0.9% in placebo-treated patients (n=38).
- In a subset of seven patients with FCS and average incoming triglyceride level of 2,280 mg/dL, volanesorsen-treated patients (n=5) achieved a mean reduction in triglycerides of 73% from baseline after 13 weeks of treatment, compared with a mean increase of 70% in placebo-treated patients (n=2).
- In addition, 82% of patients treated with volanesorsen, including three of the FCS patients, achieved triglyceride levels less than 500 mg/dl after 13 weeks of treatment, compared to 14% of placebo-treated patients (p<0.0001).
Treatment with volanesorsen was also found to correlate with significantly reduced pancreatitis events (P = .036). No events occurred in the volanesorsen group during the study period vs. five events in the placebo group. Three months after the last dose, one patient assigned volanesorsen experienced a pancreatitis event.
The most common adverse event was injection site reactions, occurring in 23.5% of volanesorsen injections. There were no serious platelet events in the study. There was one potentially related serious adverse event reported as serum sickness that occurred two weeks after the last study dose.
Targeting Improvements in Standard of Care
Unfortunately, we do not currently have many treatment options for patients with hypertriglyceridemia. According to guidelines established by the Endocrine Society, initial treatment of mild to moderate hypertriglyceridemia should include dietary counseling and weight loss in patients who are overweight or obese. For patients with severe to very severe hypertriglyceridemia, reduced intake of dietary fat and simple carbohydrates is recommended, in combination with drug treatment such as fibrates, niacin, omega-3 fatty acids or statins, alone or in combination. However, these treatment options are often unable to normalize triglyceride levels in patients or to even bring them below the threshold level for pancreatitis, which ranges according to guidelines between 500-880 mg/dL.
While encouraging findings from the COMPASS study show that robust lipid lowering was achieved in patients with severe hypertriglyceridemia who were treated with volanesorsen, the findings related to patients with FCS specifically may be of special interest.
FCS is a rare, genetic disease characterized by the build-up of chylomicrons the largest lipoprotein particle that transports dietary fat and cholesterol.1-3 While normally the enzyme lipoprotein lipase (LPL) breaks down chylomicrons, patients with FCS do not have functioning LPL resulting in circulating triglyceride levels in the thousands (mg/dL) or more than 10 times the upper limit of normal. FCS patients have a significant risk of morbidity and mortality, including recurrent episodes of acute pancreatitis, which can be fatal.
Current TG-lowering drugs work mainly through the LPL pathway, thus being largely ineffective in patients with FCS. The results of the COMPASS study provide strong additional support for therapeutic strategies decreasing triglycerides levels by reducing apoC-III concentrations in patients with severe hypertriglyceridemia including the very difficult to treat FCS patients.