Date: 2014-03-31
Type of information: Results
phase: 2
Announcement: results
Company: Isis Pharmaceuticals (USA - CA)
Product: volanesorsen (ISIS-APOCIIIRx)
Action
mechanism: antisense oligonucleotide. ISIS-APOCIIIRx is an antisense drug intended to treat patients with severely high triglycerides either as a single agent or in combination with other triglyceride-lowering agents. ISIS-APOCIIIRx targets apoC-III, a protein produced in the liver that plays a central role in the regulation of serum triglycerides. Humans who do not produce apoC-III have lower levels of triglycerides and lower instances of cardiovascular disease. Humans with elevated levels of apoC-III have high triglycerides associated with multiple metabolic abnormalities, such as insulin resistance and/or metabolic syndrome. In addition, the prevalence of type 2 diabetes is increased in patients with elevated triglycerides.
Disease: patients with high to severely high triglycerides on stable doses of fibrates
Therapeutic area: Cardiovascular diseases - Metabolic diseases
Country:
Trial
details: The Phase 2 study of ISIS-APOCIIIRx was a double-blind, randomized, placebo-controlled 13 week study designed to assess the safety and activity of 200 mg and 300 mg doses of ISIS-APOCIIIRx.
Latest
news: * On March 31, 2014, Isis Pharmaceuticals has announced the final results from its Phase 2 study of ISIS-APOCIIIRx in patients with high to severely high triglycerides on stable doses of fibrates. In this study, patients treated with ISIS-APOCIIIRx achieved average reductions of up to 71 percent in apolipoprotein C-III (apoC-III) and up to 64 percent in triglycerides, and average increases of up to 52 percent in high-density lipoprotein cholesterol (HDL-C), the 'good' cholesterol. While the starting average triglyceride level in the 300 mg group was 384 mg/dL, 70% of these patients reduced their triglyceride level to below the normal level of 150 mg/dL. In addition, lipoprotein particle analysis showed significant dose-dependent reductions in the number of very low-density lipoprotein (VLDL) particles and significant increases in the number of HDL particles. These new data for ISIS-APOCIIIRx were presented by Dr. Vickie Alexander at the American College of Cardiology meeting in Washington DC. The data reported are the final data analysis (including treatment and follow up period through day 176) in patients with high to severely high triglyceride levels on stable doses of fibrates. Isis reported an interim analysis of these data in July 2013. Consistent with the interim analysis, ISIS-APOCIIIRx produced statistically significant mean percent reductions from baseline in triglycerides and apoC-III and apoC-III-associated VLDL in both dose cohorts. Furthermore, patients treated with ISIS-APOCIIIRx demonstrated a rapid, prolonged and statistically significant mean percent increase from baseline in HDL-cholesterol in both dose cohorts. The effects of ISIS-APOCIIIRx observed on these lipid parameters were sustained for at least six weeks after the last dose and in addition to those achieved with each patient's existing therapeutic regimen of fibrates. Placebo + Fibrate ISIS-APOCIIIRx 200 mg + Fibrate (n=8) ISIS-APOCIIIRx 300 mg + Fibrate (n=10) Triglycerides [% patients achieving triglyceride level -8% [0%] -51% (p=0.008) [63%] -64% (p=0.002) [70%] In addition to measuring changes in lipoprotein cholesterol levels in the blood, changes in lipoprotein particle numbers were evaluated in these patients. In this study, patients treated with ISIS-APOCIIIRx demonstrated dose-dependent reductions in atherogenic particle numbers and increases in HDL-C particle numbers compared to placebo. These results are consistent with the observed changes in lipoprotein cholesterol levels in the blood and provide further evidence of enhanced clearance of triglycerides associated with reduction of apoC-III. In this study 28 patients received either 200 mg or 300 mg dose of ISIS-APOCIIIRx or placebo via weekly subcutaneous injections. All patients were on stable doses of fibrates with average baseline levels of fasting triglycerides between 282 and 457 mg/dL. The three groups of patients were reasonably well balanced in baseline characteristics. In this study, ISIS-APOCIIIRx was found to be generally safe and well tolerated. The most common adverse event was injection site reactions, which were infrequent and consisted of mild erythema that typically resolved within one to two days. In this study, there were no flu-like symptoms, no elevations of liver enzymes greater than three times upper limit of normal, no abnormalities in renal function and no clinically meaningful changes in other laboratory values. ApoC-III -2% -60% (p<0.001) -71% (p<0.001) ApoC-III VLDL +8% -66% (p<0.001) -77% (p<0.001) HDL-C +6% +51% (p=0.02) +52% (p=0.008) P value = vs. placebo + fibrate
