In this study, patients treated withISIS-APOCIIIRx experienced reductions of as much as 70 percent in apolipoproteinC-III (apoC-III) and as much as 64 percent in triglycerides. In addition,patients treated with ISIS-APOCIIIRx experienced as much as a 52-percentincrease in high-density lipoprotein cholesterol (HDL-C), the so-called "goodcholesterol," along with as much as a 77-percent reduction inapoC-III-associated very low-density lipoprotein (VLDL) particles.
Isis notes that it is also evaluatingISIS-APOCIIIRx in this Phase II study as a monotherapy in patients withseverely high triglycerides, with plans to report these data at the EuropeanSociety of Cardiology on August 31 in Amsterdam.
"Patients with very high levels oftriglycerides are at significant risk for cardiovascular disease, diabetes,pancreatitis and other complications. For these patients, there are verylimited treatment options. Fibrates have been shown to reduce triglycerides;however, fibrate therapy is not always effective nor widely used by thesepatients," said Dr. Daniel Gaudet of the Department of Medicine at the Universityof Montreal and scientific director of Genome Quebec Biobank Technology Center,in the Isis news release about the study. "The data presented today onISIS-APOCIIIRx are very encouraging because they show that ISIS-APOCIIIRx isadditive to fibrates and are consistent with Isis' previous Phase II data inpatients with moderately elevated triglycerides and type 2 diabetes. In bothstudies, rapid, robust reductions in apoC-III and triglycerides were observed.The positive effect of ISIS-APOCIIIRx on other key lipid parametersdemonstrates the potential for ISIS-APOCIIIRx to provide therapeutic benefit topatients with very high triglycerides."
The study was a double-blind, randomized,placebo-controlled 13-week study designed to assess the safety and activity ofISIS-APOCIIIRx. The portion of the study reported today was conducted inpatients with high to severely elevated triglyceride levels (between 225 and2,000 mg/dL) on stable doses of fibrates.
After 13 weeks of dosing, robust and prolonged,statistically significant mean percent reductions from baseline in apoC-III,triglycerides and VLDL-associated apoC-III particles were observed in both dosecohorts. Furthermore, patients treated with ISIS-APOCIIIRx reportedly demonstrateda rapid, prolonged and statistically significant mean percent increase frombaseline in HDL-C in both dose cohorts with no statistically significantincrease in low-density lipoprotein cholesterol (LDL-C) or non-HDL-C. Theeffects of ISIS-APOCIIIRx observed on these lipid parameters were in additionto those achieved with each patient's existing therapeutic regimen of fibrates.
Study data so far show ISIS-APOCIIIRx to begenerally safe and well tolerated. The most common adverse event was injectionsite reactions, which reportedly were infrequent and consisted of mild erythemathat typically resolved within one to two days. According to Isis, "there wereno flu-like symptoms, no elevations of liver enzymes greater than three timesupper limit of normal, no abnormalities in renal function and no clinicallymeaningful changes in other laboratory values. There was one patient who, fourdays after treatment, experienced a transient episode of a rash, low-gradefever, chills and headache, which resolved completely. This event was reportedby the investigator as related to treatment, and classified as a serumsickness-like reaction. Subsequent detailed investigations demonstrated that itwas not serum sickness."
"We are very encouraged by the two sets ofpositive data we have reported this summer demonstrating that treatment withISIS-APOCIIIRx produced highly statistically significant and clinically meaningfulreductions in apoC-III and triglycerides, and increases in HDL-C in patientswith high triglycerides," said Dr. Richard Geary, senior vice president ofdevelopment at Isis. "In addition, the positive effect of ISIS-APOCIIIRxtreatment on lipid parameters, improvements in glucose control and trendstoward improvements in insulin sensitivity, suggest that ISIS-APOCIIIRx couldhave a broad therapeutic profile in addition to triglyceride lowering forpatients with severely high triglycerides."
ISIS-APOCIIIRx is an antisense drug intended totreat patients with severely high triglycerides either as a single agent or incombination with other triglyceride-lowering agents. ISIS-APOCIIIRx targetsapoC-III, a gene produced in the liver that plays a central role in theregulation of serum triglycerides. Humans who do not produce apoC-III havelower levels of triglycerides and lower instances of cardiovascular disease. Inclinical studies, patients with lower levels of apoC-III and triglyceridesexhibit lower cardiovascular event rates. Humans with elevated levels ofapoC-III have increased dyslipidemia associated with multiple metabolicabnormalities, such as insulin resistance and/or metabolic syndrome. Inaddition, the prevalence of type 2 diabetes is increased in patients withelevated triglycerides.