Presentation Number: 1190-529
An Antisense Inhibitor of Apolipoprotein C-III Lowers Fasting Plasma Apolipoprotein C-III and Triglyceride Concentrations in Healthy Volunteers
Presentation Time: Sunday, Mar 25, 2012, 9:30 AM -10:30 AM
Topic: 9. Prevention: Clinical
Author Block: Vickie Alexander, Trish Novak, Nicholas Viney, John Su, Jennifer Burkey, Walter Singleton, Richard Geary, Isis Pharmaceuticals, Inc, Carlsbad, CA, USA
Keywords: Cardiovascular disease, Cardiovascular risk reduction, Lipid‐lowering therapy
Background: Apolipoprotein C-III (apoC-III) plays a pivotal role in regulating plasma triglyceride (TG) levels and is recognized as a CV risk factor. ISIS-ApoCIIIRx selectively inhibits apoC-III protein synthesis in the liver. This study assesses safety, tolerability, pharmacokinetics and pharmacodynamics of ISIS-ApoCIIIRx in healthy volunteers.
Methods: In this double-blind, single and multiple ascending-dose (MAD) study, healthy subjects, 18 to 55 years, were randomly assigned in a 3:1 ratio to receive ISIS-ApoCIIIRx or placebo (normal saline) administered as single or multiple subcutaneous (SC) injections at 50, 100, 200, and 400 mg (n=4/cohort). MAD cohort subjects received 6 doses over 4-weeks (a loading regimen of 3 doses the first week followed by once weekly dosing for 3 weeks).
Results: SC administration of all doses of ISIS-apoCIIIRx was generally safe and well tolerated. There were no clinically meaningful changes of liver tests or ALT elevations, and no serious adverse events. Pharmacodynamic results showed dose-dependent sustained reductions in total apoC-III and TG levels. Median percent change from baseline values in the 50, 100, 200 and 400 mg multiple-dose groups showed reductions of total apoC-III of 20, 17, 71, and 78%, and of TG of 20, 25, 43, and 44%, respectively, 1 week after the last dose. Reductions were sustained for at least 4 weeks after the last dose in the higher dose cohorts, consistent with the drug’s long terminal elimination half-life. In addition, LDL-C values did not change while HDL-C values tended to increase in a dose-dependent manner. Pharmacokinetic results showed dose dependent exposure with time to maximum plasma concentrations between 2 and 4 hours and terminal elimination half life of about 2 to 4 weeks.
Conclusions: This first in man study demonstrates potent dose dependent, selective reduction of apoC-III and TG, two risk factors for CV disease. Based on the encouraging activity and tolerability seen in this study, phase 2 trials in patients with high TG are planned, both as a single agent and in combination. A selective inhibitor of apoC-III that can be used safely in combination with other agents could be of potential value in the treatment of CV disease.
Presentation Number: 1202-221
Effect of Mipomersen on Lipoprotein(a) in Patients with Hypercholesterolemia Across Four Phase III Studies
Presentation Time: Monday, Mar 26, 2012, 11:00 AM -12:00 PM
Topic: 2. Chronic CAD/Stable Ischemic Heart Disease: Clinical
Author Block: Sotirios Tsimikas, Joseph Witztum, Alberico Catapano, University of California San Diego, La Jolla, CA, USA
Keywords: Lipoprotein(a), Therapy, Hypercholesterolemia
Lipoprotein(a) [Lp(a)] is an independent, causal, genetic risk factor for cardiovascular disease (CVD). Elevated Lp(a) levels confer additional CVD risk to that predicted by LDL-C levels alone. Patients with Familial Hypercholesterolemia (FH) generally have a 2-fold increase in Lp(a) levels compared to non-FH patients. Current pharmacological lipid lowering therapies are ineffective in optimally treating elevated Lp(a) levels.
We evaluated the effect of mipomersen, an antisense apoB synthesis inhibitor, on Lp(a) levels in 4 Phase III studies in patients with FH or severe hypercholesterolemia at risk for CVD already receiving maximally tolerated lipid lowering therapy. Patients were randomized 2:1 to weekly subcutaneous injections of mipomersen 200 mg or placebo for 26 weeks. We present data in a subset of patients with a baseline Lp(a) >30 mg/dL, the threshold at which Lp(a) atherogenicity increases significantly.
At baseline, 216 of the 391 randomized patients in the four studies had Lp(a) levels >30 mg/dL; 152 of these were treated with mipomersen. After 26 weeks of mipomersen treatment, the fraction of patients with baseline Lp(a) levels > 30 mg/dL that achieved Lp(a) levels ≤ 30 mg/dL ranged from 10 to 32% per study, with the greatest fractions in the homozygous FH (32%) and severe heterozygous FH (29%) studies. The median Lp(a) in mipomersen-treated patients was reduced from a range of 61 to 93 mg/dL across studies at baseline to 39.5 to 81 mg/dL after treatment. Significant reductions in mean apo B (26-36%) and LDL-C (24-35%) were also noted. Mipomersen treatment was associated with a safety profile consistent with that in earlier clinical trials. The most commonly reported adverse events were injection site reactions and flu-like symptoms.
Mipomersen is the first pharmacological therapy to consistently and effectively reduce Lp(a) levels in patients with FH or severe hypercholesterolemia and high CVD risk. Future studies need to confirm the role of Lp(a) as a modifiable risk factor in FH and CVD.