Physicians' Academy for Cardiovascular Education

Antisense ANGPTL3 is able to reduce ANGPTL3 and various lipid levels in phase I study

News - Nov. 15, 2016

Ionis-angptl3-lRx, An Antisense Inhibitor To Angiopoietin-like Protein 3 [angptl3] Reduces Plasma Angptl3 And Lipids In Healthy Volunteers With Elevated Triglycerides

Presented on AHA Scientific Sessions 2016 by: Teresa Brandt, IONIS PHARMACEUTICALS, Carlsbad, CA
Antisense therapeutic IONIS-ANGPTL3Rx­ was able to substantially reduce fasting plasma ANGPTL3 levels as well as various lipid levels in a phase I setting.
Genetic variants that result in loss-of-function of angiopoietin-like 3 (ANGPTL3) have been linked to familial combined hypolipidemia. ANGPTL3 encodes for a protein that influences the lipid metabolism by several mechanisms, including very low density lipoproteins (VLDL) and chylomicron secretion, lipolysis and lipoprotein lipase activity. In a phase I trial, it has been demonstrated that administration with a second-generation antisense oligonucleotide (ASO) targeting ANGPTL3 (IONIS-ANGPTL3Rx­) for a duration of 6 weeks, resulted in a dose-dependent reduction of plasma ANGPTL3, triglycerides (TG), and total cholesterol (TC) in healthy individuals.
During the AHA 2016, a consecutive study was presented, in which the ANGPTL3-suppressing effect of a hepatocyte-specific IONIS-ANGPTL3Rx­ (conjugated to GalNac) was investigated in healthy individuals with elevated TG levels.
In this study, healthy individuals between 18 and 65 years of age, a BMI below 35 kg/m2, TG levels above 150 mg/dL and LDL-c above 70 mg/dL were assigned to the single ascending dose cohort (n=12) or multiple ascending dose cohort (MAD, n=32). Concerning the single dose cohort, 4 individuals were treated per dose (3:1 for active:placebo) of 20, 40 or 80 mg. For the MAD cohort, 8 individuals were treated per dose of 10, 20, 40 or 60 mg that were 6 times once-weekly administrated (6:2 for active:placebo).
The results showed that a single dose of 80 mg IONIS-ANGPTL3Rx­ immediately and dramatically dropped down fasting plasma ANGPTL3 levels to almost -70% at day 8, which during 90 days returned to approximately a 30% reduction. Also TG and VLDL-c levels were more than halve reduced at day 8 and 15, but in contrast to ANGPTL3 levels, not on day 3. TC, non-HDL-c and LDL-c were modestly reduced at these days, whereas HDL-c was slightly reduced at day 15 only.
Results from the MAD cohort showed a dose-dependent reduction of plasma ANGPLT3 levels, which were almost comparable for the 40 mg and 60 mg dose. These highest doses reached a maximum reduction of 83%. Furthermore, the maximal reductions for TC, non-HDL-c, LDL-c and HDL-c were 36%, 40%, 35% and 25%, respectively, which were all achieved at day 37 using the 60 mg dose. In contrast, maximal TG, VLDL-c and apoC-III reductions were achieved with the 40 mg dose and were much higher; these corresponded to reductions of 66%, 61% and 68%, respectively.
In addition, no safety concerns were identified; local injection side adverse events occurred in only one patient, no serious adverse events, no study discontinuations due to adverse events and no flu-like symptoms or platelet reductions.
Therefore, IONIS-ANGPTL3Rx­ seems a promising candidate for patients with poorly controlled LDL-c and elevated TGs and possibly for patients with non-alcoholic steatohepatitis (NASH).
- Our reporting is based on the information provided during the AHA congress