BOSTON, MA and LONDON, UK — Novel "antisense" drugs may be effective in targeting different apolipoproteins in patients with dyslipidemia, suggest two early studies.
The first report, published in the July 30, 2015 issue of the New England Journal of Medicine, described a phase 2 randomized trial assessing the apolipoprotein C-III (apoC-3) inhibitor known as ISIS 304801. Among the participants who were previously untreated and had triglyceride levels between 350 and 2000 mg/dL, those who received the active drug once weekly as monotherapy had up to an 80% mean reduction in plasma apoC-3 levels after 13 weeks and a 71% reduction in triglycerides vs those receiving placebo[1].
Analysis of a second cohort of patients with triglyceride levels between 225 and 2000 mg/dL, who were already taking stable fibrate therapy, also showed that those who received ISIS 304801 had significantly lower apoC-3 and triglyceride levels vs the placebo group.
These reductions "could have clinical relevance," according to Dr Daniel Gaudet (University of Montreal, Quebec) and colleagues. "Increased apoC-3 levels are an independent risk factor for coronary heart disease and are implicated in atherogenesis."
The second study, published online July 22, 2015 in the Lancet, examined the effect of the apolipoprotein A–inhibiting drug known as ISIS-apo(a)Rx in participants with lipoprotein(a) levels of at least 100 mg/L[2]. In single-dose analysis, those receiving just one subcutaneous injection of the active drug in doses between 50 and 400 mg did not show significant decreases in Lp(a) 30 days later compared with those who received matching placebo. However, multidose analysis showed those who received six injections of the active drug (600–1800 mg total) over a 4-week period had reductions in levels that ranged from 40% to 80%.
The investigators, led by Dr Sotirios Tsimikas (University of California, San Diego), note that there are currently "no effective therapies" available for lowering Lp(a) levels.
ApoC-3 and Triglycerides
In the Canadian study, the investigators sought to examine the inhibition of apoC-3, "a key regulator of plasma triglyceride levels." ISIS 304801 is a second-generation antisense inhibitor of apoC-3.
The monotherapy cohort analysis included 57 patients between the ages of 28 and 81 years with severe or uncontrollable hypertriglyceridemia. A total of 41 of these participants were randomly assigned to receive the 304801 drug and 16 were assigned to placebo. Together, the mean triglyceride level at baseline was 581 mg/dL and the mean body-mass index (BMI) "indicated borderline obesity," report the researchers.
At 13-week follow-up, there was a 40% mean reduction in apoC-3 levels from baseline in the group that received a 100-mg dose of ISIS 304801, a 63.8% reduction in those receiving a 200-mg dose, and a 79.6% reduction in those receiving a 300-mg dose. In contrast, the placebo group had a 4.2% mean increase in apoC-3 levels (difference between placebo and 300-mg drug group, P<0.001).
There was also a mean reduction of 70.9% in triglyceride levels in the 300-mg group vs a 20.1% increase in the placebo group (P<0.001) and a significant increase in HDL-cholesterol concentrations (45.7% vs 0.7%, respectively, P<0.001).
A second cohort (mean triglyceride level of 376 mg/dL) included 20 participants who received the active drug plus fibrates and eight who received placebo plus fibrates.
ApoC-3 levels decreased by a mean of 60.2% and 70.9% in the groups receiving fibrates plus 200 mg and 300 mg of the active drug, respectively. The placebo/fibrates group showed a 2.2% increase in levels (vs the 300-mg group, P<0.001).
"The results of our study support the continued development of ISIS 304801 for the treatment of patients who remain at risk for [CV] events and pancreatitis because of very high triglyceride levels," write the investigators.
"Potent, Dose-Dependent Reductions"
In the second study, the investigators enrolled 47 participants (age 18–65 years) with high levels of Lp(a) between February and July 2013 at a research institute in Middlesex, UK. Of these, 16 were included in the single-dose analysis and randomly assigned to receive ISIS-apo(a)Rx injections of either 50, 100, 200, or 400 mg (n=3 in each of the four groups) or a placebo injection (n=4). At 30-day follow-up, there were no significant differences between any of the active treatment groups vs the placebo group.
Further analysis was conducted in 31 participants who received six total injections over 4 weeks. Of these, eight were randomly assigned to 100-mg doses of the active drug, nine to 200 mg, eight to 300 mg, and six to placebo.
There was a significant reduction in Lp(a) of 39.6% in the 100-mg group vs placebo (P=0.005), as well as significant reductions of 59% and 77.8% in the 200- and 300 mg-groups, respectively (P=0.001 for both).
"Administration of ISIS-apo(a)Rx in this study resulted in potent, dose-dependent, selective reductions of plasma Lp(a)," write the investigators. "These results provide the basis for future clinical trials to test the hypothesis that lowering [these] concentrations will reduce cardiovascular disease and calcific aortic stenosis."
Exciting . . . but Questions Remain
"Following an era in which Lp(a) was merely a potent but nonmodifiable cardiovascular risk factor, the advent of a selective . . . lowering strategy is very exciting," write Drs Erik S Stroes and Fleur M van der Valk (Academic Medical Center, Amsterdam, the Netherlands) in an editorial accompanying the Lancet study[3].
"While waiting for further data on apo-A antisense, now would be the time to revisit the existing consensus statements by the European Atherosclerosis Society and the National Lipid Association advising active measurement . . . in patients with intermediate or high risk of [CV] disease, " they add.
The editorialists note that because high Lp(a) concentrations are estimated to affect 20% of individuals throughout the world, "it is tempting to speculate that in the near future raised Lp(a) will not only be measured but actually treated."
Still, they note that study limitations include that the participants' baseline plasma levels were only between 78.4 and 152.3 nmol/L. So whether the drug can be effective at lowering levels in those considered to be in the atherogenic range of 125 to 500 nmol/L "remains to be seen."
Both studies were funded by Isis Pharmaceuticals. Gaudet reports receiving other support from Isis during the study, as well as other support from Cerenis and AstraZeneca and personal fees from Isis, Novartis, Sanofi, Aegerion, Catabasis, Regeneron/Amgen, and Uniqure. Tsimikas reports being a coinventor for and receiving royalties from UCSD-owned patents "for oxidation-specific antibodies," having a coappointment at Isis Pharmaceuticals, and having been a consultant to Pfizer, Genzyme, and Sanofi. Disclosures for the coauthors are listed in the articles. Stroes reports receiving grants from Amgen, Sanofi, Novartis, and Merck. van der Valk reports no relevant financial relationships.
Heartwire from Medscape © 2015 Medscape, LLC
Cite this: Novel Antisense Inhibitors May Lower Triglyceride, Lipoprotein(a) Levels - Medscape - Jul 31, 2015.
Comments