Antisense oligonucleotide reduces Lp(a) in patients at high residual risk
CHICAGO — An N-acetyl-galactosamine-conjugated antisense oligonucleotide significantly reduced lipoprotein(a), oxidized phospholipid apolipoprotein B, oxidized phospholipid apolipoprotein(a), LDL and ApoB levels in patients with preexisting CVD and a baseline lipoprotein(a) level greater than 60 mg/dL, according to data presented at the American Heart Association Scientific Sessions.
Safety concerns regarding liver function, platelet counts and renal function were not an issue for patients assigned the N-acetyl-galactosamine-conjugated antisense oligonucleotide (AKCEA-APO(a)-LRx, Akcea), according to the presentation.
“We now have a potential therapy for a protein that’s atherogenic and also causes aortic valve disease that’s been very hard to create a drug for,” Sotirios Tsimikas, MD, FACC, FAHA, FSCAI, vice president of global cardiovascular development at Ionis Pharmaceuticals, which is affiliated with Akcea, and professor of medicine and director of vascular medicine at University of California San Diego School of Medicine, told Cardiology Today. “This study suggests that it is highly effective in getting 80% reduction in the Lp(a) levels, but also getting about 98% of patients to a specific goal that’s accepted as least harmful.”
Researchers analyzed data from patients with a history of established CVD and lipoprotein(a) levels greater than 60 mg/dL. Patients were assigned one of five doses (20 mg per month, 40 mg per month, 60 mg per month, 20 mg every 2 weeks and 20 mg per week) of N-acetyl-galactosamine-conjugated antisense oligonucleotide (n = 239; mean age, 60 years; 66% men) or placebo (n = 47; mean age = 60 years; 68% men).
“The average age of these patients is approximately 60 years old, which is lower than what you see in typical cardiovascular outcomes trials, likely reflecting the fact that this is a genetic risk factor that’s present at birth,” Tsimikas said during the presentation.
Patients were treated for a minimum of 6 months for up to 12 months, and follow-up was conducted for 16 weeks after the treatment duration. The primary efficacy endpoint was the percent change in Lp(a) from baseline to 25 weeks for patients who received the treatment per month and 27 weeks for those who received treatment every 2 weeks or weekly.
The mean percent change in Lp(a) from baseline to week 25 through week 27 was the following:
- –6% in the pooled placebo group,
- –35% for the 20 mg per month group (P = .0032),
- –56% for the 40 mg per month group (P < .0001),
- –58% for the 30 mg every 2 weeks group (P < .0001),
- –72% for the 60 mg per month group (P < .0001) and
- –80% for the 20 mg per week group (P < .0001).
The primary efficacy endpoint was not affected by statin use, lipoprotein(a) levels or PCSK9 inhibitors, according to the presentation.
The absolute change in Lp(a) from baseline to week 25 through week 27 was greatest in patients assigned 20 mg per week at –75.1 mg/dL.
The 20 mg per week group had the highest percent of patients who achieved lipoprotein(a) levels less than 50 mg/dL (97.7%; P < .0001), followed by the 60 mg per month group (80.9%; P < .0001), 20 mg every 2 weeks group (64.6%; P < .0001), 40 mg per month group (62.5%; P < .0001) and 20 mg per month group (25%; P = .029) vs. the placebo group.
Compared with patients assigned placebo, patients assigned 20 mg per week had greater decreases in oxidized phospholipid apolipoprotein B (–81.8%; P < .001), oxidized phospholipid apolipoprotein(a) (–61.2%; P < .001), LDL (–20.5%; P < .01) and ApoB (–14.5%; P < .001).
“This really sets the stage for designing a phase 3 outcomes trial where we can actually test the Lp(a) hypothesis, which is if we lower Lp(a) levels, will patients get a clinical benefit,” Tsimikas said in an interview.
“This trial demonstrates that this ASO safely and effectively reduces the lipoprotein(a) concentrations and therefore strongly supports the idea of going forward with a cardiovascular outcomes trial,” Brian A. Ference, MD, MPhil, MSc, FACC, director of research, professor in translational therapeutics and executive director of the Centre for Naturally Randomized Trials at University of Cambridge, said during the discussant portion of the presentation. “However, as we’ve just seen with the CIRT trial, in order to fairly test the Lp(a) hypothesis, it is absolutely critical that Lp(a) be reduced enough to produce a clinically meaningful reduction within a short-term trial. How much Lp(a) must be reduced to produce a clinically meaningful reduction in cardiovascular events remains uncertain.” – by Darlene Dobkowski
Tsimikas S, et al. LBS.02 – Novel Approaches to CV Prevention. Presented at: American Heart Association Scientific Sessions; Nov. 10-12, 2018; Chicago.
Disclosure s : The study was sponsored by Ionis Pharmaceuticals and Akcea Therapeutics. Tsimikas reports he is employed by Ionis Pharmaceuticals, has ownership interest in Oxitope, served on an advisory board for Boston Heart Diagnostics and has patents with University of California San Diego. Ference reports he received research grants from Amgen, Esperion, Merck and Novartis, honoraria from Amgen, Merck, Pfizer, Regeneron, Sanofi and The Medicines Company and has served as a consultant and/or advisory board member for Amgen, Esperion, Merck, Regeneron and Sanofi.