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Antisense oligonucleotide associated with substantial reductions in Lp(a) concentrations
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A novel antisense oligonucleotide targeting apolipoprotein(a) was safe and conferred a decline in concentrations of lipoprotein(a), according to findings published in The Lancet.
Researcher Sotirios Tsimikas, MD, told Cardiology Today that there is no approved therapy for reduction of Lp(a), and reducing it may make an impact on the components of CVD risk not currently addressed by available therapies and lifestyle modifications.
“The hypothesis is that [reducing Lp(a)] will reduce the risk for stroke, MI and peripheral artery disease and reduce the need for procedures like CABG and PCI,” he said in an interview. “If you look at the epidemiology data, if you’re born with high Lp(a), a genetic causal risk factor not affected much by diet and current drugs, you are at much higher risk for heart disease and procedures, because the Lp(a) circulating in the blood interferes with normal functioning of arteries. We are in a sense trying to change Mother Nature’s genetics from a high Lp(a) phenotype to someone who would have been born with a low Lp(a), and if we do that, all the risk driven by high Lp(a) should go away.”
Tsimikas and colleagues conducted two randomized, double blind, placebo-controlled trials of two antisense oligonucleotide formulations — IONIS-APO(a)Rx and IONIS APO(a)-LRx (Akcea Therapeutics/Ionis Pharmaceuticals).
“The technology has evolved very quickly, so we ended up having two different molecules and two different trials,” Tsimikas, vice president of clinical development at Ionis Pharmaceuticals and professor of medicine and director of vascular medicine at the University of California – San Diego School of Medicine, La Jolla, said in an interview.
Parent compound
In the phase 2 trial of IONIS-APO(a)Rx, two cohorts of patients, one with 51 patients with Lp(a) 125 nmol/L (50 mg/dL) to 437 nmol/L (175 mg/dL) and one with 13 patients with Lp(a) of at least 438 nmol/L ( 175 mg/dL), were randomly assigned to subcutaneous administration of increasing concentrations of the study drug or placebo once weekly for 12 weeks. Endpoints of interest were mean percentage change in fasting Lp(a) concentration at day 85 or day 99, and safety and tolerability.
In the lower Lp(a)-level cohort of the phase 2 trial, participants assigned the antisense oligonucleotide at day 85 had a mean reduction in Lp(a) of 66.8% (standard deviation, 20.6) compared with those assigned placebo. In the higher Lp(a)-level cohort of the phase 2 trial, participants assigned the antisense oligonucleotide at day 99 had a mean reduction in Lp(a) of 71.6% (standard deviation, 13; P for both groups vs. pooled placebo < .0001).
“That study shows for the first time that in patients with high Lp(a), you can reduce the Lp(a) substantially; some existing therapies lower it by approximately 20%,” Tsimikas told Cardiology Today, noting a concurrent in vitro analysis showed that the antisense oligonucleotide reduced activity of activated monocytes, which are associated with inflammation.
Tsimikas and colleagues reported two MIs in the phase 2 trial, one in the antisense oligonucleotide group and one in the placebo group, neither of which were determined to be related to the therapy, and a 12% rate of injection-site reactions in the treatment group.
Newer compound
In the phase 1/2a first-in-human trial of IONIS APO(a)-LRx, a ligand-conjugated formulation designed to be taken up by hepatocytes to a great degree, healthy volunteers (n = 58) with Lp(a) of at least 75 nmol/L were randomly assigned to a subcutaneous single or multiple dose of the study drug or placebo in an ascending dose. Endpoints of interest were mean percentage change in fasting Lp(a) concentration, safety and tolerability at 30 days in the single-dose phase and 36 days in the multiple-dose phase.
“We have developed a new way to deliver these drugs to the ‘factory’ that makes Lp(a), a hepatocyte in the liver,” Tsimikas said in an interview. “The antisense approach is ideally suited for what we’re doing. The hepatocyte has an asialoglycoprotein receptor, which is very prevalent because the liver is involved in removing old proteins. ... We’ve taken advantage of this natural pathway for proteins to get into calls by attaching N-acetylgalactosamine to the antisense molecule. When it’s injected subcutaneously and goes to the liver, instead of using inefficient pathways for the drug to get into the liver, there is more efficient delivery of the drug to the hepatocyte. An advantage is delivering the same amount of drug to the liver but injecting a 30-fold lower amount. And any time you reduce the dose of a drug, you get fewer side effects.”
According to the researchers, in the phase 1/2a trial, those assigned a single dose of the ligand-conjugated antisense oligonucleotide had reduced Lp(a) concentration at 30 days compared with those assigned a single-dose placebo.
Among those assigned multiple doses of the study drug, those assigned a dose of 10 mg had a mean Lp(a) reduction of 66% (standard deviation, 21.8), those assigned a dose of 20 mg had a mean Lp(a) reduction of 80% (standard deviation, 13.7) and those assigned a dose of 40 mg had a mean Lp(a) reduction of 92% (standard deviation, 6.5) compared with those assigned placebo (P = .0007), the researchers wrote. “Some [participants] even had 99% reductions,” Tsimikas said. “With this amount of efficacy, we can get almost everybody’s Lp(a) level to normal, no matter where they start.”
The researchers reported no injection-site reactions in the therapy groups of the phase 1/2a trial. “This is the first time we’ve seen this with a locally injected antisense drug,” Tsimikas said. “It’s like a quantum leap in tolerability.”
Ionis will proceed with development of IONIS APO(a)-LRx, Tsimikas told Cardiology Today. A phase 2 dose-ranging study in patients with elevated Lp(a) must be performed, and two other studies are planned, one on reduction of CV events and one on reduction of calcific aortic stenosis, he said. – by Erik Swain
Disclosure: The studies were funded by Ionis Pharmaceuticals. Tsimikas is an employee of Ionis Pharmaceuticals and reports receiving royalties from patents owned by the University of California – San Diego for oxidation-specific antibodies for which he was a co-inventor.
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