Novel Antisense Inhibitors Cut Lp(a) Levels in Small Phase 2 Studies

Larry Hand

September 29, 2016

SAN DIEGO, CA — Two novel antisense oligonucleotide therapies in development significantly reduced levels of lipoprotein(a) in individuals with elevated Lp(a) in two clinical trials, according to a new report[1].

No approved specific therapy exists for Lp(a), a modified LDL particle that is recognized as a major genetic risk factor for cardiovascular disease and calcific aortic-valve stenosis, researchers say.

"Lp(a) has been an underappreciated risk factor for many years, and cardiologists haven't measured the levels because often they say, 'If I can't do anything about it, why should I measure it?' " Dr Sotirios Tsimikas (University of California, San Diego) told heartwire from Medscape.

"What we have shown in this study is that you can actually do something about it, and you can do it much better than what's been available previously. With two drugs—and the main one is Ionis-APO(a)-Lrx, which is an optimized molecule—we can get Lp(a) levels to normal in just about everybody who wants to because it's so potent," he said.

Dr Mark W Feinberg (Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts) writes in an accompanying comment[2], "The therapeutic opportunity to target Lp(a) calls for rigorous standardization of these assays and consideration of potential cutoffs, as we excitedly await advanced-stage clinical trials that will finally examine whether Lp(a) lowering reduces cardiovascular events and potentially aortic stenosis—and that's no small task."

Tsimikas and colleagues conducted two randomized, double-blind, placebo-controlled clinical trials to evaluate two antisense oligonucleotides, Ionis-APO(a)rx and Ionis-APO(a)-Lrx, in reducing Lp(a) levels in patients with highly elevated Lp(a) levels. The drugs are designed to reduce Lp(a) by targeting hepatocytes.

The results were published online September 21, 2016 in the Lancet. Most of the authors are listed as employees of the sponsor, Ionis Pharmaceuticals.

In a phase 2 trial conducted between June 25, 2014 and November 18, 2015, they randomized 64 participants to receive either Ionis-APO(a)rx (n=35) or placebo (n=29). Participants received either escalating subcutaneous doses of the study drug (100 mg, 200 mg, 300 mg) once a week for 4 weeks each or injections of saline placebo weekly for 12 weeks. At day 85 or 99, participants receiving the study drug experienced Lp(a) reductions ranging from 66.8% for participants whose Lp(a) concentrations were 125 to 437 nmol/L to 71.6% for participants whose Lp(a) concentrations were >438 nmol/L (P<0.0001 vs pooled placebo for both).

In a phase 1–2a trial conducted between April 15, 2015 and January 11, 2016, the researchers evaluated Ionis-APO(a)-Lrx, a ligand-conjugated antisense oligonucleotide.

In a single-ascending-dose phase, they randomized 28 healthy participants (Lp(a) 75 nmol or higher) to receive 10- to 120-mg subcutaneous doses of the study drug on specific study days (1–22) or placebo. In a multiple-ascending-dose phase, they randomized 30 participants to receive either the study drug (10–40 mg) or placebo on specific study days.

While they observed significant reductions in Lp(a) in the single-ascending phase at day 30, the results were more resounding in the multiple-ascending phase, in which mean Lp(a) reductions ranged from 66% in the 10-mg group to 92% in the 40-mg group (P<0.0007) at day 36.

The researchers also saw significant reductions in LDL cholesterol, apolipoprotein B, and oxidized phospholipids in patients receiving study drugs.

The researchers observed no treatment-related adverse events.

"As the clinical development of this drug proceeds, what the cardiologist realizes is two things. The first is that Lp(a) is a risk factor and it probably causes cardiovascular disease and aortic stenosis in a lot of our patients; and second, that there's hope on the horizon that we have an emerging therapy that's able to treat the residual risks in their patients due to high Lp(a) if these drugs prove efficacious in the outcomes trials," Tsimikas told heartwire.

"This is a new technology, and we're really breaking new ground. Lp(a) is not an enzyme, and it has such high levels in the circulation that you can't really use a small molecule or an antibody. You have to direct your treatment to the factory that makes Lp(a). That factory is a hepatocyte," he added.

"That's why it's so successful in Lp(a) lowering. We've developed a new way with antisense technology to target diseases that previously were not targetable by traditional medicines," he said.

Ionis Pharmaceuticals funded the study. Tsimikas reported being coinventor and receiving royalties from patents owned by the University of California, San Diego on oxidation-specific antibodies. Disclosures for the coauthors are listed in the article. Feinberg has no relevant financial relationships.

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