Final Results on Lipoprotein(a)-Lowering Drug Published

Patrice Wendling

January 02, 2020

A phase 2 trial showing that the novel antisense agent AKCEA-APO(a)-LRx dramatically lowers lipoprotein(a) levels in patients with elevated Lp(a) and established cardiovascular disease (CVD) has been published online in the New England Journal of Medicine.

As previously reported, positive topline results were released in September 2018, followed by a formal presentation at the American Heart Association Scientific Sessions 2018.

In the 286-patient dose-ranging study, which was funded by Akcea Therapeutics, subcutaneous injections of AKCEA-APO(a)-LRx resulted in dose-dependent reductions in Lp(a) averaging 35% at a dose of 20 mg every 4 weeks, 56% at 40 mg every 4 weeks, 58% at 20 mg every 2 weeks, 72% at 60 mg every 4 weeks, and 80% at 20 mg every week, compared with 6% for the pooled placebo group.

At the highest cumulative dose, equivalent to 80 mg monthly, 98% of participants achieved an Lp(a) < 50 mg/dL — a target supported by European and US guidelines.

A phase 3 cardiovascular outcomes trial, called Lp(a)HORIZON, is just starting at the 80 mg/month dose, lead study author Sotirios Tsimikas, MD, vice president of clinical development at Ionis Pharmaceuticals and professor of medicine at the University of California, San Diego, noted in an email exchange.

"I get very many emails of investigators wanting to be in the trial, but I believe it is now overprescribed," he told | Medscape Cardiology. "I get a huge number of emails from patients that want to be in the trial. I think there will be very rapid recruitment based on my gestalt of the queries."

The pivotal phase 3 study is being sponsored by Novartis, which recently exercised its option to license AKCEA-APO(a)-LRx from Akcea Therapeutics/Ionis Pharmaceuticals, which codeveloped the agent, previously called IONIS-APO(a)-LRx

Currently, there are no approved therapies specifically targeting Lp(a), an independent genetic risk factor for cardiovascular disease. However, emerging evidence is rekindling interest in the lipoprotein particle.

A recent analysis from the FOURIER trial showed that higher baseline Lp(a) levels were associated with greater benefit in terms of CV risk reduction from the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab (Repatha, Amgen) in patients with CVD and elevated low-density lipoprotein (LDL) cholesterol on optimal statin therapy.

A large patient-level meta-analysis, coauthored by Tsimikas, also showed an independent relationship between elevated Lp(a) levels and CV risk in statin-treated patients with established CVD.

"The idea of Lp(a) as an unaddressed risk has caught on (you can see from my Twitter activity) and there is now lots of interest," Tsimikas said. "And it will only grow exponentially with Lp(a) testing now making it to most guidelines, including EAS/ESC, recommending everyone get Lp(a) checked at least once in their lifetime."

Tsimikas is a member of the scientific advisory board for Akcea and has received personal fees from Ionis Pharmaceuticals, Boston Heart Diagnostics, and Sanofi.

In the phase 2 study, reductions were observed in LDL cholesterol and apolipoprotein B in patients receiving AKCEA-APO(a)-LRx, beyond those achieved with aggressive background lipid-lowering therapy. 

There were no significant differences between any AKCEA-APO(a)-LRx dose and placebo in platelet counts, liver and renal measures, or influenza-like symptoms. The most frequent adverse events leading to discontinuation of AKCEA-APO(a)-LRx were myalgia, arthralgia, and post-injection malaise.

The phase 3 double-blind Lp(a)HORIZON trial will enroll 7680 participants with established CVD and elevated Lp(a) and test the superiority of a single 80-mg monthly injection against placebo to reduce the risk of expanded MACE (CV death, MI, stroke, and urgent coronary revascularization requiring hospitalization) in patients with an Lp(a) ≥ 70 mg/dL and those with an Lp(a) ≥ 90 mg/dL. The study is scheduled to be completed in 2024.

N Engl J Med. Published online January 1, 2020. Abstract

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