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AHA: Novel Agent Promising for Lowering Lp(a) Levels

— Treatment with AKCEA-APO(a)-LRx better than placebo at multiple doses

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CHICAGO -- An experimental agent seemed to successfully lower lipoprotein(a), an independent, genetic risk factor for atherosclerotic cardiovascular disease and calcific aortic valve stenosis, in patients with established cardiovascular disease (CVD), researchers reported here.

In a phase II, placebo-controlled study, patients with high levels of lipoprotein(a), or Lp(a), treated with AKCEA-APO(a)-LRx had a reduction in Lp(a) in a dose-dependent manner versus, reported Sotirios Tsimikas, MD, of the University of California San Diego.

Virtually all the 45 patients (97.7%) taking the agent at the highest dosing level (20 mg weekly) achieved lower of Lp(a) ≤50 mg/dl versus placebo, Tsimikas said in a presentation at the American Heart Association (AHA) annual meeting.

The agent is a second-generation, N-acetyl-galactosamine-conjugated, antisense oligonucleotide targeted to apolipoprotein(a), the authors explained. In a phase I trial with healthy volunteers with elevated Lp(a) levels, treatment with AKCEA-APO(a)-LRx reduced those levels by up to 92% and showed a sustained duration of effect that may allow flexibility in dose intervals, they added.

Tsimikas said that when levels of Lp(a) are >50 mg/dl, cardiac events occur even when patient are on statins, as the latter do not appear to have an impact on levels of Lp(a).

Tsimikas reported treatment at every dosage level of AKCEA-APO(a)-LRx were significantly better than placebo in reducing Lp(a):

  • 20 mg every 4-weeks dose: 35% reduction in Lp(a) vs 6% in placebo patients (P=0.0032); 25% of patients at <50 mg/dl threshold vs 6.4% of placebo patients (P=0.029)
  • 40 mg every 4-weeks dose: 56%vs 6% (P<0.0001); 62.5% vs 6.4% (P<0.0001)
  • 20 mg every 2-weeks dose: 58% vs 6% (P<0.0001); 64.6% vs 6.4% (P<0.0001)
  • 60 mg every 4-weeks dose: 72% vs 6% (P<0.0001); 80.9% vs 6.4% (P<0.0001)
  • 20 mg every week dose: 80% vs 6% (P<0.0001); 97.7% vs 6.4% (P<0.0001)

Tsimikas and colleagues enrolled patients with a history of established CVD and entry Lp(a) levels of ≥60 mg. They assigned 286 patients in a 5:1 ratio to one of the doses of AKCEA or placebo. All patients were treated for a minimum of 6 months, with some patients for up to 12 months, depending on time of entry into the trial.

The participants were about age 60 and about two-thirds were men. Also, more than 90% were taking antiplatelet therapy, and 90% were on statins, while 50% were taking ezetimibe (Zetia) and 20% were on a PCSK9 inhibitors.

In terms of safety, the most common adverse event was injection site reactions, and these were mostly mild and occurred in a minority of patients, according to a . None of the patients experienced a confirmed platelet level <100,000/mm3. The incidence of platelet levels below normal (140,000/mm3) was comparable between the agent arm (10.5%) and placebo (14.9%) arm.

Finally, about 90% of patients completed treatment, and the rate of treatment discontinuation was comparable between the two groups.

"This study provides a rationale for the initiation of a phase III outcomes study to test the 'Lp(a) hypothesis,' namely that lowering Lp(a) will reduce cardiovascular events," Tsimikas said.

AHA discussant Brian Ference, MD, of Wayne State University School of Medicine in Detroit, said, "The study shows that the antisense oligonucleotide safely and effectively lowered Lp(a)."

He suggested that a phase III trial should use 20 mg every week dosage; that the target study group should be patients with Lp(a) levels of 100 mg/dl; and aim for a reduction of 65% to 75% of the Lp(a) levels, as well as aim for a relative risk reduction of 15% in cardiovascular events. He suggested a treatment time of at least 4 years for the trial.

Disclosures

The trial was supported by Ionis Pharmaceuticals.

Tsimikas disclosed relevant relationships with Ionis, Oxitope, and Boston Heart Diagnostics.

Ference disclosed relevant relationships with Merck, Amgen, Esperion, Novartis, Sanofi, Regeneron, the Medicines Company, Pfizer, and KrKa.

Primary Source

American Heart Association

Tsimikas S, et al "Safety and Efficacy of AKCEA-APO(a)-LRx to Lower Lipoprotein(a) Levels in Patients with Established Cardiovascular Disease: A Phase 2 Dose-Ranging Trial" AHA 2018