Dose-Dependent Reduction of Lipoprotein(a) With APO(a)-LRx

The hepatocyte-directed antisense oligonucleotide AKCEA-APO(a)-LRx, APO(a)-LRx was found to lower in a dose-dependent manner lipoprotein(a) levels in patients with elevated lipoprotein(a) levels and established cardiovascular disease, according to a study published in The New England Journal of Medicine.

Elevated levels of lipoprotein(a) are a risk factor for cardiovascular disease and aortic stenosis but at present, there are no approved pharmacologic therapies to reduce these levels. In this randomized double-blind placebo-controlled, dose-ranging trial conducted at 30 sites in 5 countries (Clinicaltrials.gov identifier: NCT03070782), 459 patients aged 18 to 80 years (participants <60 years, 60%; women, >30% were women were enrolled. In this cohort, 286 participants had lipoprotein(a) levels ≥60 mg/dL (150 nmol/L) and established cardiovascular disease. Participants were randomly assigned to receive for 6 to 12 months saline placebo or 1 of the 5 following treatment regimens: subcutaneous injections of APO(a)-LRx at 20, 40, or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week. Lipoprotein(a) levels were measured with an isoform-independent assay. Mean baseline lipoprotein(a) levels in the cohort ranged from 204.5 to 246.6 nmol/L. The primary end point was percent change in lipoprotein(a) levels from baseline to month 6 of exposure to treatment (week 25 for those who received monthly doses and week 27 for those who received more frequent doses).

Treatment with APO(a)-LRx resulted in dose-dependent reductions in lipoprotein(a) levels, with the following mean percent decreases: 35% for patients receiving 20 mg every 4 weeks, 56% for participants receiving 40 mg every 4 weeks, 58% for those administered 20 mg every 2 weeks, 72% for patients in the 60-mg dose every 4 weeks, and 80% for participants administered 20 mg every week, as compared with 6% for participants receiving placebo (P values for the comparison ranged from .003 to <.001). The 2 regimens with a 40-mg monthly dose (40 mg every 4 weeks and 20 mg every 2 weeks) were associated with a comparable reduction in lipoprotein(a) levels. This effect on lipoprotein(a) levels was noted within the first month of treatment, peaked by week 16, and returned to baseline within 16 weeks of the final dose of APO(a)-LRx. No significant between-group differences were observed for influenza-like symptoms, liver and renal measures, or platelet counts. Injection site reactions were the most common adverse events [7% with APO(a)-LRx, and 6% with placebo].

 “In this trial, we found that APO(a)-LRx provided potent reductions in levels of lipoprotein(a) in patients with cardiovascular disease,” concluded the study authors.

Disclosure: This clinical trial was supported by Akcea Therapeutics. Please see the original reference for a full list of authors’ disclosures.

Reference

Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, et al. Lipoprotein(a) reduction in persons with cardiovascular disease [published online January 1, 2020]. N Engl J Med. doi: 10.1056/NEJMoa1905239