Temporal variability in lipoprotein(a) levels in patients enrolled in the placebo arms of IONIS-APO(a)Rx and IONIS-APO(a)-LRx antisense oligonucleotide clinical trials

Background Lipoprotein(a) [Lp(a)] levels are primarily genetically determined, but their natural variability is not well known. Objective The aim of the study was to evaluate the short-term temporal variability in Lp(a) in 3 placebo groups from the IONIS-APO(a) Rx and IONIS-APO(a)-L Rx trials. Methods The placebo groups comprised 3 studies: Study 1 with 10 subjects with any Lp(a) concentration; Study 2 with 13 subjects with Lp(a) ≥75 nmol/L (∼30 mg/dL); and Study 3 with 29 patients with Lp(a) ≥125 nmol/L (≥∼50 mg/dL). Lp(a) was measured in serial blood samples (range 7–12 samples up to 190 days of follow-up) and analyzed as absolute change and mean percent change from baseline. Outliers were defined as having a > ±25% difference in Lp(a) from baseline at any future time point. Results No significant temporal differences in mean absolute Lp(a) levels were present in any group. However, among individuals, the mean change in absolute Lp(a) levels at any time point ranged from −16.2 to +7.0 nmol/L in Study 1, −15.8 to +9.8 nmol/L in Study 2, and −60.2 to +16.6 nmol/L in Study 3. The mean percent change from baseline ranged from −9.4% to +21.6% for Study 1, −13.1% to 2.8% for Study 2, and −12.1% to +4.9% in Study 3. A total of 21 of 52 subjects (40.4%) were outliers, with 13 (62%) >25% up and 8 (38%) >25% down. Significant variability was also noted in other lipid parameters, but no outliers were noted with serum albumin. Conclusion In subjects randomized to placebo in Lp(a) lowering trials, modest intra-individual temporal variability of mean Lp(a) levels was present. Significant number of subjects had > ±25% variation in Lp(a) in at least 1 time point. Although Lp(a) levels are primarily genetically determined, further study is required to define additional factors mediating short-term variability.