RNA therapeutics
Antisense oligonucleotide cuts Lp(a) by 69%, but does not affect fibrinolysis, a placebo-controlled trial of 17 patients (J Lipid Res 2019)
Original title: Potent reduction of plasma lipoprotein (a) with an antisense oligonucleotide in human subjects does not affect ex vivo fibrinolysis
Patients with elevated Lp(a) were randomised to the antisense oligonucleotide IONIS-APO(a)Rx (n=7) or placebo (n=10) to test whether lowering Lp(a) affects ex vivo fibrinolysis. Baseline Lp(a) averaged 477.3±55.9 nmol/L in the treatment group and 362.1±89.9 nmol/L in placebo. At peak drug effect (day 85-99), Lp(a) fell by 69.3±12.2% with IONIS-APO(a)Rx versus 5.4±6.9% with placebo (P<0.0010), and remained reduced by 15.6±8.9% versus 3.2±12.2% at day 190, three months after stopping treatment (P=0.003). Clot lysis times and coagulation and fibrinolysis biomarkers showed no significant differences between groups at any time point, and exogenous Lp(a) up to 200 nmol/L did not affect clot lysis, whereas recombinant apo(a) had a potent antifibrinolytic effect. The findings show potent pharmacological Lp(a) reduction does not affect ex vivo fibrinolysis, despite Lp(a) postulated antifibrinolytic role.
Original abstract
It is postulated that lipoprotein (a) [Lp(a)] inhibits fibrinolysis, but this hypothesis has not been tested in humans due to the lack of specific Lp(a) lowering agents. Patients with elevated Lp(a) were randomized to antisense oligonucleotide [IONIS-APO(a)Rx] directed to apo(a) (n = 7) or placebo (n = 10). Ex vivo plasma lysis times and antigen concentrations of plasminogen, factor XI, plasminogen activator inhibitor 1, thrombin activatable fibrinolysis inhibitor, and fibrinogen at baseline, day 85/92/99 (peak drug effect), and day 190 (3 months off drug) were measured. The mean ± SD baseline Lp(a) levels were 477.3 ± 55.9 nmol/l in IONIS-APO(a)Rx and 362.1 ± 89.9 nmol/l in placebo. The mean± SD percentage change in Lp(a) for IONIS-APO(a)Rx was -69.3 ± 12.2% versus -5.4 ± 6.9% placebo (P < 0.0010) at day 85/92/99 and -15.6 ± 8.9% versus 3.2 ± 12.2% (P = 0.003) at day 190. Clot lysis times and coagulation/fibrinolysis-related biomarkers showed no significant differences between IONIS-APO(a)Rx and placebo at all time points. Clot lysis times were not affected by exogenously added Lp(a) at concentrations up to 200 nmol/l to plasma with very low (12.5 nmol/l) Lp(a) levels, whereas recombinant apo(a) had a potent antifibrinolytic effect. In conclusion, potent reductions of Lp(a) in patients with highly elevated Lp(a) levels do not affect ex vivo measures of fibrinolysis; the relevance of any putative antifibrinolytic effects of Lp(a) in vivo needs further study.
mechanismsphase 1phase 2RNA therapeutics
Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.