Ziltivekimab and Pelacarsen Show No Clinical Benefit Despite Effective Biomarker Lowering

Two randomized, placebo-controlled trials of targeted therapies—ziltivekimab, a monoclonal antibody neutralizing interleukin-6, and pelacarsen, an antisense oligonucleotide lowering lipoprotein(a)—both failed to reduce major adverse cardiovascular events despite effectively lowering their respective biomarkers. In the ziltivekimab trial, 6,376 adults with established atherosclerotic cardiovascular disease, chronic kidney disease, and cardiovascular inflammation (high-sensitivity C-reactive protein ≥2 mg per liter) were randomly assigned in a 1:1 ratio to subcutaneous ziltivekimab (15 mg once monthly) or placebo; at 24 months, the between-group difference in median percent change was −76 percentage points for free interleukin-6 and −64 percentage points for high-sensitivity CRP, yet over a median follow-up of 33 months a primary end-point event (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) occurred in 561 patients (17.6%) in the ziltivekimab group and 565 (17.7%) in the placebo group (hazard ratio, 0.99), with serious adverse events in 54.6% versus 54.8% and serious infections in 20.4% versus 17.9%, respectively. In the pelacarsen trial, 8,350 patients with preexisting cardiovascular disease and a lipoprotein(a) level of at least 70 mg per deciliter were randomly assigned in a 1:1 ratio to subcutaneous pelacarsen (80 mg monthly) or matching placebo; among 8,322 patients in the efficacy analysis (mean age, 59.7 years; 27.0% women; median baseline lipoprotein(a), 236 nmol per liter), lipoprotein(a) levels at 12 months were 64.4 nmol per liter with pelacarsen versus 233.4 nmol per liter with placebo, but over a median follow-up of 4.7 years a primary end-point event (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or urgent coronary revascularization) occurred in 511 patients (12.3%) in the pelacarsen group and 503 (12.1%) in the placebo group (hazard ratio, 1.02), with consistent results among patients with baseline lipoprotein(a) of at least 90 mg per deciliter (12.3% vs. 12.3%; hazard ratio, 1.00) and serious adverse events in 37.3% versus 41.1%. Together, these findings indicate that lowering interleukin-6 or lipoprotein(a) with these agents did not translate into a lower risk of cardiovascular events than placebo. Source: https://www.nejm.org/