The Phase 3 trial failure of Novartis and Ionis Pharmaceuticals' heart drug pelacarsen has raised fundamental questions about whether targeting lipoprotein(a) reduces cardiovascular risk. Despite lowering Lp(a) levels by 80%, pelacarsen failed to significantly cut heart attack and stroke risks, triggering a 16% drop in Novartis shares. Cardiologists point to trial design factors, unstudied monthly dosages, and heavy background use of PCSK9 inhibitors as possible explanations.
Pelacarsen Phase 3 trial results
- ▪Pelacarsen lowered blood levels of lipoprotein(a) by approximately 80%, but this reduction failed to translate into a lower risk of heart attack and stroke in trial participants
- ▪Full results of Novartis and Ionis Pharmaceuticals' pelacarsen Phase 3 trial, which was launched in 2019, will be presented on Saturday at the American Heart Association annual scientific meeting in Chicago
- ▪Novartis and Ionis Pharmaceuticals' experimental heart drug pelacarsen failed to significantly reduce cardiovascular events in a Phase 3 trial, contributing to a 16% drop in Novartis' share price
- ▪Novartis and Ionis Pharmaceuticals' pelacarsen Phase 3 trial's primary composite endpoint included death, heart attack, stroke, and revascularization procedures to restore blood flow in blocked blood vessels
Characteristics and guidelines for lipoprotein(a)
- ▪American Heart Association and American College of Cardiology guidelines recommend that all adults have their lipoprotein(a) levels measured at least once in their lifetime
- ▪Unlike standard LDL cholesterol that deposits fat and plaque in arteries, blood levels of lipoprotein(a) are genetically determined and unaffected by diet, exercise, or lifestyle changes
- ▪Lipoprotein(a) is an inherited, extra-sticky cholesterol particle produced by the liver that affects roughly 20% of people, with higher prevalence in African or South Asian ancestries
Competing lipoprotein(a) drug trials
- ▪Amgen's olpasiran and Eli Lilly's lepodisiran are experimental drugs designed to lower lipoprotein(a) levels by approximately 95%
- ▪Competing lipoprotein(a) trials by Amgen and Eli Lilly enrolled only patients with higher baseline lipoprotein(a) levels than many who participated in Novartis's pelacarsen Phase 3 trial
Questions surrounding lipoprotein(a)
- ▪The failure of pelacarsen in its Phase 3 trial raised questions among cardiologists whether lipoprotein(a) is a direct cause of cardiovascular disease or merely a biomarker indicating risk
- ▪Pelacarsen study investigator Dr. Parag Joshi stated that a total lack of positive signals in trial data would dampen enthusiasm for targeting lipoprotein(a)
Pelacarsen trial dosage
- ▪A previous midstage trial for pelacarsen tested a maximum monthly dose of 60 milligrams as well as a weekly 20 milligram dose
- ▪The pelacarsen Phase 3 trial tested an 80 milligram monthly dose for the first time, prompting questions from cardiologists about potential patient dropouts tied to drug tolerance
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