Lp(a)-Lowering Drug Pelacarsen Falls Short

Why did an Lp(a)-lowering drug fail to reduce heart attacks?

Lipoprotein(a) is a cholesterol-carrying particle similar to LDL, with an additional protein, apolipoprotein(a), attached to it. Blood levels are largely set by genetics and change little with diet or exercise. Roughly one in five people are thought to have elevated levels, and large genetic and epidemiological studies have linked high Lp(a) to a greater risk of heart attack, stroke and aortic valve disease. That evidence made it one of the most closely watched targets in cardiovascular drug development.

Novartis's candidate, pelacarsen, is an antisense oligonucleotide, a short strand of genetic material that reduces production of apolipoprotein(a) in the liver. Press coverage of the AHA presentation, including STAT News, described a puzzling result: the drug lowered Lp(a) but did not lower the chance of heart attack or stroke. Full details, including the size of the Lp(a) reduction and the confidence intervals around the clinical outcomes, should be read in the peer-reviewed publication. Until then, any interpretation remains provisional.

What could explain the gap between a lower biomarker and unchanged outcomes?

Several hypotheses are being discussed by cardiologists. One is that the degree of Lp(a) reduction was not large enough to change risk, since some researchers have argued that very substantial lowering may be needed. Another is that the trial population or follow-up time did not capture the full benefit, as atherosclerosis develops over decades and cardiovascular outcome trials typically last only a few years. A third possibility is that Lp(a) is more a marker of risk than a causal driver at the levels studied, although genetic data have long supported a causal role.

The result also matters for other programs. Several companies are testing different approaches to Lp(a) lowering, including small interfering RNA drugs and oral agents. Each differs in mechanism and potency, so a neutral result for one agent does not automatically predict the outcome for the others. It does underline an old lesson in cardiology: improving a biomarker is not the same as improving patient outcomes, and only outcome trials can settle the question.

What should patients with high Lp(a) do now?

No Lp(a)-specific drug is currently approved, so management focuses on lowering overall cardiovascular risk. Clinicians typically recommend more intensive control of LDL cholesterol, blood pressure, blood sugar and smoking, along with healthy diet and physical activity. Some guidelines suggest measuring Lp(a) at least once in adults to identify people at higher inherited risk, and relatives of affected individuals may also consider testing.

Patients should not stop or change prescribed medicines because of a single trial headline. Statins, PCSK9 inhibitors and other established therapies have proven outcome benefits in the right patients. A person with high Lp(a) and a strong family history of early heart disease should talk with a cardiologist about an individualized prevention plan.