What's Happening?
Novartis' drug pelacarsen, designed to lower lipoprotein(a) or Lp(a), failed to reduce the risk of major cardiovascular events in its pivotal Lp(a)HORIZON trial. The study, presented at the AHA cardiology congress in Chicago and published in the New England
Journal of Medicine, involved 8,300 subjects with elevated Lp(a) and cardiovascular disease. Despite effectively reducing Lp(a) levels by 78% with once-monthly subcutaneous injections over nearly five years, pelacarsen showed no significant effect on a composite endpoint of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and urgent coronary revascularization. All secondary cardiovascular outcome measures also showed no benefit. Steven Nissen of the Cleveland Clinic, the trial's senior author, expressed disappointment, stating there was "basically no effect on outcomes, not even a trend." This outcome has cast doubt on the efficacy of other Lp(a)-targeting drugs currently in development.
Why It's Important?
This trial's results are a significant setback for the cardiovascular drug development landscape and for the millions of individuals with elevated Lp(a). Elevated Lp(a) is recognized as an independent genetic risk factor for various cardiovascular diseases, including coronary artery disease, heart attack, and stroke, affecting approximately 20% of the global population. The failure of pelacarsen, despite its potent Lp(a)-lowering effect, suggests that simply reducing Lp(a) levels may not translate into improved cardiovascular outcomes, or that the mechanisms are more complex than previously understood. This outcome could lead to a re-evaluation of the therapeutic strategy for Lp(a) and impact the development timelines and investment in other Lp(a)-targeting drugs from companies like Amgen and Eli Lilly. Patients with elevated Lp(a) currently have no approved therapies to reduce this risk factor, making this a critical area of unmet medical need.
What's Next?
The comprehensive failure of pelacarsen in the Lp(a)HORIZON trial will likely prompt intense scrutiny of other Lp(a)-targeting drugs in development. Amgen's olpasiran and Eli Lilly's lepodisiran, both similarly acting injectables, are currently in outcomes trials (OCEAN(a)-Outcomes and ACCLAIM-Lp(a), respectively) with results expected in the coming years. Eli Lilly is also developing an oral Lp(a) inhibitor, muvalaplin, in the phase 3 MOVE-Lp(a) trial. Researchers, including Steven Nissen, are eager to see the results of these trials to gain a more robust understanding of the relationship between Lp(a) lowering and cardiovascular outcomes. The scientific community will likely engage in more in-depth research to understand the underlying mechanisms of Lp(a), its interactions with other cardiovascular disease risk factors, and how it impacts cardiovascular outcomes, rather than abandoning Lp(a) as a target entirely.
Beyond the Headlines
The pelacarsen trial's outcome highlights a recurring challenge in drug development: the translation of biomarker reduction into clinical benefit. While Lp(a) is a well-established risk factor, its precise role in the causal pathway of cardiovascular events may be more nuanced than initially assumed. This failure could lead to a re-evaluation of the 'Lp(a) hypothesis' and encourage exploration into other aspects of Lp(a) biology, such as its inflammatory or thrombotic properties, beyond just its concentration. It also underscores the complexity of cardiovascular disease, where multiple interacting factors contribute to pathology. The disappointment may also shift focus towards combination therapies or more personalized approaches to cardiovascular risk management, especially for patients with high Lp(a) who currently lack effective treatment options. The pharmaceutical industry may become more cautious in investing in therapies solely based on biomarker modulation without clear evidence of clinical outcome improvement.
