Zerlasiran Achieves Durable Lp(a) Reductions at 60 Weeks, with Stephen J. Nicholls, MD, PhD

Data from the ALPACAR-360 trial, presented at the American Heart Association (AHA) Scientific Sessions 2024, confirm that zerlasiran (formerly SLN360) achieves sustained reductions in lipoprotein(a) [Lp(a)] through 60 weeks. Zerlasiran, a gene-silencing therapy, offers a potential treatment for elevated Lp(a), a genetic risk factor affecting 20% of the global population and a significant driver of cardiovascular disease.

Launched in 2023, the Phase 2 trial randomized 178 patients with baseline Lp(a) levels >125 nmol/L and high cardiovascular risk to 3 dosing regimens of zerlasiran or placebo therapy. Upon analysis, at 36 weeks, zerlasiran showed a least-squares mean time-averaged Lp(a) reduction of –81.3% to –85.6%.

“I think there’s two elements to the efficacy. There’s the degree of Lp(a) lowering that we can but then there’s the durability,” Stephen J. Nicholls, MD, PhD, Victorian Heart Institute, Monash University, told HCPLive. “If we follow patients out 3-, 6-, and 12-months after an injection, what we’re seeing with these agents is that your Lp(a) doesn’t come back to beeline. Our ability to show more and more durability, more Lp(a) lowering 6-, 12-months after injections, has implications for potentially less frequent dosing.”

These dose reductions were observed in the zerlasiran 450 mg every 24 weeks (–85.6%; 95% CI, –90.9% to −80.3%), 300 mg every 16 weeks (–82.8%; 95% CI, –88.2% to –77.4%), and 300 mg every 24 weeks (–81.3%; 95% CI, –86.7 to 76.0) cohorts, respectively. These reductions remained consistent through 60 weeks, and zerlasiran was well-tolerated. A total of 20 serious adverse events in 17 patients, but none were deemed to be related to the study drug—injection site reactions were the most common treatment-related adverse event.

Nicholls indicated data from the ALPACAR-360 trial demonstrate the competitive profile of zerlasiran as a potential long-term, infrequent-dose therapy. Zerlasiran will progress into Phase 3 trials as a potentially promising new treatment for patients with high Lp(a).

“I think that finding suggests that if you do big enough trials, you do see adverse events.,” Nicholls told HCPLive. “...All seemed to be pretty mild in severity, and they resolve pretty quickly. These are important, not only in terms of the conversation we have with our patients about starting therapy, but then about kind of keeping patients on treatment long term.”

Disclosures: Nicholls reports relevant disclosures including Amgen, Eli Lilly, Novartis, Sanofi-Regeneron, Silence Therapeutics, and others.

References

_{Nissen SE, Wang Q, Nicholls SJ, et al. Zerlasiran—A Small-Interfering RNA Targeting Lipoprotein(a): A Phase 2 Randomized Clinical Trial. JAMA. Published online November 18, 2024. doi:10.1001/jama.2024.21957}

_{Packer M. Tirzepatide for Patients with Heart Failure with Preserved Ejection Fraction and Obesity: the SUMMIT Trial. Paper presented at: American Heart Association Scientific Sessions 2024; November 15 - 18; Chicago, Il. Accessed November 16, 2024.}