Professor Stephen Nicholls is a world-renowned cardiologist, and leads the Victorian Heart Hospital (VHH) at Monash University.

Stephen J. Nicholls, MD, PhD

New findings from the KRAKEN trial highlight the potential of muvalaplin, an oral treatment, for lowering lipoprotein (a) [Lp(a)] levels in adults with elevated Lp(a) and high cardiovascular risk.

American Heart Association (AHA) Annual Scientific Sessions 2024

, the trial represents the first evidence of an oral agent for lowering Lp(a), according to trial sponsor Eli Lilly and Company.

“High levels of Lp(a) have been shown to be a significant risk factor for atherosclerotic cardiovascular disease, affecting over one billion adults globally," said principal investigator Stephen J. Nicholls, MBBS, PhD, director of the Victorian Heart Hospital and Institute, and professor of cardiology at Monash University, Australia. "Current cholesterol-lowering therapies are not approved to lower Lp(a) levels, highlighting an unmet need for people living with cardiovascular disease. These data represent a needed scientific advancement with the potential to reduce the risk of cardiovascular events such as heart attacks or strokes with a once-daily pill."

A 12-week, double-blind, placebo-controlled, phase 2, 233-patient trial conducted in 43 sites across 5 countries, KRAKEN was designed to assess the efficacy and safety of muvalaplin at doses of 10 mg/d, 60 mg/d, or 240 mg/d. The trial’s primary endpoint, placebo-adjusted percentage change in Lp(a) levels, was assessed using intact Lp(a) and apolipoprotein(a)-based assays.

For inclusion in the trial, patients were required to have Lp(a) levels of at least 175 nmol/L and a history of atherosclerotic cardiovascular disease, diabetes, or familial hypercholesterolemia.

At 12 weeks, placebo-adjusted reductions in Lp(a) using the intact assay were 47.6% (95% CI, 35.1% to 57.7%), 81.7% (95% CI, 78.1% to 84.6%), and 85.8% (95% CI, 83.1% to 88.0%) with muvalaplin 10 mg, 60 mg, and 240 mg doses, respectively. Using the apo(a)-based assay, the corresponding reductions were 40.4% (95% CI, 28.3% to 50.5%), 70.0% (95% CI, 65.0% to 74.2%), and 68.9% (95% CI, 63.8% to 73.3%). Secondary endpoints showed reductions in apolipoprotein B levels, while high-sensitivity C-reactive protein remained unchanged.

For more on the trial and the potential of muvalaplin, check out our interview with Nicholls from the floor of AHA 2024.

 HCPLive Nicholls KRAKEN AHA 24

Relevant disclsoures for Nicholls include Amgen, Eli Lilly, Novartis, Sanofi-Regeneron, Silence Therapeutics, and others.

Nicholls SJ, Ni W, Rhodes GM, et al. Oral Muvalaplin for Lowering of Lipoprotein(a): A Randomized Clinical Trial. 

 Published online November 18, 2024. doi:10.1001/jama.2024.24017

Eli Lilly and Company. Lilly’s muvalaplin lowered lipoprotein(a) levels in adults with high risk for cardiovascular events by up to 85% at highest tested dose. Eli Lilly and Company. November 18, 2024. Accessed November 18, 2024. https://investor.lilly.com/news-releases/news-release-details/lillys-muvalaplin-lowered-lipoproteina-levels-adults-high-risk.

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Muvalaplin, an oral treatment, shows promise in reducing lipoprotein (a) [Lp(a)] levels in high cardiovascular risk patients, as demonstrated in the KRAKEN trial. This phase 2 trial, presented at the AHA Annual Scientific Sessions 2024, is the first to provide evidence of an oral agent effectively lowering Lp(a). Conducted across 43 sites, the trial involved 233 patients and revealed significant placebo-adjusted reductions in Lp(a) levels with muvalaplin doses of 10 mg, 60 mg, and 240 mg. Secondary endpoints indicated reductions in apolipoprotein B levels, with no change in high-sensitivity C-reactive protein.

Stephen Nicholls, MBBS, PhD, provides additional insight into KRAKEN trial data and the potential of muvalaplin.

Phase 2 Data Support Muvalaplin for Lowering Lp(a), with Stephen Nicholls, MBBS, PhD

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 

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.

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.

Zerlasiran, a gene-silencing therapy, has shown promising results in the ALPACAR-360 trial, achieving sustained reductions in lipoprotein(a) [Lp(a)] levels over 60 weeks. This Phase 2 trial involved 178 patients with high cardiovascular risk and elevated Lp(a) levels, demonstrating significant Lp(a) reductions across various dosing regimens. Zerlasiran was well-tolerated, with no serious adverse events linked to the drug. The trial's findings suggest zerlasiran's potential as a long-term, infrequent-dose therapy for managing elevated Lp(a), a genetic risk factor for cardiovascular disease, warranting progression to Phase 3 trials.

Stephen J. Nicholls, MD, PhD discusses the robust efficacy and tolerability of zerlasiran for Lp(a) lowering, paving the way for Phase 3 development.

Stephen J. Nicholls, MD, PhD

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