Muvalaplin and Olpasiran Show Promise in Lowering Lp(a)

Investigational muvalaplin (Eli Lilly), the first oral therapy being developed to lower lipoprotein (a) levels, was shown to reduce levels in a phase 1 trial, with no safety concerns, researchers report.

In a separate phase 2 study, olpasiran (Amgen), which is given by injection, lowered Lp(a) levels for nearly 1 year after the last dose, also without safety concerns, in a phase 2 trial extension.

Researchers presented these findings in two late breaking science sessions at the recent European Society of Cardiology (ESC) Congress 2023 in Amsterdam, the Netherlands. The muvalaplin trial was also simultaneously published online as a preliminary communication in JAMA.

Phase 1 Trial of Muvalaplin

Epidemiologic and genetic evidence suggests that Lp(a) has a causal role in cardiovascular disease (CVD) events, Stephen J. Nicholls, MBBS, PhD, and colleagues write.

In initial studies, Lp(a) was reduced by approximately 80% with an antisense oligonucleotide (pelacarsen, Ionis) and by up to 98% with RNA interference (olpasiran) — both injectable therapies.

Muvalaplin is a small molecule that disrupts the binding of apolipoprotein(a) to apo B100 that forms Lp(a), said Nicholls, from Monash University and Victoria Heart Institute, Melbourne, Australia.  

In this first-in-human, phase 1 trial in 114 healthy individuals, Lp(a) levels were reduced up to 65% following daily administration of 100 to 800 mg of muvalaplin for 14 days, without safety or tolerability concerns or significant effects on plasminogen, a homologous protein, he told | Medscape Cardiology.

Approximately 20% of the population have high LP(a) levels, Nicholls noted.

“We saw in the PCSK9 inhibitor trials that Lp(a) lowering is associated with benefit, but those agents substantially lower LDL-cholesterol,” he said. “Now, here for the first time we have an oral agent” that lowers Lp(a) levels. However, “we will still need to determine if this leads to a reduction in cardiovascular risk,” in longer and larger trials, he added.

The researchers randomly assigned healthy adults aged 18-69 with a BMI of 30 kg/m2 or less, into two groups.

The 55 participants in the single ascending dose group were randomly assigned to receive muvalaplin (1 mg, 10 mg, 30 mg, 100 mg, 200 mg, 400 mg, or 800 mg) or matching placebo daily for 14 days. They had a mean age of 29 years; 64% were female and 91% were white. Their median Lp(a) level was 10.3 mg/dL.

The 59 participants in the multiple ascending dose group, who were required to have Lp(a) ≥30 mg/dL, were randomly assigned to receive muvalaplin (30 mg, 100 mg, 300 mg, 500 mg, or 800 mg) or placebo daily for 14 days. They had a mean age of 32; 58% were female and 80% were white. Their median Lp(a) level was 58.4 mg/dL.

The maximum placebo-adjusted Lp(a) reduction was 63% to 65%, which occurred on days 14 and 15, in participants who received doses of 100 mg.

The levels returned to baseline by day 29 for the 30-mg dose, day 43 for the 100-mg dose, and day 64 for the 300-mg to 800-mg doses. 

There were no deaths or serious adverse events. Treatment-associated adverse events were reported by 62% in the single ascending dose group and by 80% in the multiple ascending dose group; these were mild and transient and included headache, fatigue, and vomiting.  

Muvalaplin had no significant effects on LDL, HDL, or total cholesterol or apo B100, and did not significantly affect plasminogen levels or activity.

The team is currently conducting the phase 2 KRAKEN trial. They plan to enroll 233 patients aged 40 and older with elevated Lp(a) levels (≥175 nmol/L) and high risk for cardiovascular events. The primary outcome is change in Lp(a) levels at 12 weeks, and the estimated primary trial completion is this coming January.

OCEAN (a)-DOSE Extended Study of Olpasiran

In a separate presentation, Michelle L. O’Donoghue, MD, MPH, reported findings from an extension of the phase 2 trial of olpasiran in patients with atherosclerotic CVD and elevated Lp(a).

Olpasiran is a small interfering RNA (siRNA) molecule directed to the liver that prevents the assembly of Lp(a).

As previously reported, O’Donoghue, from Brigham and Women’s Hospital and Harvard Medical School in Boston, presented the main results from the OCEAN(a) DOSE (TIMI 67) study of olpasiran, at the American Heart Association Scientific Sessions 2022, and the trial was simultaneously published online in the New England Journal of Medicine.

The trial included 281 patients with established atherosclerotic CVD and Lp(a) >150 nmol/L (60 mg/dL). Participants were randomly assigned to one of four doses of olpasiran (10 mg, 75 mg, or 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously.

At 36 weeks, doses of 75 mg or more of olpasiran every 12 weeks led to reductions of more than 95% in levels of Lp(a).

The extension study aimed to examine the effects of olpasiran on levels of the oxidized phospholipids on apolipoprotein B100 [OxPL-apoB] and on levels of Lp(a), as well as safety, after the last administered dose.

The minimum extended off-treatment period was 72 weeks from randomization (in 276 patients). Complete follow-up was a median of 86 weeks (50 weeks after the last administered dose).

The study showed that “olpasiran is an siRNA that robustly lowers Lp(a) levels” and “leads to a marked and durable reduction” in proatherogenic OxPL-apoB, O’Donoghue reported.

Patients on doses ≥75 mg every 12 weeks, “sustained around a 40% to 50% placebo-adjusted reduction in Lp(a) levels close to 1 year after the last dose.”

The long-term clinical efficacy and safety of olpasiran are being further evaluated in the ongoing phase 3 OCEAN(a)-Outcomes trial which has as an estimated enrollment of 6000 and projected completion in December 2026.

These are “exciting” results, and “we’re all waiting with bated breath for more news,” said session co-chairperson Louise Bowman, MD, University of Oxford, United Kingdom.

In reply to questions from the audience, O’Donoghue said that the only adverse events that were imbalanced during the on-treatment phase were injection site reactions and localized hypersensitivity reactions, which were not reported during the off-treatment period. There was also no evidence of a proinflammatory increase in phospholipids, or of a rebound effect on Lp(a) levels after stopping olpasiran.

The muvalaplin study was funded by Eli Lilly. Nicholls reports receiving grants from Esperion, AstraZeneca, New Amsterdam Pharma, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron, and LipoScience; receiving honoraria to his institution from AstraZeneca, Amarin, Akcea, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, Boehringer Ingelheim, Vaxxinity, and Sequiris; and that he is a named inventor on a patent for PCSK9 inhibitors and atherosclerosis. O’Donoghue reports receiving research grants from Amgen, AstraZeneca, Merck, and Novartis, and she is a consultant for Amgen and Novartis, and a data and safety monitor for AstraZeneca and Janssen.

European Society of Cardiology (ESC) Congress 2023. Presented August 26 (muvalaplin study) and August 28 (olpasiran study).

JAMA. Published online August 26, 2023. Full text

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