The highest dose of an experimental pill has dramatically lowered an inherited form of high cholesterol in a mid-stage trial.
Eli Lilly announced that, according to the data, the drug, muvalaplin, reduced levels of lipoprotein(a), or Lp(a), by 70% using a traditional blood test and by nearly 86% based on a more specific test developed by the company, researchers reported at the American Heart Association meeting in Chicago.
Reuters reports that the drug is the only oral treatment in a field of several injectable therapies being tested to treat high Lp(a), a risk factor for heart disease that affects one in five individuals globally.
Unlike low-density lipoprotein, or LDL, the so-called bad cholesterol that can be treated with diet and statins, there are no approved treatments for Lp(a) and few individuals even know they have it.
Elevated Lp(a) can significantly increase the risk of heart attack, stroke, narrowing of the aortic valve, and peripheral artery disease, a build-up of fatty plaques in the arteries.
People of African and South Asian ancestry are at highest risk.
The trial compared three daily doses of muvalaplin – 10, 60 and 240mg – with a placebo in 233 adults with high levels of Lp(a). Researchers tested Lp(a) levels using a traditional blood test and a new method that measures levels of intact Lp(a) particles in the blood.
Muvalaplin reduced Lp(a) by 47.6% at 10 mg, 81.7% at 60 mg and 85.8% on 240 mg as measured by the intact blood test versus placebo. It was reduced by 40.4%, 70.0%, and 68.9%, respectively, as measured by the traditional test.
More in the wings
At the same meeting, London-based Silence Therapeutics reported 60-week results of a 180-patient phase 2 trial of zerlasiran, which works by dampening the activity of the LPA gene that leads to high levels of Lp(a), using a technology known as short interfering RNA, or siRNA.
A 300mg or 450mg injection of zerlasiran given every 16 or 24 weeks reduced Lp(a) by 80% to 85% during 36 to 60 weeks of follow up, with no major safety issues.
“We saw profound knockdown, as we saw in the phase one,” said Dr Curtis Rambaran, the company’s chief medical officer.
Silence will test the 300mg dose in a late-stage trial set to start in the middle of next year, he said.
Results of both studies were published in JAMA Network.
Other injectable Lp(a) treatments in clinical testing include Lilly’s lepodisiran, Amgen’s olpasiran, and pelacarsen from Novartis.
Study 1 details
Oral Muvalaplin for Lowering of Lipoprotein(a)A Randomised Clinical Trial
Stephen Nicholls, Wei Ni, Grace Rhodes, et al.
Published in JAMA Network on 18 November 2024
Abstract
Importance
Muvalaplin inhibits lipoprotein(a) formation. A 14-day phase 1 study demonstrated that muvalaplin was well tolerated and reduced lipoprotein(a) levels up to 65%. The effect of longer administration of muvalaplin on lipoprotein(a) levels in individuals at high cardiovascular risk remains uncertain.
Objectives
To determine the effect of muvalaplin on lipoprotein(a) levels and to assess safety and tolerability.
Design, Setting, and Participants
Phase 2, placebo-controlled, randomised, double-blind trial enrolling 233 participants with lipoprotein(a) concentrations of 175 nmol/L or greater with atherosclerotic cardiovascular disease, diabetes, or familial hypercholesterolemia at 43 sites in Asia, Europe, Australia, Brazil, and the United States between December 10, 2022, and November 22, 2023.
Interventions
Participants were randomised to receive orally administered muvalaplin at dosages of 10 mg/d (n = 34), 60 mg/d (n = 64), or 240 mg/d (n = 68) or placebo (n = 67) for 12 weeks.
Main Outcomes and Measures
The primary end point was the placebo-adjusted percentage change from baseline in lipoprotein(a) molar concentration at week 12, using an assay to measure intact lipoprotein(a) and a traditional apolipoprotein(a)-based assay. Secondary end points included the percentage change in apolipoprotein B and high-sensitivity C-reactive protein.
Results
The median age of study participants was 66 years; 33% were female; and 27% identified as Asian, 4% as black, and 66% as white. Muvalaplin resulted in placebo-adjusted reductions in lipoprotein(a) of 47.6% (95% CI, 35.1%-57.7%), 81.7% (95% CI, 78.1%-84.6%), and 85.8% (95% CI, 83.1%-88.0%) for the 10-mg/d, 60-mg/d, and 240-mg/d dosages, respectively, using an intact lipoprotein(a) assay and 40.4% (95% CI, 28.3%-50.5%), 70.0% (95% CI, 65.0%-74.2%), and 68.9% (95% CI, 63.8%-73.3%) using an apolipoprotein(a)-based assay. Dose-dependent reductions in apolipoprotein B were observed at 8.9% (95% CI, −2.2% to 18.8%), 13.1% (95% CI, 4.4%-20.9%), and 16.1% (95% CI, 7.8%-23.7%) at 10 mg/d, 60 mg/d, and 240 mg/d, respectively. No change in high-sensitivity C-reactive protein was observed. No safety or tolerability concerns were observed at any dosage.
Conclusions and Relevance
Muvalaplin reduced lipoprotein(a) measured using intact lipoprotein(a) and apolipoprotein(a)-based assays and was well tolerated. The effect of muvalaplin on cardiovascular events requires further investigation.
Study 2 details
Zerlasiran—A Small-Interfering RNA Targeting Lipoprotein(a)A Phase 2 Randomized Clinical Trial
Steven Nissen, Qiuqing Wang, Curtis Rambaran et al.
Published in JAMA Network on 18 November 2024
Abstract
Importance
Elevated lipoprotein(a) increases the risk of atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis.
Objective
To evaluate the effects of zerlasiran, a small-interfering RNA targeting hepatic synthesis of apolipoprotein(a), on lipoprotein(a) serum concentration.
Design, Setting, and Participants
A multicentre trial in patients with stable ASCVD with serum lipoprotein(a) concentrations greater than or equal to 125 nmol/L at 26 sites in Europe and South Africa between January 3, 2023, and April 27, 2023, with last follow-up on July 1, 2024.
Interventions
Participants randomised to receive a subcutaneous dose of placebo every 16 weeks for 3 doses (n = 23) or every 24 weeks for 2 doses (n = 24) or zerlasiran 450 mg every 24 weeks for 2 doses (n = 45), 300 mg every 16 weeks for 3 doses (n = 42), or 300 mg every 24 weeks for 2 doses (n = 44).
Main Outcome and Measures
The primary outcome was the time-averaged percent change in lipoprotein(a) concentration from baseline to 36 weeks, with follow-up to 60 weeks.
Results
Among 178 patients, mean (SD) age was 63.7 (9.4) years, 46 (25.8%) were female, with a median (IQR) baseline lipoprotein(a) concentration of 213 (177-282) nmol/L; 172 patients completed the trial. Compared with the pooled placebo group, the least-squares mean time-averaged percent change in lipoprotein(a) concentration from baseline to week 36 was −85.6% (95% CI, −90.9% to −80.3%), −82.8% (95% CI, −88.2% to −77.4%), and −81.3% (95% CI, −86.7% to −76.0%) for the 450 mg every 24 weeks, 300 mg every 16 weeks, and 300 mg every 24 weeks groups, respectively. Median (IQR) percent change in lipoprotein(a) concentration at week 36 was −94.5% (−97.3% to −84.2%) for the 450 mg every 24 weeks group, −96.4% (−97.7% to −92.3%) for the 300 mg every 16 weeks group, and −90.0% (−93.7% to −81.3%) for the 300 mg every 24 weeks group. The most common treatment-related adverse effects were injection site reactions, with mild pain occurring in 2.3% to 7.1% of participants in the first day following drug administration. There were 20 serious adverse events in 17 patients, none considered related to the study drug.
Conclusions
Zerlasiran was well-tolerated and reduced time-averaged lipoprotein(a) concentration by more than 80% during 36 weeks of treatment in patients with ASCVD.
Reuters article – Lilly pill cuts genetic form of cholesterol nearly 86% in study (Open access)
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