Tag: lipoprotein(a)

Categories : Cardiovascular Disease New Compounds and TreatmentsTags :

Deep Depletion of Blood Lipoprotein(a) Levels with New Drug

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Image by Scientific Animations, CC4.0

In a new study, researchers found that a new drug under development, zerlasiran, depleted levels of lipoprotein(a) by more than 80% in participants with increased cardiovascular risk. The drug was well tolerated and the findings, published in JAMA Network, suggest that this could be the first viable treatment for elevated levels of lipoprotein(a).

Elevated levels of lipoprotein(a) (LPa) – a type of cholesterol – is a genetic risk factor for cardiovascular disease. Present in 20% of the population, it increases the risk of atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis. Currently, there are no interventions which can bring down high LPa levels: it is unresponsive to diet, exercise, and other lifestyle changes and there is no available drug.

Zerlasiran, a small-interfering RNA that targets synthesis of LPa serum concentration, was developed to fill this gap. It is effectively a gene silencer that shuts down LPA, a gene which produces a protein found only in LPa. This in turn is expected to reduce cardiovascular risk.

A phase I clinical trial had shown that zerlasiran was safe and effective.

For the study, researchers enrolled 178 patients (average age 63.7 years, 46 female) with ASCVD and LPa concentrations greater than or equal to 125nmol/L. They were randomised to subcutaneously receive zerlasiran 300mg or 450mg, or a placebo, every 16 or every 24 weeks. The least-squares mean placebo-adjusted time-averaged percent change in LPa serum concentrations was −85.6%, −82.8%, and −81.3% for the 450mg every 24 weeks, 300mg every 16 weeks, and 300 mg every 24 weeks groups, respectively. The most common adverse events 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. For the group receiving a 300mcg dose every 16 weeks, it was found that even at the 60 week follow-up, 28 weeks after the last administration, that lipoprotein(a) serum concentrations were still 60% lower than baseline.

Categories : Cardiovascular DiseaseTags :

Experimental Drug Slashes Levels of Lipoprotein(a) by 94% in Early Trial

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Image by Scientific Animations, CC4.0

Findings from a phase 1 trial reported by a Cleveland Clinic physician show that a single dose of an experimental therapy produced greater than 94% reductions in blood levels of lipoprotein(a), a key cardiovascular risk driver, with the results lasting for nearly a year. 

The findings were presented at the American Heart Association’s Scientific Sessions 2023 and simultaneously published in the Journal of the American Medical Association.  

Lipoprotein(a), or Lp(a), is made in the liver and has similarities to low-density lipoprotein (LDL). Unlike other types of cholesterol particles, Lp(a) levels are 80–90% genetically determined. The structure of the Lp(a) particle causes atherosclerosis, which greatly increases the risk of heart attacks and strokes. 

Although effective therapies exist to reduce the risk of heart disease by lowering LDL cholesterol and other lipids, currently there are no approved drug treatments to lower Lp(a). Since Lp(a) levels are genetically determined, lifestyle changes such as diet or exercise have no effect. 

In the trial, participants who received an injection of lepodisiran had lipoprotein(a) levels reduced by the top dose as much as 96% within two weeks and maintained levels more than 94% below baseline for 48 weeks. The drug is a small interfering RNA (siRNA) therapeutic that blocks the messenger RNA needed to manufacture a key component of lipoprotein(a) in the liver. 

The findings add lepodisiran to the growing list of therapies that could be promising treatments for atherosclerotic cardiovascular diseases in people with high levels of Lp(a), which is estimated to affect a fifth of the global population.   

“These results showed that this therapy was well tolerated and produced very long-duration reductions in Lp(a), an important risk factor that leads to heart attack, stroke and aortic stenosis,” said lead author Steven Nissen, MD, Chief Academic Officer of the Heart, Vascular & Thoracic Institute at Cleveland Clinic.  

In the trial, researchers enrolled 48 patients in the US and Singapore, average age 47. Investigators studied six different dosages and a placebo, which were all administered as injections. Participants were monitored for up to 48 weeks after administration.   

Maximum Lp(a) plasma concentrations were reduced by 49% from baseline levels for the 4mg dose and up to 96% for the 608mg dose vs a 5% decrease for the placebo. No safety issues were observed, and the only tolerability issue was mild injection site reactions. 

“Despite the strong evidence of the importance of elevated Lp(a) as a risk factor for heart disease, effective treatment has been elusive,” commented Dr Nissen. “This approach to treatment gives hope to the 20% of the world’s population who have elevated Lp(a) levels.” 

A phase 2 trial studying lepodisiran is currently underway. The trial was sponsored by Eli Lilly and Company (Lilly), the company developing lepodisiran. 

Source: Cleveland Clinic

Categories : Metabolic DisordersTags :

‘Gene Silencing’ Therapy Cuts Lipoprotein(a) by Up to 98%

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DNA repair
Source: Pixabay/CC0

Findings from a new show that an experimental ‘gene silencing’ therapy reduced blood levels of lipoprotein(a) by up 98%. This is significant as lipoprotein(a) is a key cardiovascular risk driver which is determined largely by genetics and not modifiable lifestyle factors, and which cannot be lowered by current medical means.

Findings from the Cleveland Clinic-led phase 1 trial were published in the Journal of the American Medical Association.

Trial participants receiving higher doses of SLN360 – a small interfering RNA (siRNA) therapeutic that ‘silences’ the gene responsible for lipoprotein(a) production – saw their lipoprotein(a) levels  drop by as much as 96%-98%. Five months later, these participants’ lipoprotein(a) – also known as Lp(a) – levels remained 71%-81% lower than baseline.

The findings suggest this siRNA therapy could be a promising treatment to help prevent premature heart disease in people with high levels of Lp(a), which is estimated to affect 64 million people in the United States and 1.4 billion people worldwide.

“These results showed the safety and strong efficacy of this experimental treatment at reducing levels of Lp(a), a common, but previously untreatable, genetically-determined risk factor that leads to premature heart attack, stroke and aortic stenosis,” said the study’s lead author Steven E. Nissen, MD “We hope that further development of this therapy also will be shown to reduce the consequences of Lp(a) in the clinical setting through future studies.”

Lp(a) has similarities to LDL. Lp(a) is made in the liver, where an extra protein called apolipoprotein(a) is attached to an LDL-like particle. Unlike other types of cholesterol particles, Lp(a) levels are 80 to 90% genetically determined. The structure of the Lp(a) particle causes the accumulation of plaques in arteries, which play a significant role in heart disease. Elevated Lp(a) greatly increases the risk of heart attacks and strokes.

Although cardiovascular risk-reduction therapies that lower LDL cholesterol and other lipids exist, there are treatments to lower Lp(a). Since Lp(a) levels are genetically determined, lifestyle changes such as diet or exercise have no effect. In the current study, the siRNA therapy reduces Lp(a) levels by “silencing” the gene responsible for Lp(a) production and blocking creation of apolipoprotein(a) in the liver.

In the APOLLO trial, researchers enrolled 32 participants with Lp(a) levels above 15 nmol/L, with a median level of 224nmol/L (75nmol/L or less is considered normal). Eight participants received a placebo and the remaining received one of four doses of SLN360 via a single subcutaneous injection. The doses were 30mg, 100mg, 300mg and 600mg. Participants were closely observed for the first 24 hours after their injection and then followed up for five months.

Compared to baseline, participants receiving 300mg and 600mg of SLN360 experienced a maximum of 96% and 98% reduction in Lp(a) levels, and a reduction of 71% and 81% at five months. Those receiving a placebo saw no change in Lp(a) levels. The highest doses also reduced LDL cholesterol by about 20%-25%. There were no major safety consequences reported and the most common side effect was temporary soreness at the injection site. The study was extended and researchers will continue to follow participants for a total of one year.

Source: Cleveland Clinic

Categories : Cardiovascular DiseaseTags :

High CAC and Lipoprotein(a) Scores Greatly Worsen CVD Risk

On By ModernMedia
Healthy red blood cells. Source: NIH

Having both a high lipoprotein(a) and high coronary artery calcium score (CAC) results in a 22% risk of heart attack or stroke over the following 10 years, nearly double the risk of having either condition alone. These are the findings are from a study published in the Journal of the American College of Cardiology (JACC).

Two decades ago, it was recognised that lipoprotein(a) (Lp(a)) concentrations were elevated in patients with cardiovascular disease (CVD). However Lp(a) was not yet proven to be important due to a lack of both Lp(a)-lowering therapy and evidence that reducing Lp(a) levels improves CVD risk. Recent research has added to the evidence 

“We are hopeful that by making the connection between Lp(a) and CAC as dual risk drivers, we can raise awareness in the medical community and improve earlier heart attack prevention for these patients,” said cardiologist Parag Joshi, MD, Associate Professor of Internal Medicine at UT Southwestern. “Our data may also expedite the development of treatments designed specifically for this high-risk population.”

About one sixth of people in the U.S. have high Lp(a), driven largely by genetics. Coronary artery calcium (CAC) is a marker of plaque deposits around the heart. 

Cardiology researchers confirmed the Lp(a) and CAC connection by comparing data from two landmark cardiovascular trials, the Dallas Heart Study, an ongoing comprehensive study of 6000 diverse and heart-healthy patients conducted from 2000 to present, and the Multi-Ethnic Study of Atherosclerosis (MESA) 6000-participant study investigating early-stage atherosclerosis.

The researchers found that participants with combined high Lp(a) and high CAC had a 22% 10-year risk of heart attack or stroke, compared with a 10-15% 10-year risk in patients who had either risk factor alone.

The team identified three distinct risk-related trends:

  • High Lp(a), high CAC: These individuals face the highest 10-year risk of heart attack or stroke.
  • High Lp(a), zero CAC: 10-year heart attack and stroke risk is low when there is no CAC, even if Lp(a) is high.
  • Low Lp(a), high CAC: 10-year heart attack or stroke risk is higher than average but lower than with high LP(a) and high CAC combined.

“Establishing the connection between Lp(a) and CAC means we can move to the important next phase of research, which will be defining and personalizing early screening protocols to identify patients at high risk of heart attack,” said Dr Joshi. “With further research, this could mean selectively scanning patients with high Lp(a) for their CAC score, and studying therapies specifically designed to reduce Lp(a) among patients with high CAC.”

Source: UT Southwestern Medical Center