Oral PCSK9 inhibitor significantly lowers LDL cholesterol in adults with hypercholesterolaemia

14th March 2023

MK-0616 is an investigative oral, once-daily, PCSK9 inhibitor and its manufacturer Merck has reported that it gave rise to significant reductions in LDL cholesterol in adult patients with hypercholesterolaemia.

Increased levels of PCSK9 elevate plasma LDL cholesterol and conversely, lowering PCSK9 reduces LDL cholesterol.

As a result, inhibition of PCSK9 represents a therapeutic target and drugs such as evolocumab have been recommended in the treatment of primary hypercholesterolaemia or mixed dyslipidaemia and in patients with a high or very high risk of cardiovascular disease, where LDL cholesterol levels remain above 3.5 mmol/l.

However, to date, all PCSK9 inhibitors are only available as an injectable form, whereas MK-0616 is an oral PCSK9 inhibitor.

In a study of healthy patients with hypercholesterolaemia, the use of once daily MK-0616 (dose 10 to 300 mg), exhibited a dose dependent increase in plasma exposure and a >90% mean maximum reduction of free plasma PCSK9 levels from baseline at all dose levels studied.

The recent findings are from a phase 2b clinical trial in which MK-0616 was given at varying doses (6, 12, 18 and 30 mg) to adult patients with hypercholesterolaemia and who were divided into one of three categories, in which fasting LDL cholesterol levels ranged from > 1.81 to < 6.48 mmol/l.

In addition, participants were either stable on one or more lipid lowering therapies or who had not received any such treatments for more than 30 days before screening.

Individuals were then randomised 1:1:1:1:1 (i.e. each dose and placebo) and the treatment continued for 16 weeks and the primary objective of the study was to evaluate the percent change in LDL cholesterol from baseline to Week 8.

MK-0616 and reduction in LDL cholesterol

A total of 380 participants with a median age of 62 years (49% female) with hypercholesterolaemia and a moderate to high risk of atherosclerotic cardiovascular disease were included.

At Week 8, all four doses of MK-0616 significantly reduced LDL-C compared to placebo and the placebo-adjusted reduction from baseline ranged from 41.2% with the 6 mg dose to 60.9% with the 30 mg dose (p < 0.001 for each dose).

The drug was well tolerated and the proportion of participants experiencing greater than one adverse event was similar (ranging from 39.5% to 44.2%) between the different doses and placebo (44%).

The findings of the phase 2b study have been published in the Journal of the American College of Cardiology.

Injectable cholesterol lowering drug approved by NICE

1st September 2021

Draft guidance from NICE has recommended the novel cholesterol lowering agent, inclisiran for people with established cardiovascular disease.

The presence of an elevated cholesterol level elevated cholesterol level increases the risk of several cardiovascular diseases including stroke, type 2 diabetes and peripheral arterial disease.

Hence cholesterol lowering has become an important therapeutic goal in the prevention of cardiovascular disease although much focus has been placed on the levels of low-density lipoprotein (LDL), cholesterol.

Patients with high cholesterol are normally prescribed statins, which block the rate limiting step of cholesterol biosynthesis.

However, studies have shown that adherence to treatment adherence to treatment reduces over time and, in patients who experienced an acute myocardial infarction, over a over a third with hyperlipidaemia did not achieve the low-density lipoprotein target level after six months of therapy.

A further problem with statins is the development of side effects, especially muscle-related effects. In one study, these were reported by 60% of former statin users and a quarter of current users.

The discovery of pro-protein convertase subtilisin-kexin type 9 (PCSK9), which is a protein that binds to LDL receptors, has been an important breakthrough in the management of hyperlipidaemia.

PCSK9 reduces the number of LDL receptors on cell surfaces and prevents it from recycling, hence LDL cholesterol cannot be removed and levels remain high.

Inclisiran is a new class of molecule, termed a small, interfering RNA (siRNA) and these agents are able to regulate the expression of genes. It targets the hepatic production of PCSK9 and inhibition of its action, effectively increasing the number of available LDL receptors and results in an LDL cholesterol lowering effect.

The efficacy of the drug, which is given via subcutaneous injection, at reducing LDL cholesterol levels was shown in a paper that combined the results of combined the results of two randomised, double-blind controlled, phase 3 trials in patients with LDL cholesterol levels of 1.8 mmol/L or higher.

Use of inclisiran reduced LDL cholesterol levels after 510 days by 52.3% and 49.9% in the second trial.

However, much more importantly, the trials suggested that inclisiran could be given once every six months.

NICE appraisal

In its final appraisal document, NICE has recommended that inclisiran is used in patients with a history of any cardiovascular events (e.g. acute coronary syndrome, coronary or other arterial revascularisation procedures) and where LDL cholesterol levels remain persistently above 2.6 mmol/L, despite maximum tolerated lipid-lowering therapy.

Inclisiran has been previously approved in the EU for the management of adults with primary hypercholesterolaemia or mixed dyslipidaemia as an adjunct to diet in combination with a statin or other lipid-lowering treatment in patients unable to reach their LDL cholesterol targets.

Alternatively, it can be used alone or in combination with any lipid-lowering therapy for patients intolerant of statins.

Despite this licensed use, NICE did not recommend the use of inclisiran as a preventative treatment (i.e. in those with familial hypercholesterolaemia).

While the drug appears to be very effective at LDL cholesterol lowering, NICE accepted the lack of long-term data although ongoing trials should provide this information in the future.

Elevated low-density lipoprotein in childhood highlights the need for early risk screening

23rd July 2021

An analysis of low-density lipoprotein levels in children found similar levels at ages 9 and 18, indicating the importance of early screening.

Elevated levels of low-density lipoprotein cholesterol (LDL-C) leads to the development of atherosclerosis and is a risk factor for cardiovascular disease. Some evidence suggests an association between childhood obesity and the subsequent risk of biochemical abnormalities in adults. Nevertheless, there is a lack of longitudinal data linking the presence of childhood cardiovascular risk factors with adult disease. Furthermore, little is known about the extent to which risk factors such as LDL-C levels vary during childhood and how this might contribute towards atherosclerosis and adverse cardiovascular outcomes in adult life. A better understanding the childhood trajectories of LDL-C cholesterol could lead to improved preventative strategies. In trying to shed more light on this topic, a team from the Division of General Medicine, Columbia University, Irving Medical Centre, New York, turned to data available in the International Childhood Cardiovascular Cohort (i3C) Consortium. While children virtually never experience adverse cardiovascular events, the i3C is the first longitudinal cohort study designed to locate adults with detailed and repeated childhood biological, and physical measurements and includes over 10,000 individuals from several countries. The Irving Medical Centre team used data from i3C individuals who had at least one LDL-C measurement between the ages of 3 and 17 years of age and extracted demographic and body mass index information from these participants. The team considered LDL-C levels greater than 160mg/dl (4.14mmol/l) as consistent with probable familial hypercholesterolaemia (FH) and used the more stringent criteria of an LDL-C of greater than 160mg/dl on at least two occasions and a level of LDL-C of 190mg/dl or greater as a threshold for FH. In order to examine LDL-C trajectories during childhood, the team fitted a linear model of LDL-C against age, adjusting for sex, ethnicity and body mass index.

Findings
A total of 15,045 children with a mean age of 9.9 years (48.7% male) were included in the analysis. Overall, 2.8% of children had an LDL-C greater than 160mg/dl and 0.6% had values exceeding 190mg/dL. Using the more stringent criteria, 1% of children had elevated LDL-C levels (> 160mg/dL) on two occasions and 0.3%, levels above 190mg/dl, consistent with FH. Using the linear model it could be seen that mean LDL-C cholesterol levels increased from age 3 to 10 years, decreased from age 10 to 15 but then increased again to reach adult levels. LDL-C levels were consistently and significantly higher in female children and those of Black ethnicity or with a higher body mass index.

In a discussion of their findings, the authors noted how LDL-C levels peaked between ages 9 and 11 and that these levels were comparable to those aged 18 years. This, the authors suggested, highlighted the importance of childhood lipid screening from as early as 9 years of age.

Citation
Zhang Y et al. Low-Density Lipoprotein Cholesterol Trajectories and Prevalence of High Low-Density Lipoprotein Cholesterol Consistent with Heterozygous Familial Hypercholesterolemia in US Children. JAMA Pediatr 2021