Hasta La Vista, LDL

11. July 2017

A single injection of a short ribonucleic acid removes LDL cholesterol from the blood, according to a study. What is remarkable moreover is that all patients with elevated LDL cholesterol levels responded to the treatment. The success rate was higher than with established statin therapy.

Statins are among the most economically successful drugs in recent decades, even though they do not reliably work in every patient with elevated LDL cholesterol and continually have partly serious side effects.

Two-component drug inclisiran

Scientists at the Charité Berlin and the Berlin Institute for Health Research have together with colleagues from the Imperial College London conducted a phase II study on 501 high-risk patients with elevated LDL cholesterol levels. The point of attack of the new therapy is the enzyme PCSK-9 (proprotein-convertase subtilisin/kexin type 9).

PCSK-9 is mainly present in the liver, binds to the low density lipoprotein (LDL) cholesterol receptor there and degrades it. Thus the enzyme prevents LDL cholesterol from being recognised and metabolised by the cell. If there is too much LDL cholesterol in the blood, there is then a threat of arteriosclerosis, which can result in a heart attack or a stroke.

The active agent known as inclisiran consists of two building blocks: a short ribonucleic acid (siRNA: small interfering RNA) and a “triantennary” N-acetylgalactosamine. The siRNA links up with the messenger RNA (mRNA) of the PCSK gene in the cell nucleus of liver cells and thus prevents the gene from translating a protein. This process is referred to as RNA interference.

The second component, the “triantennary” N-acetylgalactosamine, is a complex sugar molecule which binds to an asialoglycoprotein receptor of the liver cells. It guides the siRNA in the liver cells to the gene of the cholesterol regulator PCSK9, which the siRNA ultimately switches off at the mRNA level. Because inclisiran in so doing acts only in the liver, the cardiologists were able to reduce the concentration of the active agent.

Structure of the phase II study

Patients included were those with an LDL concentration of at least 70 mg/dL and an arteriosclerotic cardiovascular disease, or an LDL concentration of at least 100 mg/dl without arteriosclerotic cardiovascular disease. All patients received statin therapy at the maximum possible dosage for a minimum of 30 days. The patients were divided into eight different groups according to Principle of Randomness: they received either a single dose of a placebo, or in each case 200 mg, 300 mg or 500 mg inclisiran on day 1 of the study. Alternatively they received 2 doses of a placebo, or in each case 100 mg, 200 mg or 300 mg inclisiran on day 1 and day 90 of the study. Inclisiran was administered subcutaneously.

Primary endpoint: LDL concentration after 180 days

The primary endpoint of the study was the LDL concentration after 180 days. The decrease in the LDL concentration was dose-dependent: by as much as 41.9 per cent after a single dose and by as much as 52.6 per cent after a double dose.

Patients who received two doses inclisiran at 300 mg on day 1 and day 90 benefited most from the treatment. 48% of these patients undergoing this treatment regimen had LDL levels of less than 50 mg/dl (1.3 mmol/ l) on day 180.

All patients responded to inclisiran

After 240 days, the PCSK9 and LDL cholesterol levels for all inclisiran treated patients were significantly lower than at the beginning of the study (P<0.001 for all doses vs placebo). “The fact that all patients responded to the treatment without exception is particularly noteworthy. With statin therapy the success rate is lower”, Prof. Ulf Landmesser from the Charité Berlin gives as his comments on the results of the study.

Severe adverse events occurred with 11 percent of the inclisiran treated patients and 8% of the placebo-treated patients. With 5 percent of the patients who received inclisiran in injected form, skin reactions occurred at the injection site. Activation of the immune system, and a platelet decrease – which can occur in some siRNA therapies at the RNA level – were not observed by the cardiologists in this study. There were some patients who had flu-like symptoms, but without an increase in C-reactive protein.

“The long-lasting effect of the treatment, which was visible for nine months after a single dose, is especially interesting to us”, Landmesser says. “In the next step we want to further develop the treatment in a large clinical trial program as a new therapy to prevent heart attack and stroke in high-risk patients”, he added.

How compatible is the therapy?

The randomised phase I study of 69 healthy volunteers with an LDL of at least 100 mg/dl already showed in 2016 that inclisiran can lower LDL levels for 180 days. In this tolerability study, dosages of up to 300 mg were well tolerated. The most common side effects were cough, musculoskeletal pain, nasopharyngitis, head­ache, back pain and diarrhoea. Administration of 500 mg in one male patient was followed by an increase in hepatic enzymes. Serious undesired events did not occur.

Antibody already approved

Two monoclonal antibodies (evolocumab and alirocumab) have been available since 2015 as inhibitors of PCSK9. Both antibodies inhibit the degradation of LDL receptors – albeit through the entire body – and thus promote the uptake of LDL cholesterol in the liver. As a consequence, the LDL concentration in the blood drops. In constrast to siRNA therapy, the antibodies have a crucial disadvantage: their subcutaneous injection must be repeated every 2 to 4 weeks.

Who gets the expensive treatment?

“A study of this length and size cannot, of course, investigate all long-term effects of inclisiran-based treatment”, the cardiologists write. The long-established and – on account of patent-expiry – cost-effective statin therapy will not be replaced by inclisiran. The cost of the promising siRNA treatment, according to the developer’s estimates, will run up to five to ten times as much as statin therapy.

Nonetheless should the positive effect of the siRNA-PCSK9 blocker also be confirmed by long-term study, physicians will be confronted with the question of which patients ought to benefit from this relatively expensive treatment. Given directly to statin-intolerant patients only? Or to patients with a particularly high risk of a cardiovascular event? Or to patients who when treated with statins treatment alone do not achieve good LDL cholesterol levels?


A Highly Durable RNAi Therapeutic Inhibitor of PCSK9
Kevin Fitzgerald et al.; NEJM doi:10.1056/NEJMoa1609243; 2017

Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol
Kausik K. Ray et al.; NEJM, doi:10.1056/NEJMoa1615758; 2017

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1 comment:

Tarek Hussein
Tarek Hussein

could be a turning point in LDL treatment!!

#1 |

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