A novel anti-cholesterol drug known as inclisiran has been shown to reduce cholesterol levels in patients by as much as 53%, according to a new study. The research, completed by scientists at Imperial College London and published in the New England Journal of Medicine, demonstrated that by manipulating the RNA interference system, inclisiran could effectively silence one of the genes linked to elevated cholesterol levels. This is thought to be the largest trial so far to test the efficacy and safety of this type of therapy.

High levels of low-density lipoprotein (LDL) cholesterol have previously been closely linked with cardiovascular disease and obstructions of blood vessels, both of which can lead to heart attack or stroke. Currently the main treatment methods for reducing LDL levels use a combination of improved diet and exercise, alongside a class of drugs called statins. While statins can be effective in some patients, many people are unable to tolerate higher doses and the drugs need to be taken continually. Additionally, some patients taking high doses of statins will not see an improvement in their LDL levels.

This new study examined the effects of injecting patients with inclisiran, either alone or with statins. The team worked with 497 patients with high cholesterol and an increased risk of cardiovascular disease, recruited from Canada, the USA, Germany, the Netherlands, and the UK. 73% of the participants were taking statins prior to the start of the study and 31% were taking a drug called ezetimibe, which lowers LDL levels by restricting cholesterol absorption in the small intestine. Any patients currently taking monoclonal antibodies to treat high cholesterol were excluded from the study.

The patients were given a single dose of inclisiran, two doses three months apart, or a placebo. All groups were then monitored periodically for the following 8 months, through blood tests and side effects. The group receiving a single 300mg dose displayed LDL levels 42% lower after 6 months, compared with an increase of 2% in the matched placebo group. Participants who received two 300mg doses showed a decrease of up to 53% after 6 months, and all participants displayed at least some level of decrease. 48% of the two-dose group had cholesterol levels below 50 ml/dl after the trial.

“These initial results are hugely exciting for patients and clinicians,” said Professor Kausik Ray, lead author of the study from the School of Public Health at Imperial. “We appear to have found a versatile, easy-to-take, safe, treatment that provides sustained lowering of cholesterol levels and is therefore likely to reduce the risk of cardiovascular disease, heart attacks, and stroke. These reductions are over and above what can be already be achieved with statins alone or statins plus ezetemibe, another class of cholesterol-lowering drug.”

The team intend to continue their monitoring of the participants for a further four months, bringing the total study time to a year. Once that is completed, the next stage in inclisiran development will be to perform a longer study with more patients to examine what effect the drug has on the frequency of heart attacks or strokes.

The paper also stresses that inclisiran uses a different biological pathway to statins. It is therefore likely that the best results will come from patients who take statins and inclisiran together to keep cholesterol levels down.

“Even the single dose of inclisiran appears to lower cholesterol by 35-40% at eight months,” said Professor Ray. “We could essentially experiment with how often to give the drug based on levels of cardiovascular risk for each patient. Lower risk patients could in theory have once yearly injections whereas higher risk patients might have two injections a year.”

The conclusion of the phase 2 trial is a good indication that inclisiran may be an effective, safe treatment for high cholesterol in the future, but more work is needed before it can be considered a part of clinical practice. However, this is a good step forwards in creating a manageable treatment plan for a common problem.

“The effectiveness of statins and other cholesterol-lowering treatments such as monoclonal antibodies relies on patients’ ability to take them consistently,” Professor Ray said. “Therefore, giving inclisiran up to twice yearly at a GP surgery, much in the same way flu vaccinations are provided, might be more effective. We believe that these clinical visits might only be twice a year at most, so ultimately, they are more convenient and more effective for patients and their health.”

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