RNAi for hypercholesterolemia enters Phase III trial with NHS

Written by Alexander Marshall
Clinical trials Gene editing Heart News UK and Europe

The National Health Service (UK) has granted permission for Inclisiran, an RNAi drug developed by Alnylam Pharmaceuticals (MA, USA), to enter a Phase III clinical trial for cardiovascular disease.

The National Health Service (NHS; UK) has given approval for Inclisiran to enter into a large Phase III clinical trial for atheroschlerosis and cardiovascular disease after reaching an agreement with the drug’s new owner Novartis (Basel, Switzerland). The partnership with the NHS was announced at a conference on healthcare investment in San Francisco (CA, USA), by Lord Prior, the chair of NHS England.

High cholesterol and the associated heart conditions significantly impact the NHS ever year with millions of people taking medication to manage the condition. The simple injection of the cutting-edge, RNAi treatment — originally developed by Alnylam Pharmaceuticals’s (MA, USA) — into the patient every 6 months could replace the current treatment regime if successful, saving an estimated 30,000 lives over the next 10 years.

While high cholesterol can currently be medicated and managed in most patients, the regime centers around statins, a class of pills with a history of patient-horror stories and scare-mongering, which leads many to give up on the treatment. Statins are effective in around 50% of patients and can have a range of side effects, but there are a large variety of drugs available and changing brands can often suit a patient better. Unfortunately, following poor experiences, it can be difficult to convince patients to resume their treatment, leaving them vulnerable to atherosclerosis, heart attacks and strokes.

The new RNAi treatment, Inclisiran (also known as ANL-PCSSC), will target the transcription of PCSK9, a gene which regulates the cholesterol levels within the bloodstream through the availability of low-density lipoprotein receptors. Utilizing endocytosis, the low-density lipoprotein receptors internalize the low-density lipoproteins:lipid complexes from the blood and into cells; these complexes are then degraded, along with PCSK9, within a lysosome. By removing PCSK9 from the complex, however, the receptor escapes the degradation within the vesicle and returns to the surface membrane to collect more low-density lipoprotein.

In smaller early trials, the drug was capable of cutting the blood cholesterol level in half, so the Novartis team will probably be hopeful for positive results on the effect of cardiovascular events, and then the quick roll out of the treatment; however, some, such as Professor Naveed Sattar (University of Glasgow, UK), warn that while it appears promising, there has yet to be any long term data for the treatment.

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