Laroprovstat

Table of contents

• What is laroprovstat?
• How does laroprovstat work?
• Which conditions is laroprovstat studied for?
• How is laroprovstat given?
• What do the clinical trials show?
• What side effects are known?

What is laroprovstat?

Laroprovstat is a chemically synthesised small-molecule medicine being developed as an oral treatment for high cholesterol. It is also known by its development code AZD0780.^[2] The substance is classified in the cardiovascular disease therapeutic area and is supplied by AstraZeneca AB.^[3] According to the product records in the EU Clinical Trials Information System, laroprovstat has no marketing authorisation and remains an investigational substance.^[1] A peer-reviewed article published in Circulation describes laroprovstat as the first oral small-molecule PCSK9 inhibitor for the treatment of hypercholesterolaemia.^[7]

How does laroprovstat work?

Laroprovstat inhibits a protein called PCSK9 (proprotein convertase subtilisin/kexin type 9). PCSK9 normally marks LDL receptors in the liver for destruction. By blocking PCSK9, laroprovstat allows more LDL receptors to remain on the surface of liver cells, which helps the liver remove more LDL cholesterol from the blood.^[7] Unlike earlier PCSK9 inhibitors, which are given by injection, laroprovstat is a small molecule that can be taken by mouth.^[7]

Which conditions is laroprovstat studied for?

• Heterozygous familial hypercholesterolaemia — an inherited condition that causes very high LDL cholesterol from birth and raises the risk of early heart disease. One Phase 3 trial with 473 participants studies laroprovstat in this population.^[2]
• Hypercholesterolaemia — a general term for elevated cholesterol levels in the blood. Two Phase 3 trials test a fixed-dose combination of laroprovstat with rosuvastatin in people with this condition.^[5][4]
• Atherosclerotic cardiovascular disease — a condition in which fatty plaques build up inside arteries, increasing the risk of heart attack, stroke and poor circulation. Two large Phase 3 trials study laroprovstat in people with this disease or at high risk of it.^[3][1]
• Hyperlipidemia — a broader term for high levels of fats in the blood, including cholesterol and triglycerides. One Phase 3 trial lists hyperlipidemia together with atherosclerotic cardiovascular disease.^[3]

How is laroprovstat given?

Laroprovstat is given as a film-coated tablet for oral use.^[2] The product records describe the pharmaceutical form as a film-coated tablet and the route of administration as oral use.^[3] A paediatric investigation plan decision from the UK medicines regulator also lists the pharmaceutical form as film-coated tablet and the route as oral use.^[6] In two of the Phase 3 trials, laroprovstat is studied as a fixed-dose combination with rosuvastatin, a widely used statin.^[5][4]

What do the clinical trials show?

Five Phase 3 trials involving laroprovstat are authorised in the EU Clinical Trials Information System, all sponsored by AstraZeneca. All five are interventional studies and all are currently authorised but not yet reporting results.^[1]–[5]

The largest trial is a cardiovascular outcomes study with 15,100 planned participants. It measures the time to a first major adverse cardiovascular event, defined as cardiovascular death, myocardial infarction, ischaemic stroke, acute lower limb ischaemia, major amputation due to vascular disease, or urgent arterial revascularisation — a composite endpoint called MACE PLUS.^[1]

A second large trial with 3,104 participants studies laroprovstat in people with hyperlipidemia and atherosclerotic cardiovascular disease or at risk of such disease. Its primary outcome is the relative change in LDL cholesterol from baseline to 12 weeks.^[3] A third trial with 473 participants focuses on heterozygous familial hypercholesterolaemia and uses the same 12-week LDL cholesterol change as its main measure.^[2]

Two further trials evaluate a fixed-dose combination of laroprovstat with rosuvastatin. One, with 200 participants, compares the combination against rosuvastatin alone in people with hypercholesterolaemia, measuring the relative change in LDL cholesterol at 8 weeks.^[5] The other, with 515 participants, compares two strengths of the combination against placebo, rosuvastatin and laroprovstat alone in people who have not previously received lipid-lowering treatment.^[4]

None of the five trials has reported results yet. The registry records describe the studies as authorised, meaning they have received regulatory approval to proceed but have not yet published outcome data.^[1]–[5]

What side effects are known?

The Phase 1 trial published in Circulation provides information on laroprovstat in treatment-naïve patients, but the available source does not list specific side effect frequencies in the excerpt provided.^[7] The Phase 3 registry records do not yet report safety data because the trials are still ongoing.^[1]–[5]Side effect information will become available as the trials report results.