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Having just enough of a fatty substance (lipid) called cholesterol in your body is important for bodily functions, but having too much of it, known as high cholesterol, can increase your risk of having a heart attack or stroke. Fortunately, high cholesterol treatments are available to control this, and biotechs are working on even more effective ones with a range of different targets that play a role in increased cholesterol levels.
The liver makes roughly 80% of all the cholesterol in your body, while the rest, which your body does not need, comes from food. Although your body should be able to filter out this unnecessary cholesterol, certain factors can prevent this from happening, such as genetic conditions like familial hypercholesterolemia or eating foods high in saturated fats.
The two main types of high cholesterol are named after the two types of lipoproteins that carry cholesterol through the body. These are: LDL (low-density lipoprotein) cholesterol, often referred to as “bad cholesterol”, and HDL (high-density lipoprotein) cholesterol, often called “good cholesterol.” While HDL cholesterol absorbs cholesterol in the blood and carries it back to the liver, which subsequently flushes it from the body, LDL cholesterol, which makes up most of the body’s cholesterol, can potentially build up on the walls of blood vessels if you have too much of it, in turn raising the risk of cardiovascular disease.
Statins, first approved in 1987, are still the most common medication for high cholesterol, and work by reducing the amount of cholesterol your body makes. Other treatment options include bile acid sequestrants, cholesterol absorption inhibitors, and fibrates, as well as PCSK9 inhibitors – a much more recent and revolutionary class of high cholesterol treatment, with Amgen’s Repatha becoming the world’s first approved PCSK9 inhibitor when it was given the green light by the European Commission in 2015.
These medicines work by inhibiting PCSK9, a protein that reduces the body’s ability to remove LDL-C from the blood. Studies show that they can lower LDL cholesterol by up to 60%. Additionally, using them as part of a combination therapy with statins is particularly efficacious, as statins have been shown to upregulate the production of PCSK9.
Nevertheless, PCSK9 inhibitors are currently only prescribed for certain patient populations, such as those who have had a heart attack or stroke already, or those with the genetic condition familial hypercholesterolaemia, which can lead to very high cholesterol levels. This is largely because statins have been around for much longer, and, therefore, there is more data on their efficacy and safety, whereas PCSK9 inhibitors are newer and have less long-term data. PCSK9 inhibitors are also very expensive compared to statins, and their administration is likely more of a burden for patients, as they need to be given via an injection once every two to four weeks.
Biotech and big pharma are now working toward bringing the next generation of high cholesterol medicines to the market, with a variety of candidates currently in the pipeline.
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A growing trend: Targeting the ANGPTL3 gene to reduce cholesterol levels
Several new cholesterol drugs in development target angiopoietin-like 3 (ANGPTL3), a protein encoded by the ANGPTL3 gene that plays a crucial role in regulating lipid metabolism. It primarily acts as an inhibitor of two enzymes involved in lipoprotein metabolism called lipoprotein lipase (LPL) and endothelial lipase (EL). By inhibiting these lipases, ANGPTL3 increases the levels of LDL cholesterol and triglycerides – another type of lipid that poses a risk of cardiovascular disease – in the bloodstream.
A study published in the New England Journal of Medicine in 2017 by scientists from the Regeneron Genetics Center found that patients whose ANGPTL3 gene did not function properly, called a “loss-of-function mutation,” had significantly lower levels of key blood lipids, including LDL cholesterol.
Indeed, in 2021, it was Regeneron’s Evkeeza that became the first treatment to be approved by the U.S. Food and Drug Administration (FDA) that binds to and blocks the function of ANGPTL3. The monoclonal antibody was greenlit due to results from a phase 3 trial that showed that patients with homozygous familial hypercholesterolemia – an ultra-rare inherited condition resulting in extremely high levels of cholesterol in the blood – who took Evkeeza along with other lipid-lowering therapies experienced LDL cholesterol reductions of 49% from baseline on average compared to placebo at 24 weeks.
Now, other drug developers are attempting to target ANGPTL3 with a variety of approaches. For example, CRISPR Therapeutics recently shared positive topline data from a phase 1 trial of its in vivo gene editing candidate CTX310, which is designed to knock out hepatic expression of ANGPTL3, in patients with elevated LDL, triglycerides, or both. The data, retrieved from the first 10 patients across the first four cohorts, demonstrated dose-dependent decreases in triglycerides and LDL cholesterol, with a peak reduction of up to 82% in triglycerides and up to 81% in LDL cholesterol.
Verve Therapeutics is also taking a gene editing approach to targeting ANGPTL3 with its candidate VERVE-201. The in vivo base editing therapy is being developed for two patient populations: patients with refractory hypercholesterolemia, defined as those who are unable to achieve adequate LDL cholesterol reduction with maximally tolerated standard of care therapies, and patients living with homozygous familial hypercholesterolemia. The candidate is currently being tested in a phase 1b trial, with Verve stating last month that it remains on track to provide a program update in the second half of 2025.
Meanwhile, according to recent findings presented at the American College of Cardiology Scientific Session, both Eli Lilly and Jiangsu Hengrui Pharmaceuticals are making headway with their own ANGPTL3-targeting drugs. Eli Lilly’s solbinsiran, a small interfering RNA (siRNA) therapy, was found to reduce apolipoprotein B, a protein involved in the metabolism of lipids such as LDL, in patients with mixed dyslipidemia (a term for unhealthy levels of one or more kinds of lipid in your blood) in a phase 2 trial. Also in a phase 2 study, Jiangsu Hengrui Pharmaceuticals’ monoclonal antibody SHR-1918 was associated with reductions in LDL, triglycerides, and other lipids in patients with suboptimally treated hyperlipidemia (high cholesterol).
The targeting of ANGPTL3 certainly appears to be a growing trend in the field of high cholesterol, and it is likely that we will see more therapies enter the clinic in the coming years, especially if the ones mentioned above are successful in progressing through late-stage trials.
Arrowhead’s APOC3-targeting RNAi cholesterol treatment shows promise in multiple studies
Arrowhead Pharmaceuticals is working on the development of an RNA interference (RNAi) therapy, called plozasiran, which is designed to reduce the production of apolipoprotein C-III (APOC3), a protein found on triglyceride-rich lipoproteins (TRLs), remnant lipoproteins, and HDL that is involved in slowing the clearance of TRLs and increasing plasma triglycerides and cholesterol.
Plozasiran is being investigated in multiple clinical trials, including phase 3 studies in patients with familial chylomicronemia syndrome (a rare, genetic disorder characterized by extremely high levels of triglycerides in the blood) and severe hypertriglyceridemia (defined as triglyceride levels of 500 mg/dL or higher). In the familial chylomicronemia syndrome study, Arrowhead’s drug achieved deep and durable reductions in triglycerides with a median change from baseline of 80% in the plozasiran 25mg group, and a statistically significant 83% reduction in the risk of developing acute pancreatitis compared to placebo in the pooled plozasiran 25mg and 50mg group.
Additionally, Arrowhead presented results last year from a phase 2b study evaluating plozasiran in adults with mixed hyperlipidemia, a condition characterized by elevated levels of both LDL cholesterol and triglycerides. In the trial, the drug was shown to significantly lower triglyceride levels with commensurate reductions in APOC3, non-HDL cholesterol, and remnant cholesterol. Based on the positive results from the phase 2 study, Arrowhead announced that it is advancing plozasiran into a phase 3 trial in patients with mixed hyperlipidemia and residual risk of atherosclerotic cardiovascular disease.
The therapy has been granted orphan drug and fast track designations by the FDA, as well as orphan drug designation in Europe. According to a report from GlobalData, if approved, it could reach sales of around $707 million by 2032, thanks to its ability to fill a gap in the market; its promise in reducing triglycerides and APOC3 means that it could be used to treat many forms of dyslipidemia, a family of diseases in which lipids or lipoproteins are found in extremely high or low amounts in the blood.
Amgen, Novartis, and Eli Lilly go after lipoprotein(a) to reduce cholesterol levels
Some of the biggest names in industry have chosen to go after a protein particle called lipoprotein(a) in their attempt to tackle high cholesterol. The particle is essentially a type of lipoprotein that is similar to LDL cholesterol, but with an additional protein called apolipoprotein(a) attached to it. And, just like LDL, elevated levels of lipoprotein(a) are a significant risk factor for heart disease, stroke, and other cardiovascular problems.
Amgen took the lead in this space in 2022 when it reported placebo-adjusted lipoprotein(a) reductions of 95% in its phase 2 trial that suggested its interfering RNA treatment, olpasiran, had an advantage over Novartis’ antisense therapy, pelacarsen, which is also being investigated to reduce lipoprotein(a). Additionally, almost one year after stopping olpasiran, lipoprotein(a) levels in people who took olpasiran remained 40% to 50% lower than patients on placebo.
Both Amgen and Novartis gained access to their drugs through licensing deals with Arrowhead and Ionis, respectively. They are currently both in phase 3 trials that are scheduled to be completed next year.
Meanwhile, Eli Lilly is developing an siRNA candidate called lepodisiran that is designed to lower the production of lipoprotein(a). In March 2025, the big pharma announced that lepodisiran significantly reduced lipoprotein(a) levels by an average of 93.9% over the 60 to 180-day period after treatment with the highest tested dose (400mg), meeting the primary endpoint of its phase 2 trial.
Rising prevalence of cardiovascular and lipid disorders is driving development of new therapies
The presence of lipid disorders in the global population is rising due to factors like dietary changes, sedentary lifestyles, and increasing obesity rates. This trend is particularly concerning as these types of disorders are a major risk factor for cardiovascular disease, which is the leading cause of death worldwide, responsible for an estimated 17.9 million deaths annually.
This rise in prevalence is also what is driving the development of new therapies aimed at tackling high cholesterol. As an example, the ANGPTL3 inhibitor market is now witnessing significant growth and is expected to surge significantly by 2034 because of the rising prevalence of cardiovascular and lipid disorders, particularly familial hypercholesterolemia. Additionally, the anticipated launch of emerging therapies by key companies like those mentioned in this article will further boost the market.
The lipid-lowering drugs market size as a whole is expected to increase from $35.46 billion in 2025 to approximately $48.11 billion by 2034, expanding at a compound annual growth rate (CAGR) of 3.45% during the forecast period. Once again, the global rise in cases of cardiovascular diseases is cited as the main reason for this growth.
Needless to say, this makes the buzz of activity currently going on in the high cholesterol treatment space extremely positive, with patients likely to have access in the coming years to a variety of different treatments that can help them reduce one of the main risk factors for cardiovascular events.
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