Sekar Kathiresan, M.D.
Co-Founder and Chief Executive Officer, Verve Therapeutics
People with high cholesterol need daily medication to lower their risk of heart disease. A ‘one and done’ treatment that could lower cholesterol permanently is in development.
High cholesterol can be a killer. Worryingly, while cholesterol-lowering medications are readily available, many people who need these drugs are not taking them properly — this can be due to a variety of reasons including high costs of medication, side effects, issues with access or poor adherence. Consequently, these individuals are at increased risk of developing potentially fatal atherosclerotic cardiovascular disease (ASCVD).
Why cholesterol can be dangerous to health
It’s important to put cholesterol in context, however. This lipid, or fat, which is produced in the liver, gets bad press — but not all cholesterol is harmful. Indeed, a certain amount of it is important for our metabolism, hormone production and tissue repair.
However, a potentially life-threatening problem occurs when high levels of low-density lipoprotein cholesterol (LDL-C) — so-called ‘bad cholesterol’ — cause fatty deposits to build up in the arteries over time.
“As we age, this can result in atherosclerotic cardiovascular disease, which is the leading cause of death worldwide,” explains Dr. Sekar Kathiresan, Co-Founder and Chief Executive Officer of genetic medicines company, Verve Therapeutics. “If the arteries become clogged or blocked due to LDL-C, blood flow can be restricted or cut off. The outcome can be a stroke or heart attack.”
Keeping ‘bad cholesterol’ low for as long as possible
Fortunately, the solution to this global health problem is well-understood. To prevent ASCVD, it’s necessary to keep LDL-C as low as possible, for as long as possible. The challenge is that, while this is straightforward in theory, it’s not so easy to do in practice.
“Cholesterol-lowering medications can be delivered via daily pills or intermittent injections,” says Dr. Kathiresan. “Yet, there is still a large unmet need because the majority of patients who should have this type of treatment are not receiving it. Take those with ASCVD who have already had a heart attack. Only 50% of them are taking any sort of medication to lower their cholesterol. That’s an unbelievably low figure.”
The chronic care model for disease is broken.
Genetic disease causing high cholesterol
Then, there are the approximately 3 million patients in the U.S. and Europe who have heterozygous familial hypercholesterolemia (HeFH) — a genetic condition that causes extremely high cholesterol levels from birth. More than 95% of these patients have not achieved their LDL-C goal.
Why not? It can be a challenge to reduce LDL-C to guideline-recommended levels in HeFH patients because of the current model of care for chronic disease, acknowledges Dr. Kathiresan. A new treatment approach could be beneficial to reduce the global burden of HeFH.
Why the care model to treat chronic disease is broken
There is a fundamental reason why many people with high levels of LDL-C remain untreated, Kathiresan explains: the chronic care model for disease is broken. “That’s because patients have to be motivated to take a daily pill, or be given a regular injection, for several decades,” says Dr. Kathiresan. “They have to choose to do it — and they have to remember to do it. They also need regular access to the healthcare infrastructure. This puts a heavy burden on patients, providers and the healthcare system as a whole.”
Certainly, the statistics regarding patient adherence to cholesterol-lowering drugs are alarming. Statins are the standard of care for patients who are at increased risk of ASCVD. Taken daily, they remain one of the most commonly used and effective drugs for reducing LDL-C. Even so, studies show that long-term statin use is extremely low; less than 25% of people who are prescribed the medication are still taking it five years later.
Fortunately, gene editing technology could change the treatment paradigm of cardiovascular disease by offering a more convenient — and, crucially, permanent — cholesterol-lowering solution.
A revolutionary concept that turns off a cholesterol-raising gene
Verve has been pioneering a pipeline of genetic medicines for patients who have or are at risk of developing ASCVD. The company’s first medicine being studied in clinical trials, VERVE-101, can be delivered in just one or two hours by intravenous infusion and has the potential to dramatically lower LDL-C levels. The key point here, though, is that it is a ‘one and done’ single treatment, explains Dr. Kathiresan.
“Once a patient receives the treatment, there’s a potential that their LDL-C will be lowered for life. A one and done treatment could improve the way patients with ASCVD are treated,” he says.
Dr. Kathiresan and the Verve team began to develop the treatment when researchers discovered a group of people who lacked a cholesterol-raising gene called PCSK9. “We realised they had hit the jackpot,” he says. “They lacked the gene but were fit and healthy and had very low levels of LDL-C in their blood, and this lifelong low blood cholesterol naturally protected them from the risk of heart attacks. Our idea was to develop a medicine that could mimic the natural protection they experienced by turning off the PCSK9 gene in high-risk people.”
Once a patient receives the treatment, there’s a potential that their LDL-C will be lowered for life.
Studying the safety and efficacy of treatment in clinical trials
Verve is pursuing this with a next-generation gene editing technology called base editing. While first-generation gene editing technology cuts the DNA in the gene in a specific location, base editing offers an even more targeted approach — making just a single spelling change in the DNA sequence of the PCSK9 gene turns off PCSK9 protein production by the liver, ultimately, lowering LDL-C levels in the blood. Dr. Kathiresan likens it to correcting a spelling mistake with a pencil, erasing and rewriting a specific letter in the gene.
Verve is currently studying the safety and efficacy of the treatment in clinical trials in both the UK and New Zealand, and initial data is expected later this year. “This is the first time this kind of medicine has ever been tested in patients,” says Dr.Kathiresan. “It’s a remarkable concept — like molecular surgery. Our first two investigational medicines are designed to target PCSK9 safely and effectively, an approach that has been validated by human genetics and pharmacology”.
Value of developing additional treatment options for patients
Understanding the vast unmet medical need in ASCVD, Verve is working as expeditiously as possible to provide patients with an additional treatment option that could be a longer-term solution. “We began this journey in 2018,” Dr. Kathiresan says. “On average, it takes 10 to 12 years for drugs to go through the development and trials process and then receive approval from the UK regulator — the MHRA (The Medicines and Healthcare products Regulatory Agency) — and the US regulator — the FDA (Food and Drug Administration).” If approved by the MHRA in the UK, Dr. Kathiresan hopes that it will be made available through the National Health Service (NHS).
Dr. Kathiresan’s research and founding of the company stems from his family’s connection to ASCVD. “There is a history of high cholesterol in my family,” he reveals. “My brother passed away when he was just 42 after a heart attack. One of the motivations behind Verve was the realisation that we need to do more to avert such tragedies.”
This isn’t about replacing conventional therapies, notes Dr. Kathiresan. The company’s aim has always been to develop additional treatment options that could benefit patients and their healthcare providers. “We think a ‘one and done’ medication could add real value,” he says. “It’s new, it’s exciting and, if approved, it could offer a single treatment alternative for those who need to lower their cholesterol.”