Can Sekar Kathiresan kill heart attacks?

Dr Sekar Kathiresan, cofounder and chief executive officer of Verve Therapeutics.
Dr Sekar Kathiresan, cofounder and chief executive officer of Verve Therapeutics.

Summary

  • Early results of the researcher’s path-breaking gene editing treatment to permanently reduce cholesterol and prevent heart attacks have been mixed

Chennai: Dr Sekar Kathiresan, co-founder and chief executive officer (CEO) of Boston-based Verve Therapeutics, hails from a family that is genetically prone to heart attacks. Myocardial infarctions, as heart attacks are medically known, cause 32% of all deaths worldwide, and claimed the lives of his grandmother, uncle and elder brother. His father, too, had suffered a heart attack but survived. It was this constant threat that drove the India-born doctor to become a cardiologist. Sek, as he is referred to by friends and colleagues, completed his medical studies in 1997. Not content with just treating cardiovascular disease (CVD), he immersed himself into genetics, in the hope of finding a way to prevent heart attacks.

In 2018, Sekar co-founded Verve Therapeutics with the goal of finding a way to permanently lower cholesterol. He aims to do this in a very different and more effective way—meaning, no more daily pills, constant monitoring of risk factors, or periodic hospital visits. The clinical stage startup is in the process of developing a single-dose gene-editing drug that will try to switch off the gene in the liver that causes elevated levels of low-density lipoprotein cholesterol (LDL-C).

“Verve was born out of the deep conviction that cholesterol can be lowered permanently," Sekar, 52, told Mint in a telephonic conversation from Boston in the early hours.

On 12 November, Verve released its first early-stage human trial data. The next day the company’s stock was hammered on the bourses, crashing 40% to $8.66 on the Nasdaq. The results of the clinical trial, which analysts perceived as underwhelming, were the reason for the carnage.

While the trial established the fact that gene-editing does work, and helped reduce LDL-C levels in patients who otherwise did not respond to cholesterol-lowering medication (it did so by 55%), the accompanying side-effects were unnerving. One patient died and another suffered a heart attack. The 55% efficacy, in the analysts’ view, was not too different from levels the latest versions of traditional cholesterol drugs were delivering.

The market reaction is an indication of the tough path ahead for Verve, as regulators will tighten the screws and increase oversight considering the risks that the clinical trial data outlined. “The regulators’ concern is understandable. What is the guarantee that gene-editing medicine edits only defective genes?" asks Dr Devi Shetty, cardiac surgeon, founder and chairman of Narayana Health, a private hospital network.

Clearly, Sekar and his team at Verve have to navigate a plaque-ridden path before they can find a breakthrough to save the world from heart attacks.

Early Days

Sekar’s family is originally from Viramathi, a village in Sivaganga district in southern Tamil Nadu, 370 km from Chennai. His father, an engineer, enrolled in the University of Pittsburgh for a PhD programme on a full scholarship. He left for the US in 1975, leaving Sekar, 4, and his brother Senthil with their grandparents. “He could not afford to take all of us," Sekar recalls.

The brothers studied in a boarding school and grew close. “It was a very difficult period. I did not hear my parents’ voice for five years as we did not have a phone at home," he says. It was only in 1980, after his father had completed his PhD, that the brothers joined their parents in the US. They settled in Pittsburgh. Sekar graduated in History and then shifted his focus to medicine, motivated by the premature deaths in his family from heart attacks. He studied medicine at Harvard Medical School and completed his clinical training in internal medicine and cardiology at Massachusetts General Hospital in 2003. It did not take him long to realize that treating CVD was a losing battle.

Despite advances in treatment, deaths on account of CVD have reached epidemic proportions. One person dies from the disease in the US every 34 seconds. In the US alone, there are 800,000 heart attacks each year. “Across the world, CVD is the leading cause of deaths and its incidence has increased significantly in the last 20 years. This is even more so after the covid-19 pandemic," says Dr Sowmya Swaminathan, former chief scientist, World Health Organization, who is currently chairperson of the Chennai-based MS Swaminathan Research Foundation.

The situation in India is not very different. Heart attacks account for the bulk of deaths caused by non-communicable diseases. Also, CVD strikes at least a decade earlier in India than in Western countries. The CVD death rate in the country, at 272 per 100,000 people, is far higher than the global average of 235 deaths. In fact, the country has the dubious reputation of being known as the ‘chronic heart disease capital of the world’.

Shift to genetics

 It is possible to permanently reduce cholesterol by switching off certain genes and help people lead a healthy life without fear of a heart attack, Sekar Kathiresan says.
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It is possible to permanently reduce cholesterol by switching off certain genes and help people lead a healthy life without fear of a heart attack, Sekar Kathiresan says.

Sekar began to think big. He wanted to prevent CVDs rather than treat them. In 2008, he entered the world of genetics. Over the next decade, he studied the genetics of coronary heart diseases, identifying markers for heart attacks. He focussed on prevention of myocardial infarctions in individuals with a family history of the disease.

In 2012, he studied the genes of over 100,000 people to ascertain if the presence of high-density lipoprotein cholesterol (HDL-C), or good cholesterol as it is colloquially known, would reduce the risk of heart attacks. His results stunned the pharma and medical world. Sekar was able to establish that patients with higher HDL-C levels were not immune from heart attacks. Some global pharma majors, who were busy developing drugs to boost HDL-C levels in humans, were forced to withdraw them, media reports stated at that time.

In 2018, Sekar was awarded the Curt Stern Award by the American Society of Human Genetics for his research contributions.

The sudden death of his otherwise healthy brother Senthil, 42, due to a heart attack forced Sekar to move from research to the industry. He wanted to translate all that he had learnt into a solution to prevent heart attacks. “By then I had understood that if cholesterol is low, it is very difficult to get a heart attack. And that it is possible to permanently reduce cholesterol by switching off certain genes and helping people lead a healthy life without fear of a heart attack," he says.

That led him to start Verve. With initial funding of $60 million from Google Ventures and a few other funds, Verve began work to develop a drug that would edit the faulty genes that lead to the elevation of LDL-C in the blood. The goal was to develop a one-shot medication that would permanently reduce cholesterol.

Gene-editing

Gene-editing is a process by which a permanent change is made in the defective target gene causing an underlying disease.
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Gene-editing is a process by which a permanent change is made in the defective target gene causing an underlying disease. (Pixabay)

Human DNA has four types of bases (sets of genetic letters): Adenine (A), Cytosine (C), Guanine (G) and Thymine (T). These bases are present as pairs in the DNA and each human genome consists of six billion base pairs. A single misspelling in the code can cause serious illness.

Gene-editing is a process by which a permanent change is made in the defective target gene causing an underlying disease. For instance, the liver produces a protein called PCSK9. High levels of PCSK9 result in elevated levels of LDL-C in patients, and this is a major cause for heart attacks at a younger age. The liver generates a higher amount of PCSK9 protein due to a genetic defect. This condition is called heterozygous familial hypercholesterolemia (HeFH), and 20 million adults suffer from it across the world.

Verve is developing medicines that will make a single A-to-G spelling change at a specific site in the PCSK9 gene, thereby switching it off. This disrupts production of the PCSK9 protein by the liver, resulting in lower levels of LDL-C, and a permanent reduction in cholesterol. This will prevent a patient from having a heart attack.

“For people with HeFH, regular medication involving statins does not work, and as a result they have a high risk of heart attack at an early age. For them, gene-editing medicines are a miracle," says Shetty. Swaminathan agrees; “gene-editing has a lot of potential. In plants there are already a lot of applications. It will be useful to treat humans with genetic disorders," she says.

CRISPR-Cas9, which has come to be known as a genetic scissors, is the most common form of gene-editing technology in use today. Once activated, it cuts out the target DNA. But CRISP-Cas9, according to Verve, does not have full control of the editing outcome. And so, the company has opted to go with a next-generation gene-editing technology called base editing, which has not been used before in treating CVD. “CRISP-Cas9 is not precise and can lead to unwanted DNA modifications. On the other hand, base editing has the ability to erase and rewrite a specific letter in the gene," says Sekar, explaining the rationale.

Not an easy start

Sekar’s company Verve had mixed results in human trials in the UK and New Zealand. The US FDA has looked at the data and allowed human trials to go ahead.
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Sekar’s company Verve had mixed results in human trials in the UK and New Zealand. The US FDA has looked at the data and allowed human trials to go ahead.

Despite opting for a safer form of gene-editing, Verve’s initial journey was not easy. In July 2022, it started human trials in New Zealand and the UK on patients with an inherited form of high cholesterol. That November, however, the US Food and Drug Administration (FDA) put a clinical hold on Verve’s plan to test its medicine in the US. This was the company’s first major setback. The FDA was closely scrutinizing all gene-editing medicines as it had safety concerns about permanently altering human DNA. Earlier, it had paused applications for gene-editing drugs by Vertex Phamaceuticals and CRISPR Therapeutics. A similar request by Beam Therapeutics was also halted.

Almost a year later, in October 2023, the FDA lifted the clinical hold, after Verve addressed the regulator’s questions. “We answered all their questions and concerns. They also looked at our phase-1 clinical trial data from New Zealand and the UK before giving us the go-ahead," says Sekar.

On 12 November, Verve released the early-stage data of VERVE 101, a phase-1 human trial involving 10 HeFH patients and the base editing technique. One month after the treatment, three patients who were given the two strongest doses showed LDL-C reductions of up to 55%. This clearly established that gene-editing to reduce cholesterol using base editing works. But analysts were unhappy. They were worried about two elements of the interim data. One, the side effects. Patients who received a low, sub-therapeutic dosage (a dosage lower than what will eventually be given to patients) showed strong side effects. One patient died after a month while another suffered a heart attack the very next day. Also, some patients showed elevation in a liver enzyme, which analysts felt was a potential sign of liver damage.

Verve’s chief scientific officer, Andrew Bellinger, told analysts that the elevation was transient, asymptomatic, and would cause no long-term damage to the liver. But the analysts were worried about whether, given the safety issues, regulators would allow the trial to proceed to the next stage. Their fears proved to be unfounded.

“The Data Safety Monitor Board has reviewed the side effects and has given the go-ahead for the trial to proceed to the next stage. The US FDA also looked into the data before approving human trials in the US," says Sekar. Verve’s stock price has since rebounded to $13 levels.

The second issue was efficacy. A 55% reduction is LDL-C is not significant, analysts asserted, considering that existing drugs, which do not require any permanent change to the DNA, reduce LDL-C levels by similar levels. Novartis’ recently approved PCSK9 drug Leqvio, which is injected twice a year, brings down LDL-C by 50%. There are other drugs that reduce cholesterol by even 60%.

“This is a misunderstanding," explains Sekar. “Our medicine has delivered a 55% reduction in LDL-C among patients who have HeFH. Such patients are difficult to treat as medicines don’t work on them. The drugs from competition showed 50% efficacy on patients with moderate levels of cholesterol."

He explained that it took a while for the market to realize the other aspect of the results. For instance, the drug established strong durability. Six months after treatment, the patients continued to show a 55% reduction in LDL-C levels. “The monkeys that we first tested the drug on have shown reduced levels even two-and-a-half years after the dosage," says Sekar. This is an important parameter as Verve is developing a single-dose medicine and its efficacy has to be long-lasting.

One thing is certain: Verve is many years away from releasing its first product in the market and earning its first dollar of revenue. Keeping that in mind, it has been raising funds periodically. The company came out with an IPO in 2021 and followed up with more public and private offerings, one as recent as earlier this month. “Cumulatively we have so far raised $1.1 billion. We have $640 million in the bank. That is good enough to last us till the end of 2026," says Sekar.

Even assuming he succeeds, and Verve launches a drug, the moot question is how costly the treatment will be. “It will be very costly initially. Only those with conditions such as HeFH will use it. It will gradually become affordable and will be useful to people with moderate levels of cholesterol," says Shetty. However, Swaminathan doesn’t see it becoming a common standard of treatment. CVD will continue to be tackled by attending to risk factors such as diet, alcohol, tobacco, diabetes and air pollution, she adds.

Sekar begs to differ. “Our medicine is different from all other gene-editing therapies as it is based on mRNA technology, which some covid vaccines were developed on. This will ensure that the cost of making it is reasonable and will be affordable to all," he says.

mRNA technology is simple, and products based on it can be produced in a laboratory easily, without investment in costly facilities. Usage, as a result, will not be restricted to those with genetic defects but will be open to all those who have suffered a heart attack. “Almost 5% of the world’s population has suffered a heart attack," he adds. It will thus become a common standard of treatment, asserts Sekar.

The good news is that the FDA, on December 9, greenlighted a gene-editing treatment for the first time, when it approved a drug to treat Sickle Cell disease, an inherited blood disorder. The approval indicates that regulators are now open to permitting gene-editing therapies, as long as they work and do so safely. The ball is in Verve’s court to deliver an effective and safe gene-editing treatment to reduce cholesterol. “We will have our drug in the market by the end of this decade," says a confident Sekar.

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