Podcast recap: Sek Kathiresan on developing gene editing for cardiovascular disease

In the latest episode of The Genetics Podcast, host Patrick Short speaks with Dr. Sekar (Sek) Kathiresan, CEO of Verve Therapeutics and SVP, Head of Obesity Research and Early Development at Eli Lilly. Sek spent the first part of his career as a cardiologist and geneticist at Mass General Hospital and the Broad Institute. His research found mutations that give people naturally low cholesterol and a much lower lifetime risk of heart attack.

His argument runs through the whole conversation. Heart disease builds over decades, so the medicines with the most impact will copy nature's protective mutations: lower LDL early, keep it low for life, and do it once.

The discussion covers how that idea became a one-time gene editing therapy and the phase 1 results for VERVE-102. It also covers what recent trial failures mean for genetic target validation, and where obesity treatment goes next.

Protective mutations pointed to one target

Sek's move from genetics research to therapeutics followed a family history of early heart attacks. His uncle, grandmother, and father all had heart attacks at a young age. In 2012, his brother died after a heart attack at 42, and Sek began asking whether he should work on therapeutics that could prevent that outcome.

The scientific basis came from studying resistance rather than risk. Around 2008, his team applied exome sequencing, then newly available, to a three-generation St. Louis family with LDL cholesterol near 30 mg/dL. Two family members turned out to be human knockouts for ANGPTL3, a result published in the New England Journal of Medicine.

Sek noted that he and others went on to identify nine genes where mutations led to low lipids and protection from coronary heart disease. All nine pointed to cholesterol.

Other groups had already pursued targets such as PCSK9 with monoclonal antibodies and siRNA. Sek's design choice was to mimic the human genetics directly and keep cholesterol low for a long time. That became Verve.

The unmet need in cardiovascular prevention is efficacy

In 2018, Sek recalled, the idea was polarizing. Critics pointed out that statins and RNA therapeutics already offered convenient options.

Sek listed four risks the company faced at the start: biology, editing technology, regulatory, and commercial. He described the biology risk as well de-risked, and long-term safety as a work in progress. He also challenged the usual framing of the problem.

Sek noted that lowering LDL by 40 mg/dL for five years reduces risk by about 22%. The same lowering sustained for a lifetime is estimated to cut risk by almost 90%.

He added that one in five to almost half of patients stop cholesterol-lowering medication within a year. These drugs are meant to be taken for 40 years, so those patients do not reach even the 22% reduction seen in trials.

Heart disease as an area under the curve problem

Sek's model for the disease explains why duration carries so much weight.

"I think this disease is a cumulative exposure problem. It's an area under the curve problem. What we're trying to do is maximize that degree of reduction in two axes: on the Y axis, which is the amount of reduction, but more importantly the X axis, which is time duration."

Timing follows from the same logic. Sek pointed out that LDL lowering typically begins after someone has already had a heart attack, when treatment delivers a modest reduction. Starting earlier in a progressive disease produces outsize benefit, which he summarized as lower for longer, and start early.

For drug developers, this moves the relevant patient population upstream, toward people who have not yet had an event.

What the VERVE-102 phase 1 data show so far

VERVE-102 is a base editor: an mRNA for the editor and a guide RNA targeting PCSK9, packaged in a lipid nanoparticle. It is given as a one-time intravenous infusion over a few hours. In the liver, it makes a single A-to-G change at a splice site that turns off PCSK9, without cutting DNA.

Sek pointed listeners to the team's New England Journal of Medicine paper describing the first 35 patients across several dose levels. A single infusion lowered LDL by roughly 50 to 60% at the top two doses. Durability so far extends to a year to a year and a half.

Infusion-related reactions were mild and manageable, and no patient had major spikes in liver function tests. Long-term safety will take time to establish, and regulators require 15 years of follow-up for every patient in a gene editing or gene therapy trial. Sek said phase 2 should start before the end of the year, with roughly 175 patients across three dose levels and a placebo group.

Patient selection after the Lp(a) HORIZON result

Patrick asked what recent failures in genetically supported targets mean for target validation. Sek focused on Lp(a), where four questions remain open: how much lowering, for how long, in which patients, and for what relative risk reduction. LDL has answers to all four, while Lp(a) has none yet.

The HORIZON trial missed its primary endpoint, and its threshold captured about one in five people. Sek noted that Lp(a) has a skewed distribution, with a small fraction of people at very high levels. He suspects that group is the one that benefits.

Polygenic risk could sharpen patient selection in LDL-lowering trials. Sek cited secondary analyses of completed trials in which patients at high polygenic risk showed greater absolute and relative risk reduction from LDL lowering. Using the score to find trial participants could drive sample sizes down considerably, a thesis he said still needs to be tested.

Obesity and the move from chronic care to prevention

Sek now also leads obesity research at Lilly, overseeing programs from discovery to the end of phase 2. He noted that about 40% of US adults were obese in 2022, a figure that has since started to fall. Fewer than one in 10 eligible patients currently receive these medicines.

The remaining unmet needs he named include more weight loss, better tolerability, oral and longer-acting options, muscle preservation, and metabolic and cardiovascular benefits. He called a one-time gene therapy for obesity an audacious goal, given how precisely the therapeutic index would need to be balanced.

He traced Lilly's investment in genetic medicine to a leadership conviction. Care should shift from chronic treatment toward medicines that act on causal mechanisms early enough to cure or prevent disease.

Listen to the full episode below.