First look at Verve study data offer base editing ‘proof of principle’

Sekar Kathiresan started Verve Therapeutics five years ago in pursuit of a powerful idea: develop a one-time gene editing treatment to permanently lower cholesterol and, with it, heart disease risk. Early study results revealed Sunday show his ambitious plan has a chance at working.

The results are the first from a clinical trial begun last year to test Verve’s therapy, which uses a twist on CRISPR to inactivate a liver gene by changing a single DNA “letter,” or base. This gene, called PCSK9, controls liver cell receptors that remove cholesterol from the blood. Turning it off should help those proteins persist and thereby lower levels of LDL, or “bad,” cholesterol.

Several drugs that block PCSK9 proteins by more conventional drugmaking methods are already approved. Verve aims to accomplish the same — or better — effect by editing the genetic source, and to have that benefit last for life.

“We’re able to show for the first time that one can make a single base pair change in the liver of a human being for a clinical effect,” said Kathiresan, a cardiologist and Verve’s CEO, in an interview. “This is what we’ve been working [toward] for the last five years.”

Verve’s data, which are being presented Sunday at the American Heart Association’s annual meeting in Philadelphia, are from the first 10 people treated in the company’s trial.

All 10 were enrolled with heterozygous familial hypercholesterolemia, or HeFH, an inherited condition that causes severe elevations in LDL cholesterol. People with it typically have accelerated heart disease and experience cardiovascular complications much earlier in life. Three million adults in the U.S. and Europe are estimated to have HeFH, according to Verve.

Among three participants given the two highest tested doses, treatment with Verve’s therapy lowered LDL cholesterol levels by 39%, 48% and 55% compared to the study’s start. PCSK9 levels were also dramatically reduced, by 59%, 84% and 47%, respectively. The other participants, who were treated with two “sub-therapeutic” doses, had much lower reductions.

“This is an impressive result, period,” said Richard Lifton, president of Rockefeller University and a well-known geneticist, in an interview. “The ability to do in vivo gene editing in the liver is very significant and has implications not just for PCSK9 but [also] for other cardiovascular targets.”

Lifton reviewed the data for BioPharma Dive on condition he not share any information before it was made public Sunday.

Verve envisions its therapy as best suited to people who need many years of LDL lowering. Kathiresan pointed to the participant with the highest LDL reduction in the trial, who was already on statin therapy, as a good example. Aged 29, the man had had a heart attack the previous year and “was facing decades of LDL lowering, decades of intermittent injections,” Kathiresan said.

Karol Watson, a cardiologist and professor of medicine at the University of California, Los Angeles, described Verve’s results as a “perfect proof of principle” in a Sunday press conference held by AHA.

“This is stuff we honestly couldn’t have dreamed about years ago,” she said.

Verve’s results are a landmark for base editing, a form of CRISPR that allows scientists to make changes to individual DNA letters, and come as gene editing research accelerates.

In the U.S., the Food and Drug Administration recently gave a green light for Verve to begin enrolling U.S. participants in its PCSK9 study, which to date has involved people in the U.K. and New Zealand. The agency is also set to soon make a decision on what could be the first CRISPR-based medicine, a treatment for sickle cell disease.

Still, Verve’s results provide a limited snapshot of what benefit its therapy, dubbed VERVE-101, could offer.

The therapy promises a permanent reduction in cholesterol levels. But so far Verve has follow-up data through six months — enough to only suggest, not prove, a durable effect in humans. The LDL reductions seen in the first few participants given therapeutic-level doses might not be replicated in others as Verve enrolls more people. And the therapy’s safety will remain under close scrutiny.

“Safety is going to be of the utmost importance, especially because there are currently safe and efficacious strategies available for lipid lowering,” said Watson. “This is a strategy that could be revolutionary, but we have to make sure it’s safe.”

Among study participants on the higher doses, Verve reported infusion site reactions as well as temporary elevations in liver enzymes that, if sustained, can indicate more consequential side effects.

More notably, investigators reported two serious cardiovascular adverse events. One participant given a lower dose had a heart attack and died five weeks after treatment, which the study safety committee judged unrelated to VERVE-101. Another, on the second-highest dose, had a myocardial infarction the day after receiving Verve’s therapy. However, he had unstable chest pain symptoms prior to treatment that he didn’t report to his physicians.

“This does not immediately say, ‘Oh, gosh, I think this is a dangerous drug,’” said Lifton. “It’s not obvious to me how you would precipitate cardiovascular events through this pathway and mechanism. But that’s what clinical trials will ultimately help [us understand].”

Verve plans to enroll more patients in the U.K. and New Zealand to receive either of the two higher doses. And now, with the FDA’s green light, it will open trial sites in the U.S. as well.

Next year, the company intends to start a Phase 1 trial of an alternate version of VERVE-101 that uses a different delivery technology. After comparing results from the two approaches, it expects to choose one to advance into a randomized, placebo-controlled Phase 2 study in 2025.

“This opens a door to an entire new way to treat heart disease,” said Kathiresan. “There’s still a lot of work to do. But I think we’re on the cusp of something important.”

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