Today, Verve Therapeutics announced the first results from human trials of a gene editing treatment for high cholesterol. They show safety and effectiveness on par with the best treatments already available, but with a one-time treatment expected to last a lifetime. I’ve been excited to see these results ever since I first wrote about PCSK9 inhibitors in 2021. The history of these drugs is my favorite in modern medicine.
Background
Elevated LDL cholesterol builds up on your arteries as plaque called atherosclerosis. When enough plaque builds up, that’s atherosclerotic cardiovascular disease, which causes both heart attacks and the vast majority of strokes. It’s the leading cause of death in the US, so even average risk is high risk.
A 2006 study looked for genes related to LDL and heart disease risk. It found 3% of Black people in America had a single copy of a “nonsense” mutation on the PCSK9 gene responsible for making the PCSK9 protein. The mutation prevented them from making the protein. The protein raises LDL, so with less of it, these patients had low LDL and an 88% lower risk of heart disease.
That kicked off a frantic search for someone with two copies of the mutation. Nobody knew how low that would push LDL or if it would be dangerous for it to go so low. Two groups each found one person with the double mutation. They had record low LDL and no related health problems.
Big pharma companies raced to develop monoclonal antibodies that inhibit the PCSK9 protein, mimicking the effect of the nonsense mutation. Two were approved by the FDA after demonstrating large reductions in LDL and CVD. The drugs are expensive, so insurance companies make them difficult to get, and they’re unpopular with patients because they have to be given by injection every two to four weeks. Uptake has been low, limiting their impact. A newer drug moves one step up the pathway. It interferes with the RNA responsible for producing the protein, instead of inhibiting the protein after it’s made. That drug only has to be given every six months, but that still requires a lifetime of compliance from a patients.
Verve’s gene editing
Verve’s goal is to change people’s genes to give them the nonsense mutation for PCSK9. In principle, this could be a single infusion that lowers LDL for a lifetime. A huge body of research across the many drugs that treat high cholesterol have taught us that plaque develops over decades. It’s possible to identify people with elevated risk of CVD 30 years before they have a heart attack–it’s men in their 30s and women in their 40s with high LDL. A one-time gene editing treatment could eliminate their risk of CVD.
Verve started with a study in monkeys and found their gene editing treatment was safe and effective at reducing LDL. They’re still tracking those monkeys and after two-and-a-half years their cholesterol is still nearly 80% lower.
Today, Verve published early results from their first trial in humans. It’s a small trial without a control group, focused on patients at high risk of dying from CVD soon. They have high LDL despite being on high doses of milder drugs and they’ve already had heart attacks or heart surgery. Side effects and reduction in LDL were similar to the performance of the existing PCSK9 drugs.
What’s next
Verve is going to spend 2024 expanding this safety trial and running another for a slightly different drug. In 2025, they’ll start a randomized phase 2 trial. My guess is that will take about two years. It doesn’t need to be too long because they’ll only look at safety and LDL outcomes.
Speculating on the timeline after the phase 2 trial, they’ll probably start a phase 3 trial around 2027 that runs long enough to measure hard outcomes–heart attack and stroke. I’d guess that takes 5 years. That would put drug approval in 2032. They could speed that up by having the different phases of the trials partially overlap, which Eli Lilly did to get their weight loss drugs out faster, and by focusing on the highest risk patients. Of the ten patients dosed in the six months of the first trial, two have already had heart attacks. Choosing patients at such high risk will make data collection go faster, but the benefit for hard endpoints will still probably lag by a year or two. Plaque develops slowly, so even if you send LDL into the basement overnight there’s a lag before you see a significant benefit for plaque.
The first approval will have to match the patient population from the study, so likely patients with advanced disease. As soon as it’s approved, doctors will be able to prescribe the drug off-label to lower risk patients, but insurance won’t cover it and I’d expect it to have a six-figure (seven-figure?) price. To get broader coverage, Verve will have to run larger, longer phase 3 trials on patients at lower risk, just as happened for statins and is currently happening for the early PCSK9 inhibitors. So the dream of giving these drugs to people early in the course of CVD may not arrive until the 2040s. Still, I’m excited about this drug, which could almost eliminate the number one cause of death and extend life expectancy by years.
How to 115 