Crispr offers hope for a one-time cholesterol drug

Everyone acknowledges the need to get a firm grip on safety — and the fact that the eventual cost of the one-time treatment.

The first snippet of data from a human clinical trial suggests the viability of an experimental drug from Verve Therapeutics that uses gene editing to permanently lower cholesterol. It opens the door to a once-fantastical future when people can trade daily lipid-lowering pills for a one-time treatment.

The data for Verve-101 are also important, if preliminary, validation that a newer form of Crispr, called “base editing,” can make safe and permanent fixes to genetic flaws — in liver cells at least. For cardiologists, the early results keep hope alive that this technology could help make a dent in heart disease, the leading cause of death in the US.

The 10 people enrolled so far in the trial have an inherited form of dangerously high cholesterol called heterozygous familial hypercholesterolemia, which predisposes them to coronary heart disease and heart attacks at a young age. Verve’s drug works by turning off production of PCSK9, a protein made in the liver that regulates levels of LDL, or “bad” cholesterol.

These first data needed to start to answer three key questions: Can Verve-101 lower bad cholesterol enough to compete with existing treatments? Was the effect permanent? And were there any worrisome safety signals?

On the first point, the answer is a tentative yes. While the two low doses tested did not sufficiently lower cholesterol, the two highest doses approached or surpassed the 50 percent reduction threshold that analysts viewed as critical for demonstrating the drug’s viability.

The permanency of the effect is still to be determined, but initial signs are hopeful: In the one patient treated at the highest dose, cholesterol reduction was just as potent six months after treatment as it was a month afterward.

Six months is an important marker for drugs that target the liver, where the majority of PCSK9, the protein the drug suppresses, is made. All the liver cells called hepatocytes regenerate in that period, meaning cholesterol levels would rebound if edits weren’t passed on.

So far, Verve has shown that Verve-101 can keep cholesterol consistently low in monkeys as far out as two and a half years, Verve’s co-founder and Chief Executive Officer Sekar Kathiresan said. If it can show suppression between 18 months to two years in humans, people “will be pretty convinced that this is truly going to be durable,” he said.

The last big question, about the safety of the drug, remains the most open. News that two out of the 10 patients suffered cardiovascular events during the trials caused shares of Verve to sink by as much as 44 percent on Monday.

Most of investors’ worry centers on a patient who died of a heart attack a day after receiving the drug. But there’s also some needed context to consider. Because the Food and Drug Administration is approaching these first gene-editing studies with extreme caution, the initial tests have been in the sickest of patients who lack other treatment options. The agency has acknowledged this strategy will make it difficult to interpret safety at first because people with such advanced disease are likely to have adverse events regardless of treatment.

That appears to be what happened in the Verve trial. Kathiresan said the patient who died didn’t tell clinicians that he had been having chest pains in the days leading up to his infusion, a situation that would have made him ineligible for the trial. When doctors later did a dye test to examine his heart, they found that all three major arteries as well as the left main artery were blocked. The safety board overseeing the trial agreed the death was due to his underlying disease rather than the treatment, but the proximity to dosing required them to label it drug-related, Kathiresan said.

The safety board also did not recommend pausing the trial. More tellingly, the FDA, which had previously been much more cautious than other global regulatory agencies, subsequently allowed human tests of Verve-101 to begin in the US.

Verve is slowly adding more people to the study to try to understand the ideal dose for a larger, Phase 2 trial, expected to start in 2025. But it will also start testing the drug in people who have still serious but less advanced disease, potentially giving better insight into the drug’s true safety.

Cardiologists are regarding the drug with cautious enthusiasm. Everyone acknowledges the need to get a firm grip on safety — and the fact that the eventual cost of the one-time treatment, sure to be leagues higher than the price of cheap daily statins, will determine who can access it.

But the idea of being able to offer a lifelong fix to people before their hearts are damaged by years of high cholesterol is tantalizing. Donald Lloyd-Jones, a cardiologist who leads the preventive medicine department at Northwestern University, told journalists at the American Heart Association’s annual meeting that “the dream” would be the ability to offer this to 20-year-olds with familial hypercholesterolemia who, without daily statin pills, are at risk of a heart attack in their early 30s.

With each new scrap of data, medicine is moving cautiously toward that future — and with luck one when this type of treatment can be safely used for the millions who don’t carry that high genetic risk but still struggle to keep bad cholesterol in check. It will ideally also make the FDA move a little faster to allow human studies of other drugs that use this form of Crispr.

Lisa Jarvis is a Bloomberg Opinion columnist. Views do not represent the stand of this publication. 

Credit: Bloomberg