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Verve pauses base editing study after treatment side effect

Verve Therapeutics is pausing enrollment into a pioneering study of a gene editing treatment for heart disease, after a participant developed laboratory test abnormalities.

The update, disclosed by Verve Tuesday morning, is a jarring halt to a study that in mid-2022 became the first human test of a more precise form of CRISPR known as base editing.

The biotechnology company said it has reported the case to regulators in the U.S., U.K. and New Zealand — where the study was being run — and is conducting an investigation. The participant didn’t have any symptoms from the abnormalities, which involved an increase in a liver enzyme that can signal potential damage as well as lower counts of a clot-forming blood cell, known as thrombocytopenia. 

Still, the patient was observed in a hospital for 48 hours and received precautionary oral steroid treatment. After a few days, the abnormalities resolved fully, according to Verve.

As the events occurred within four days of drug dosing, researchers concluded the side effect was likely drug induced.

While Verve will discuss next steps with regulators following its investigation, the company plans to prioritize a back-up therapy instead. This therapy edits liver cell DNA in the same way as the treatment now in testing, but is delivered into the body with a different kind of lipid nanoparticle “shell.”

Verve believes the lipid nanoparticle, or LNP, of its current treatment to be the cause of the lab test irregularities it’s observed. In an email, company CEO Sek Kathiresan cited preclinical data that showed dose-dependent liver enzyme elevations in non-human primates following treatment, even when the therapy administered was incapable of gene editing.

“There are three components to our in vivo gene editing medicine — editor, guide, and LNP delivery system,” wrote Kathiresan. “The guide and the editor seem to be working as designed. We believe the lab safety findings are addressable with VERVE-102 which uses a different LNP delivery system,” he added, using the code name for the back-up therapy.

The construction of the LNP in VERVE-102 allows the therapy to enter liver cells by two receptors, potentially permitting lower dosing, Kathiresan said.

Last November, Verve disclosed initial data from its trial showing the company’s lead therapy, called VERVE-101, could significantly reduce LDL cholesterol levels in people with an inherited condition that causes severe elevations in the artery-clogging protein. The results were an important “proof of principle” for base editing, which adapts CRISPR editing to change a single DNA “letter,” or base.

Both of Verve’s therapies make an “A” to “G” change in the DNA sequence of a gene called PCSK9, inactivating it and lowering LDL cholesterol levels as a result. 

Several drugs that block PCSK9 by other means are already available, but Verve’s aim is a one-time treatment that can reduce cholesterol for life.

In addition to the safety findings revealed Tuesday, Verve also updated efficacy data for VERVE-101, which has been given to a total of 13 participants in the company’s study. Among the first five participants treated with a 0.45 milligram per kilogram of body weight dose, the mean time-averaged LDL-C reduction was 46% after one month. The sixth volunteer on this dose experienced the liver abnormalities.

There were already some safety concerns in the first cut of data Verve unveiled last November. One participant on a lower dose had a cardiac arrest and died five weeks later, an event study investigators judged unrelated to treatment. Another, again on a lower dose, had a heart attack the day after treatment, but had had unstable chest pain symptoms prior to infusion.

“Safety is going to be of the utmost importance, especially because there are currently safe and efficacious strategies available for lipid lowering,” said Karol Watson, a cardiologist and professor of medicine at the University of California, Los Angeles, during a November press conference on those earlier results. “This is a strategy that could be revolutionary, but we have to make sure it’s safe.”

Verve has already obtained regulatory clearance to begin testing of VERVE-102 in the U.K. and Canada, and plans to do so in the second quarter. In an email, Kathiresan said the company plans to later start clinical development in the U.S.