Verve's base editing hold lifted, starting a thaw on a regulatory blockade that sent peers ex-US

A nearly year-long clinical hold on Verve Therapeutics’ base editing therapy meant to treat a genetic form of high cholesterol has been lifted in the U.S., thanks to data from an ongoing human trial elsewhere in the world and some preclinical work that has allayed the FDA’s concerns.

“The combination of the human data and addressing the preclinical questions did the trick,” CEO Sekar Kathiresan, M.D., told Fierce Biotech in an interview.

VERVE-101, which is in development for heterozygous familial hypercholesterolemia (HeFH), had been on clinical hold since November 2022. A month later, the FDA revealed its concerns, which included questions about whether the gene edits could be passed down to a patients’ children. The agency requested more preclinical data on potency differences between human and non-human cells, the risks of germline editing and off-target analyses in non-hepatocyte cell types.

The FDA also asked for a peek at data already being generated in the phase 1 trial called heart-1 in New Zealand and the U.K.

“Some areas can be addressed with human data, but some of the theoretical concerns can't be addressed by human data and needs to be addressed in preclinical models. So we've done both,” Kathiresan said.

Verve can now move to open sites in the U.S., where the hold spurred a chilling effect for gene editing companies alike. In August, Intellia Therapeutics took a phase 2 trial of a CRISPR-based treatment in hereditary angioedema outside the U.S. after the FDA asked for a new preclinical test. The request similarly raised concerns about the impacts of the treatment, dubbed NTLA-2002, on a developing fetus.

At the time, Intellia CEO John Leonard, M.D., said the company had patients lined up waiting to enroll and those outside the country were happy to fill the slots.

While Intellia has moved on—for the moment, at least—Verve still wants to test VERVE-101 in the U.S.

“We know that the U.S. will play an important role in the development of this medicine as well as our other pipeline programs,” Kathiresan explained.

The CEO said it is great to be first but the biotech ran into an FDA that was also still gaining its footing on a treatment modality that is brand new.

“We were the first in front of them with this technology, in vivo-based editing, and being first is good in some things. Sometimes you have to work with the party on the other side to develop a set of standards for the technology and what it's going to take to move forward,” Kathiresan said.

“And that's, I think, probably the best way to characterize it,” he continued. “It's been a process—a very good process, working with them—but a process.”

Acknowledging that some peer companies have chosen to address the regulatory hurdles later in development, Kathiresan said it was important to Verve to have those conversations earlier in the process to be able to understand what the requirements will be.

“We now have a template for the rest of our pipeline so we kind of know what it takes to get through the FDA for this kind of product, both on the preclinical side and on the clinical trial design and so forth,” the CEO said. “Overall, that knowledge that we've gained over the last year is going to be really valuable as we move forward.”

Verve has been actively enrolling the ex-U.S. sites as the hold was in place. The recruitment target was listed as 44 patients on the FDA clinical trial database. Kathiresan said the company is focusing on part one of the trial at the moment, which involves a single ascending dose design at four different dose levels. Patients have been treated across all four dose levels already, he said.

An initial data cut was shared with the FDA as part of the package to respond to the hold, Kathiresan said. Verve will unveil the initial data at the Heart Association meeting in November.

“When we got the hold last year, the FDA said, ‘We know you're doing the trial ex-U.S. so we'd like to see the clinical data that you're generating ex-U.S. as part of your response, and that's what we submitted,” the CEO explained.

While Verve has cleared the regulatory path for its future pipeline, Kathiresan said the focus in the next year will be on getting the first-in-human data for this new modality and demonstrating that base editing can be done. The next step after that will be part B of the study, where dose expansion will take place.

But the company will be working toward a second human trial for VERVE-102, also in HeFH, with initiation expected in the first half of 2024. The second half of the year will see a potential trial start for VERVE-201, which is in a similar cholesterol disorder called homozygous familial hypercholesterolemia.

“Having cleared the U.S. IND we see a clear path for the other programs for clinical development in the U.S. as well, now that we have this template,” Kathiresan said.

Verve has about half a billion dollars in cash on hand, with a runway paved into 2026, Kathiresan added. That should cover all the clinical development currently planned.

“As you know, biotechs are always thinking about capital and I think we'll be opportunistic about adding to our balance sheet,” the CEO said. “But again, we have a good runway right now.”