Intellia Therapeutics has patients lined up in the U.S. for a phase 2 trial of a CRISPR-based treatment in hereditary angioedema, but the FDA has thrown down a roadblock over a request for a new preclinical test of the therapy’s impact on a developing fetus.
The FDA has asked the gene editing biotech for additional preclinical data on the inclusion of female patients of child-bearing potential. An investigative new drug application was approved for NTLA-2002 by the agency in March, but the request for an additional animal test means Intellia is revising plans for the 55-person trial.
The good news, according to CEO John Leonard, is that sites outside the U.S. were happy to fill the enrollment gap. On a second-quarter earnings call this morning, the executive said the trial is proceeding “extremely quickly” without U.S. patients, so it will go on mostly as planned.
Intellia will conduct the requested preclinical study and hopes to get the FDA’s blessing to use U.S. patients in a phase 3 trial, which Leonard said could begin as early as the third quarter of 2024.
Intellia could have proceeded with the U.S. portion of the study by filing a protocol amendment to exclude women of child-bearing potential but decided not to, a company spokesperson told Fierce Biotech. “While we do have the option to enroll U.S. patients with the exclusion of women of child-bearing potential through a protocol amendment, the global interest in NTLA-2002 enables us to proceed more quickly to a Phase 3 study by fully enrolling Phase 2 in other countries,” the company said in a statement.
While leaders tried to couch the FDA setback with the news that enrollment had gone ahead anyway, analysts peppered Leonard and his fellow executives with questions on the earnings call.
The situation immediately brought to mind the clinical hold placed in November 2022 on Verve Therapeutics over concerns that gene edits from its high cholesterol gene editing therapy could pass on to children. This is known as germline editing and has been a key concern as gene editing overtakes the clinic. As of a May earnings update, Verve was still working toward resolving the hold for VERVE-101.
Leonard did not say the words “clinical hold” and was careful to note that Intellia already submitted preclinical breeding studies for the IND request that he believes allay concerns about germline editing with the company’s products.
“That is not what this is. That question has been addressed with information that was supplied with the already-cleared IND,” Leonard said. “So as far as we can tell in our dealings with the FDA and every other regulatory agency, that particular germline question has been put to rest with the data that we've supplied.”
Instead, the FDA wants to know whether the embryological development of the fetus in mice is affected in any way by chemicals that are in the lipid nanoparticle systems used to deliver NTLA-2002. The only thing different with the FDA’s request, according to Leonard, is that this specific test is being requested earlier in the development timeline than expected.
“We've looked at germline cells specifically, we know that they're unaffected,” Leonard said. He also noted that there was no specific safety data that spurred the FDA’s request. “Our view is that this is the FDA taking a very considered view of the space and looking for us to fill out what is a typical set of data that usually is supplied a little later in a program.”
The FDA and Intellia have already come to an agreement on what’s needed, which will be an “abbreviated study” that the company is already “well on our way to completing," according to Leonard.
Meanwhile, enrollment has filled up at the ex-U.S. sites, and that includes women of child-bearing potential. Leonard said there was plenty of enthusiasm from U.S. clinicians and patients to participate, but working through these issues for the phase 2 would have “delayed the study substantially.” The goal of the trial is to establish the phase 3 dose.
“We will have an abundance of U.S. patients that I think will be well prepared to begin the phase 3 program potentially as early as the third quarter of next year and that's what we're working towards,” Leonard said.
Coincidentally, Chief Medical Officer David Lebwohl, M.D., noted that many patients with hereditary angioedema are scrambling to get into the trial in the hope that their conditions can be improved so they can go on to have successful pregnancies.
“Of course, we look forward to bringing that great result forward in the future if we can,” Lebwohl said. He does not expect any differences between males and females, older or younger women when data collection begins. Intellia will be monitoring any future pregnancies as part of long-term follow-up.
Analysts wondered whether there was any read-through to the rest of Intellia’s pipeline. Leonard assured them that there should not be any impact on the company’s other programs, including star ATTR amyloidosis therapy NTLA-2001. That disease typically impacts older patients, particularly men, anyway, according to Leonard.
Intellia’s shares were mostly steady in the opening hours of trading at $38.98, down just under 2% from $40.96 at yesterday's close.