Lonvo-z gene editing boosts quality of life in HAE, new global trial data show
Developer already seeking US approval, says launch 'expected' in 2027
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Among people with hereditary angioedema (HAE), the one-time gene-editing therapy lonvoguran ziclumeran — simply called lonvo-z — significantly reduces the frequency of swelling attacks, minimizes the need for on-demand treatment, and improves quality of life.
These are the newest findings from a global Phase 3 clinical trial, dubbed HAELO (NCT06634420), published in The New England Journal of Medicine and presented at a recent medical conference. The study, “Lonvoguran Ziclumeran — In Vivo CRISPR Gene Editing in Hereditary Angioedema,” was funded by the therapy’s developer Intellia Therapeutics.
Lonvo-z employs the Nobel Prize-winning gene-editing technology CRISPR/Cas9 to disrupt the dysregulated signaling pathway in the body that causes swelling attacks in HAE. It is an in vivo treatment, meaning the gene-editing process happens directly in the patient’s body. Should it eventually be approved, it would be the first treatment of its kind to hit the market.
“The study demonstrates that the therapy is genuinely effective and safe,” Danny Cohn, MD, PhD, a HAELO principal investigator from Amsterdam University Medical Center in the Netherlands, said in a university news story. “This confirmation is exactly what regulatory authorities need to approve the very first in vivo CRISPR gene editing treatment for the market.”
In April, Intellia began a rolling application with the U.S. Food and Drug Administration seeking lonvo-z’s approval for HAE in that country. In a company press release announcing the new data, Intellis said it “continues to anticipate regulatory approval and a U.S. launch in the first half of 2027.”
According to John Leonard, MD, president and CEO of Intellia, “these are the first Phase 3 results to deliver on the much-heralded promise of in vivo CRISPR gene editing.” Leonard noted that the positive results for patients were seen “regardless of age or prior use of long-term prophylaxis [preventive] therapies.”
“We … are excited to be advancing this highly differentiated candidate toward a potential approval,” Leonard said.
People with HAE experience unexpected swelling attacks caused by the overproduction of a molecule called bradykinin. Production of bradykinin relies on the kallikrein enzyme.
Lonvo-z, previously known as NTLA-2002, uses CRISPR/Cas9 to disrupt the gene encoding a kallikrein precursor molecule. Ultimately, this aims to reduce kallikrein production, thereby lowering bradykinin levels and reducing the risk of swelling.
Use of gene editing may lower treatment burden for patients
The treatment is intended to be given just once, potentially lowering the burden that routine preventive therapies can place on patients.
“As a clinician who has witnessed patients struggle with the unpredictability and emotional toll of HAE, the prospect of offering lasting freedom from attacks and chronic medication with a one-time treatment is incredibly exciting,” Cohn said, adding that lonvo-z could give patients the potential “to enjoy a normal life.”
HAELO enrolled 80 people ages 16 and older with HAE types 1 and 2 across 29 study sites worldwide. Participants were randomly assigned to receive a single infusion of lonvo-z or a placebo. The main efficacy evaluation period lasted about six months, from weeks five to 28 after treatment.
The results showed that the gene-editing therapy was associated with an 87% reduction in monthly HAE attacks compared with the placebo, meeting the study’s main goal.
Moreover, 62% of people given the experimental treatment remained attack-free without the need for other prophylactic treatments throughout the six-month evaluation period. That compared with 11% in the placebo group.
With lonvo-z, swelling attacks requiring on-demand treatment fell by 89% compared with the placebo, and the monthly rate of moderate to severe attacks dropped by 91%, the data showed.
Monthly attack rates were lower than reported rates when patients were receiving standard of care treatment before the study, Intellia reported. Individual patient data showed that every person given lonvo-z experienced a reduction in attack rates, regardless of a host of factors, including age or prior treatments.
Attack-free rates expected to rise with lonvo-z in trial
Overall, the data suggest the potential for a one-time treatment to manage HAE long term, without the need for routine treatments to keep swelling at bay, according to the researchers.
“This can alleviate treatment burden, reduce drug dependency, lessen the anxiety of future attacks, and ultimately improve quality of life,” Cohn said. In fact, quality-of-life measures were also significantly improved with lonvo-z compared with the placebo, the data showed.
The safety data also indicated that the therapy was generally well tolerated, with the most common side effects being infusion-related reactions, headache, fatigue, and back pain.
[Lonvo-z] can alleviate treatment burden, reduce drug dependency, lessen the anxiety of future attacks, and ultimately improve quality of life.
After the main observation period, participants could cross over to receive the opposite treatment — the trial was double-blind, meaning neither patients nor researchers knew who was receiving lonvo-z and who got the placebo — and be followed during a long-term observation period. While patients won’t know the order in which they received lonvo-z vs. placebo, they’ll know that at some point, they got the gene therapy with this switch.
Cohn thinks that “this awareness will likely give [participants] the confidence to forego on-demand therapy,” and that reported attack-free rates will consequently rise even further.
Beyond HAE, the study also opens the door to treating other hereditary disorders, according to Cohn, who noted: “Inserting, deleting, or repairing a gene — it is all possible with CRISPR technology.”
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