Most HAE Patients Attack-free After Gene-editing Therapy NTLA-2002

Data shared covered 10 patients enrolled in Phase 1 part of study

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A strand of DNA reclines on a couch next to a therapist who is taking notes.

Most hereditary angioedema (HAE) patients in a Phase 1/2 clinical trial have gone months without a swelling attack following a single infusion of the experimental gene-editing therapy NTLA-2002.

The remaining patients haven’t yet reached the pre-specified 16-week follow-up period for their attack rates to be analyzed, but their comparable reductions in plasma kallikrein — a protein involved in HAE attacks — suggest similar effects.

That’s according to new interim results shared by the therapy’s developer Intellia Therapeutics in an oral presentation at the American College of Allergy, Asthma and Immunology (ACAAI) 2022 Annual Scientific Meeting, held earlier this month in Kentucky.

The presentation was titled “In vivo CRISPR/Cas9 editing of KLKB1 in patients with Hereditary Angioedema: A First-in-Human Study.” The findings were also detailed in a company webcast.

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“We see early evidence that our one-time CRISPR-based investigational therapy may offer patients suffering from hereditary angioedema a functional cure for their disease,” John Leonard, MD, Intellia’s president and CEO, said in a company press release. “In the patients with the longest follow-up to date, their attack-free interval has been maintained 5 to 10 months from their last attack … [and] we are strongly encouraged that all patients who received a single dose of NTLA-2002 subsequently became attack-free.”

In HAE, swelling attacks are triggered by abnormally high levels of the signaling molecule bradykinin, whose production is controlled by a protein called kallikrein.

NTLA-2002 is a non-viral gene editing therapy that uses CRISPR/Cas-9 technology to lower kallikrein production by disrupting the activity of the gene that provides instructions for making the protein’s precursor. It’s administered directly into the bloodstream through a single infusion.

Adapted from a natural defense mechanism of bacteria, CRISPR/Cas9 allows researchers to edit parts of the genome — all genes that are present in people’s DNA — by adding, removing, or changing specific DNA sections.

The Phase 1/2 trial (NCT05120830) aims to evaluate NTLA-2002’s safety, pharmacological properties, and clinical efficacy in up to 55 adults with HAE types 1 and 2. Participants are still being recruited at sites in New Zealand, the Netherlands, and the U.K.

Gene editing results of 10 patients

Data shared at the ACAAI meeting covered the 10 patients enrolled in the study’s Phase 1 portion, which is testing three doses of the therapy (25, 50, and 75 mg). Results from it will help determine up to two doses to be tested against a placebo with additional patients in Phase 2.

Patients’ median age was 51 (range, 26–32), and they included six women and four men. Three received the lowest dose, four were given the 50 mg dose, and the remaining three received the highest dose.

At a data cut-off date of Sept. 28, and consistent with previous interim data, kallikrein levels in the blood were reduced in a dose-dependent way.

In the lowest dose group, with 32 weeks (more than seven months) of follow-up, blood kallikrein levels were reduced by 64%. In the highest dose group, kallikrein levels decreased by an average of 92% after 16 weeks (about four months) of follow-up.

The 50 mg dose group had the shortest follow-up time (22 days), but showed a substantial reduction in kallikrein levels, by 81% on average.

All the trial participants had at least three investigator-confirmed swelling attacks in the three months before entering the study despite most being on standard preventive treatments. During the trial, 60% of patients were on preventive therapy.

The first analysis of changes in the attack rate was set to occur after 16 weeks, which only the 25 mg and 75 mg groups had already completed.

Results showed that attack frequency dropped by 91% in the lowest dose group and by 78% in the highest dose group. From week five — after the therapy would be expected to be fully in effect — through week 16 the attack rate decreased by 89% in both groups.

All participants with evaluable data had fewer swelling attacks in the 16 weeks after treatment with NTLA-2002. As of the latest data cutoff, none of these six patients have had a swelling attack in at least two months. The patient with the longest follow-up data has been attack-free for nearly 11 months.

“Patients who discontinued [preventive] therapy after NTLA-2002 infusion remained attack-free,” the researchers wrote.

NTLA-2002 has generally been well tolerated at all doses, with most side effects being mild in severity. There have been no reports of serious or severe side effects or clinically significant laboratory abnormalities. The most commonly reported side effect so far is infusion-related reactions, which are mostly mild in severity and resolve within a day, according to Intellia.

“Importantly, the safety data from all 10 patients are highly encouraging, further supporting NTLA-2002’s potential to change the future HAE treatment paradigm,” Leonard said. “The latest interim data further reinforce the enormous potential of our modular CRISPR genome editing platform to treat a host of genetic diseases.”

The trial’s Phase 2 portion is expected to begin in the first half of 2023 and Intellia expects to expand country and site participation, including to U.S. clinical sites.