Gene-Editing Therapy Reduced Attacks in Hereditary Angioedema

A single dose of the CRISPR-based gene-editing therapy NTLA-2002 reduced angioedema attacks and led to sustained reduction in total plasma kallikrein protein levels compared with placebo in patients with hereditary angioedema, a phase II randomized trial showed.

From week 1 to week 16 among 27 patients, the estimated mean monthly angioedema attack rate was 0.70 with 25 mg of NTLA-2002, 0.65 with 50 mg, and 2.82 with placebo, with an estimated difference in the mean monthly attack rate of -75% with 25 mg and -77% with 50 mg, reported Danny M. Cohn, MD, PhD, of Amsterdam University Medical Center, and colleagues.

The study was published in the New England Journal of Medicine and results will be presented by Cohn at the American College of Allergy, Asthma & Immunology (ACAAI) annual meeting in Boston.

“Notably, four of the 10 patients in the 25-mg group were in complete response, meaning they were 100% attack-free without any other treatments, and eight out of 11 patients who received 50 mg of NTLA-2002 had a complete response,” Cohn told MedPage Today. “This happened in none of the patients who received placebo.”

“All patients had a clinically meaningful angioedema attack reduction following a single administration in both groups — most prominently in the group receiving 50 mg — leading to an intended, permanent functional cure,” he noted.

Cohn said that a key secondary endpoint was the mean number of attacks per month at weeks 5 through 16.

“This is probably more representative of the data, since it takes about a month before the existing prekallikrein — which is still in the plasma — is degraded,” he explained. “And there were 0.6 angioedema attacks per month for the NTLA-2002 groups and 3.1 on average in the placebo group.”

The mean percent change in total plasma kallikrein protein levels from baseline to week 16 was -55% with 25 mg and -86% with 50 mg, while levels remained unchanged with placebo.

Hereditary angioedema is a rare genetic disease, affecting approximately one in 50,000 persons globally. It is characterized by episodic events of severe swelling most frequently affecting the limbs, face, intestinal tract, and airway. Most of these attacks are difficult to predict and will vary from person to person, and in the case of laryngeal edema can lead to possible airway obstruction and death by asphyxiation.

Plasma kallikrein is a therapeutic target, and kallikrein inhibitors have been approved for long-term prophylaxis. However, Cohn and colleagues pointed out that while prophylactic treatments have decreased the frequency and severity of attacks, “these treatments require regular and lifelong administration, which affects overall quality of life.”

NTLA-2002 is designed to prevent hereditary angioedema attacks by inactivating the KLKB1 gene, which encodes for prekallikrein, a precursor to the kallikrein protein. It reduces kallikrein production and activity, as well as bradykinin levels, ultimately decreasing the risk of angioedema attacks.

In an editorial accompanying the study, Kiran Musunuru, MD, PhD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, looked at whether gene-editing therapies are actually helping patients.

The answer “is now an unambiguous ‘yes,'” he wrote. “We can be confident that NTLA-2002 is helping patients with hereditary angioedema, and it is only a matter of time before we will see gene-editing treatments having a transformative effect on the care of patients with a broad spectrum of diseases.”

Cohn and colleagues also reported updated data from the phase I portion of the trial, results of which were first presented at the 2022 ACAAI annual meeting.

Initial results showed no dose-limiting toxic effects among 10 patients from a single infusion of NTLA-2002 at a dose of 25 mg, 50 mg, or 75 mg, with patients having a sustained, dose-dependent reduction in plasma kallikrein protein levels and a 95% reduction from baseline in angioedema attacks.

At a median follow-up of 20.1 months, reduced plasma kallikrein protein levels have remained stable, and as of the latest follow-up, the monthly attack rate had decreased by 98% from baseline; eight of the 10 patients have remained attack-free since the end of the primary observation period.

“The durability of the therapeutic effect shows promise to last for the patients’ lifetimes, making the CRISPR-based treatment a truly ‘one-and-done’ proposition,” Musunuru observed.

The trial included adults who had received a diagnosis of type 1 or type 2 hereditary angioedema, and had three or more angioedema attacks within 90 days before the screening period and two or more attacks during the 8-week screening period.

Of 36 patients screened, 27 underwent randomization (11 to 50 mg of NTLA-2002, 10 to 25 mg, and six to placebo). In the NTLA-2002 groups, median age was 48, 57% were men, and the mean monthly attack rate at baseline was 3.6. In the placebo group, median age was 47, 33% were men, and the mean monthly attack rate at baseline was 3.7.

Median follow-up time was 8.2 months in the 25-mg group, 5.6 months in the 50-mg group, and 6.9 months in the placebo group.

The most common adverse events in the two NTLA-2002 groups combined were headache (38% of patients), fatigue (29%), and nasopharyngitis (29%). All adverse events were grade 1 or 2 except for a serious adverse event of grade 4 edema of the tongue with breathing impairment that occurred in a patient in the placebo group.

There were no serious infusion-related events.