CRISPR Gene Therapy Slashes Hereditary Angioedema Attacks

Novel in vivo CRISPR-based therapy lonvoguran ziclumeran (lonvo-z) dramatically lowered hereditary angioedema (HAE) attack frequency in the HAELO randomized trial.

HAE attacks dropped by a relative 87% after the single infusion, with 0.26 average monthly attacks from weeks 5 through 28 compared with 2.10 in the placebo group (P<0.001) while off long-term HAE prophylaxis, reported Danny Cohn, MD, PhD, of Amsterdam University Medical Center, and colleagues in the New England Journal of Medicine.

Over that same period, 62% of the patients who received lonvo-z were considered by the investigator to be HAE attack-free without the use of long-term prophylaxis, as compared with 11% in the placebo group, the researchers also reported at the European Academy of Allergy and Clinical Immunology meeting in Istanbul.

By comparison, long-term prophylaxis resulted in 40-60% attack-free rates in the pivotal trials. “However, in a 2025 survey of patients with hereditary angioedema who were not participating in clinical trials, 80% of the patients reported having attacks, even though 89% of the patients reported using long-term prophylaxis,” Cohn’s group pointed out.

“These data support the use of lonvo-z as a potential treatment for hereditary angioedema,” they concluded.

HAE is a rare genetic disorder related to low levels of C1 inhibitor, which lead to high levels of the plasma kallikrein enzyme, triggering overproduction of bradykinin. In turn, bradykinin binds to receptors on blood vessel walls that cause them to dilate and allow fluid accumulation in surrounding tissues. This results in temporary localized swelling of subcutaneous, mucosal, and submucosal tissue that primarily impacts the skin of the extremities, trunk, and face, as well as the gastrointestinal tract, genitals, and larynx.

Lonvo-z inactivates the KLKB1 gene that leads to production of bradykinin via kallikrein. It involves a lipid nanoparticle to deliver CRISPR gene editing to the liver (the primary source of the kallikrein precursor, prekallikrein) rather than a viral vector. Lonvo-z is administered as a one-time, outpatient IV infusion over 2 to 4 hours.

“Although the availability of on-demand therapy and long-term prophylaxis has improved the management of hereditary angioedema, incomplete disease control, lack of access to treatments, and the need for lifelong use still impose a burden on patients,” the researchers wrote.

The phase III HAELO trial enrolled 80 patients age 16 years and older who had hereditary angioedema with C1 inhibitor deficiency. They were randomly assigned, in a 2:1 ratio, to receive a single IV infusion of lonvo-z (50 mg) or placebo. Patients couldn’t use long-term HAE prophylaxis for a time before the start of the run-in period or through the end of week 28.

The researchers called the demographics of the cohort (median age 41.5, 69% female, 71% on long-term prophylaxis before enrollment) largely representative, with a run-in period HAE attack rate of 3.5 per month.

“The results appeared to be generally consistent in prespecified subgroup analyses,” the researchers reported.

Significant benefits were seen with lonvo-z over placebo for the key secondary endpoints of mean monthly rate of investigator-confirmed attacks requiring on-demand therapy (89% relative risk reduction) and of moderate or severe attacks (91% RRR) along with a clinically important difference in improvement in quality of life total score from baseline to week 28.

“Although the duration of follow-up in the phase 3 trial is limited beyond week 28, with data through 40 weeks for only 8 patients who were assigned to receive lonvo-z, the low attack rate in these patients was maintained,” the researchers noted. No patients in the lonvo-z group compared with two in the placebo group restarted long-term prophylactic therapy.

Nearly all patients reported adverse events (AEs) around infusion of lonvo-z or placebo (92% and 86%, respectively) in the first 28 weeks. Of AEs that were more common with lonvo-z, those affecting more than 10% of the patients included infusion-related reaction, headache, fatigue, back pain, and upper respiratory tract infection. Transient, self-resolving elevations in liver enzymes occurred in approximately 10 to 15% of patients treated with lonvo-z.

No serious or grade 3 or worse AEs occurred with lonvo-z over a median 7.5 months of follow-up

“The edit to the gene KLKB1 is intended to be permanent after treatment with lonvo-z,” and evidence through up to 3 years of follow-up in early phase study patients suggests that is the case, the researchers wrote.

Patients with a rare congenital plasma kallikrein deficiency condition (Fletcher factor deficiency) are healthy and have prolonged activated partial-thromboplastin time without an associated bleeding risk, they noted. Although difficult to draw definitive conclusions, prolonged activated partial thromboplastin has not been seen with lonvo-z, they added, perhaps due to the presence of a low level of residual plasma kallikrein.

Developer Intellia Therapeutics announced plans to file for FDA approval in the latter half of the year. If approved, lonvo-z would be the first in vivo CRISPR-cas gene editing therapy for any indication, according to the company.