Single-dose CRISPR therapy reduces hereditary angioedema attacks

1. In this phase 3 randomized controlled trial, a single infusion of lonvoguran ziclumeran reduced hereditary angioedema attacks by 87% compared with placebo from weeks 5 through 28.

2. Among patients receiving lonvoguran ziclumeran, 62% remained attack-free compared with 11% receiving placebo. Infusion reactions were common, but all adverse events were grade 1 or 2, and no serious adverse events occurred in the treatment group.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Hereditary angioedema is a rare, potentially life-threatening genetic disorder characterized by unpredictable attacks of swelling involving the skin, gastrointestinal tract, and upper airway. In patients with C1 inhibitor deficiency, pathogenic variants in SERPING1 result in uncontrolled plasma kallikrein activity and excessive bradykinin production. Available prophylactic therapies can reduce attacks but require chronic treatment and do not provide complete disease control for many patients.

Lonvoguran ziclumeran, also known as lonvo-z or NTLA-2002, is an investigational in vivo CRISPR-Cas9 therapy. A lipid nanoparticle delivers Cas9 messenger RNA and a guide RNA to hepatocytes, where the treatment inactivates KLKB1, the gene encoding prekallikrein. Rather than correcting the causal SERPING1 variant, lonvo-z permanently targets a downstream mediator of bradykinin production.

The HAELO trial compared a single 50-mg intravenous infusion of lonvo-z with placebo in patients with hereditary angioedema due to C1 inhibitor deficiency. From weeks 5 through 28, the mean monthly attack rate was 0.26 with lonvo-z and 2.10 with placebo, representing an 87% relative reduction. Lonvo-z also reduced attacks requiring on-demand treatment by 89% and moderate or severe attacks by 91%. Overall, 62% of treated patients remained attack-free compared with 11% receiving placebo. Patients receiving lonvo-z also reported a clinically meaningful improvement in angioedema-related quality of life.

Adverse events occurred in 92% of patients receiving lonvo-z and 86% receiving placebo. Infusion-related reactions were more common with lonvo-z, occurring in 62% and 18% of patients, respectively. However, all adverse events were grade 1 or 2, and no serious adverse events occurred in the lonvo-z group. Transient, asymptomatic liver enzyme elevations occurred in 15% of treated patients and resolved without intervention.

Strengths of the study included its phase 3, randomized, double-blind, placebo-controlled design and its assessment of attack frequency, attack severity, treatment use, quality of life, and pharmacodynamic response. However, only 80 patients participated, median follow-up was 7.5 months, and not all patients had reached week 28 at the data cutoff. The study did not compare lonvo-z directly with current prophylactic treatments. Because the KLKB1 edit is intended to be permanent, substantially longer follow-up is required to evaluate durability, off-target editing, and the consequences of sustained prekallikrein reduction. These findings therefore demonstrate short-term efficacy but do not establish a cure or lifetime safety. Intellia Therapeutics funded the trial, and sponsor-funded medical writers prepared the first manuscript draft.

Click to read the study in NEJM

Relevant Reading: KLKB1 gene editing therapy reduces kallikrein levels in hereditary angioedema

In-Depth [randomized controlled trial]: HAELO was a multinational, phase 3, double-blind, placebo-controlled trial conducted at 31 sites across nine countries. Eligible patients were at least 16 years old, had hereditary angioedema due to C1 inhibitor deficiency, and experienced at least two investigator-confirmed attacks during a four- to eight-week run-in period. Long-term prophylactic therapy was discontinued before the run-in period and prohibited through week 28.

Investigators randomly assigned 80 patients in a 2:1 ratio to a single 50-mg intravenous infusion of lonvo-z or placebo. The infusion lasted approximately four hours. Patients received glucocorticoids, H1 and H2 antihistamines, and short-term C1 inhibitor prophylaxis to reduce the risks of infusion reactions and an angioedema attack during treatment. A total of 52 patients received lonvo-z and 28 received placebo. The median age was 41.5 years, 69% were female, and 71% had received long-term prophylaxis before enrollment. The mean baseline monthly attack rate was 3.5 in both groups.

The primary endpoint was the investigator-confirmed monthly attack rate from week 5 through week 28. The least-squares mean monthly attack rate was 0.26 with lonvo-z and 2.10 with placebo, corresponding to a relative difference of -87% (95% confidence interval [CI], -93% to -78%; P<0.001). The difference emerged within four weeks of infusion.

Attacks requiring on-demand therapy occurred at monthly rates of 0.19 with lonvo-z and 1.79 with placebo, a relative reduction of 89%. Moderate or severe attacks occurred at monthly rates of 0.11 and 1.23, respectively, a relative reduction of 91%. From weeks 5 through 28, 32 of 52 patients receiving lonvo-z (62%) and 3 of 28 receiving placebo (11%) remained attack-free (odds ratio, 12.81; 95% CI, 3.45 to 47.55). A reduction of at least 90% from the baseline attack rate occurred in 75% and 18% of patients, respectively.

The Angioedema Quality of Life questionnaire score improved by 23.51 points with lonvo-z and 6.47 points with placebo. The between-group difference was -17.04 points (95% CI, -24.15 to -9.93; P<0.001), exceeding the six-point threshold considered clinically meaningful.

Any adverse event occurred in 48 of 52 patients receiving lonvo-z (92%) and 24 of 28 receiving placebo (86%). Infusion-related reactions occurred in 62% and 18%, respectively, and most resolved on the day of infusion. No grade 3 or higher adverse events occurred in either group, and no serious adverse events occurred among patients receiving lonvo-z. Total plasma kallikrein levels decreased within two weeks of treatment and remained suppressed through the latest assessment.

At the data cutoff, 64 patients had reached at least week 28, while the remaining 16 had reached at least week 20. Longer-term follow-up remains underway within HAELO and a separate long-term follow-up study. The available findings show that a single infusion of lonvo-z substantially reduced hereditary angioedema attacks over the initial placebo-controlled observation period, although the long-term safety and durability of permanent KLKB1 editing remain undetermined.

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