A novel CRISPR-based therapy, NTLA-2002, offers hope for patients with hereditary angioedema (HAE) by potentially replacing the need for lifelong daily medication. The Phase 2 study, published in the New England Journal of Medicine, reveals that a single dose of this gene editing therapy significantly reduces angioedema attacks and lowers kallikrein levels, a key mediator in HAE. This development could dramatically improve the quality of life for individuals suffering from this rare and potentially life-threatening condition.
HAE is a rare genetic disorder characterized by the accumulation of fluids outside blood vessels, leading to rapid swelling in various body parts, including the hands, feet, face, and airway. Airway swelling can be life-threatening. Current treatment options often involve daily medication to manage and prevent these attacks.
NTLA-2002: A Potential Game-Changer
NTLA-2002, administered intravenously, is designed to edit the gene encoding kallikrein B1, thereby reducing total plasma kallikrein protein levels. The Phase 2 study involved 27 patients who were randomly assigned in a 2:2:1 ratio to receive a single dose of 25 mg NTLA-2002 (10 patients), a 50 mg dose (11 patients), or placebo (6 patients). The study included a 16-week primary observation period and an 88-week long-term observation period.
Significant Reduction in Angioedema Attacks
Results from the primary observation period showed a substantial decrease in the estimated mean monthly attack rate in both NTLA-2002 groups compared to the placebo group. Specifically, the mean monthly attack rate was 0.70 in the 25-mg group and 0.65 in the 50-mg group, compared to 2.82 in the placebo group. The mean percent change in the monthly attack rate from baseline through week 16 was -78% for the 25 mg dose and -79.5% for the 50 mg dose, while the placebo group experienced a -16.3% change.
Notably, four patients in the 25 mg group and eight patients in the 50 mg group were attack-free and required no other treatments during the primary observation period. In contrast, none of the patients in the placebo group achieved attack-free status.
Safety and Tolerability
The most common adverse events reported in patients receiving NTLA-2002 were headache, fatigue, and nasopharyngitis. These side effects were generally mild and manageable.
Expert Commentary
"This reduction is perhaps the most crucial as it shows us that the therapy is working," said Hilary Longhurst, M.B.B.S., Ph.D., senior medical officer of the Auckland District Health Board. "Kallikrein acts as messenger that triggers swelling, and in patients with HAE, this protein is basically let loose. The fact that we can reduce its presence tells us that we're on the right track."
Danny Cohn, Ph.D., M.D., internist at Amsterdam University Medical Center, added, "The prospect of a potential, functional cure following a single-time treatment is overwhelming both for patients and physicians."
Study Limitations
The researchers acknowledged several limitations of the study, including the small sample size, short duration of follow-up, and the limited length of the primary observation period. They also noted that the racial and ethnic composition of the trial population may not fully represent the diversity of individuals affected by HAE.
