A Single CRISPR Treatment Could Replace a Lifetime of Daily Treatment in Hereditary Angioedema

Patients with hereditary angioedema (HAE) may be able to replace their daily medication with a single treatment of a CRISPR-Cas9-based gene editing therapy, NTLA-2002.

HAE is a rare inherited disorder in which fluids accumulate outside of blood vessels and block the normal flow of blood or lymphatic fluid, which causes rapid swelling of the hands, feet, limbs, face, intestinal tract, or airway. Swelling of the airway can cause very serious complications. The severity of HAE can vary greatly among patients and can sometimes result in death.

In a new phase 2 study published in New England Journal of Medicine and presented at the American College of Allergy, Asthma & Immunology’s annual meeting, 27 patients were treated with two doses of a CRISPR-based therapy compared with placebo. Both doses of the gene therapy reduced angioedema attacks and led to sustained and meaningful reduction in kallikrein levels. Kallikrein enzymes are found in various tissues and bodily fluids and play a role in blood clotting, among other processes.

"This reduction is perhaps the most crucial as it shows us that the therapy is working,” Hilary Longhurst, M.B.B.S., Ph.D., senior medical officer of the Auckland District Health Board and an honorary senior lecturer at the University of Auckland in New Zealand, said in a statement. “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.”

NTLA-2002 is administered intravenously and is designed to edit the gene encoding kallikrein B1 to reduce total plasma kallikrein protein level. Patients were assigned in a randomized fashion 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 (six patients). The study included a primary observation period in the first 16 weeks after infusion followed by a long-term observation period of 88 weeks.

At the data cutoff date, the 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. At baseline, the mean monthly attack rate was 3.6 in the NTLA-2002 groups and 3.7 in the placebo group. During the primary observation period, the estimated mean monthly attack rate was 0.70 in the 25-mg group, 0.65 in the 50-mg group and 2.82 in the placebo group. The mean percent change in the monthly attack rate from baseline through week 16 was –78% for 25 mg, –79.5% for 50 mg and –16.3% mg for placebo.

There were four patients receiving the 25 mg dose and eight patients receiving 50 mg who were attack-free and had received no other treatments in the primary observation period. In comparison, none of the patients receiving placebo were attack-free.

The most common adverse events for patients receiving NTLA-2002 were headache, fatigue and nasopharyngitis.

The researchers noted that the small sample size in the trial, the short duration of follow-up and the short length of the primary observation period as limitations of the study. They also wrote that the race and ethnicity of the trial population does not reflect the groups affected by HAE generally.

"For many decades, patients with HAE were faced with a very limited number of treatment options to control angioedema attacks,” Danny Cohn, Ph.D., M.D., internist at Amsterdam University Medical Center, said in a statement. “The prospect of a potential, functional cure following a single-time treatment is overwhelming both for patients and physicians.”