NTLA-2002 for hereditary angioedema

Last updated Feb. 3, 2025, by Marisa Wexler, MS
Fact-checked by Joana Carvalho, PhD

What is NTLA-2002 for hereditary angioedema?

NTLA-2002 is a gene-editing therapy being developed by Intellia Therapeutics to reduce the risk of swelling attacks in people with hereditary angioedema (HAE). The treatment is given as a one-time intravenous infusion directly into the bloodstream.

A Phase 3 clinical trial testing the therapy in HAE patients is ongoing, and Intellia expects to submit an application to regulatory authorities requesting the approval of NTLA-2002 in 2026.

NTLA-2002 has received a suite of designations from regulatory authorities in the U.S. and Europe that aim to speed and incentivize its development. The U.S. Food and Drug Administration has granted NTLA-2002 orphan drug and regenerative medicine advanced therapy designations, while the U.K. Medicines and Healthcare products Regulatory Agency awarded the therapy an innovation passport. Regulators in the European Union gave NTLA-2002 orphan drug and priority medicines designations.

Therapy snapshot

How does NTLA-2002 work in HAE?

In HAE, swelling attacks are triggered by abnormally high levels of a signaling molecule called bradykinin. The production of this signaling molecule is controlled by an enzyme called kallikrein.

NTLA-2002 is a one-time gene-editing therapy that uses the CRISPR/Cas9 gene-editing tool to disrupt the activity of the KLKB1 gene. This gene provides instructions for making prekallikrein, which, as its name suggests, is a precursor to the kallikrein enzyme. By disrupting the activity of the KLKB1 gene specifically in liver cells, NTLA-2002 is expected to reduce kallikrein production and activity, thereby lowering bradykinin levels and ultimately reducing the risk of HAE swelling attacks.

According to Intellia, NTLA-2002 is the first one-time experimental treatment being investigated in clinical trials for its potential to sustainably reduce kallikrein’s activity and prevent swelling attacks in people with HAE.

How will NTLA-2002 be administered in HAE?

In a Phase 3 clinical trial involving people with HAE, NTLA-2002 is being given at a dose level of 50 mg via a single intravenous infusion.

NTLA-2002 in HAE clinical trials

NTLA-2002 has been tested in a Phase 1/2 clinical trial involving HAE patients. A Phase 3 clinical trial enrolling a similar patient population is ongoing.

Phase 1/2 study

NTLA-2002 is being tested in a Phase 1/2 clinical trial (NCT05120830) that enrolled 37 adults with HAE types 1 or 2. All patients had experienced at least three swelling attacks in the 90 days prior to screening.

The Phase 1 portion of the study enrolled 10 HAE patients, ages 26-73. All received a single intravenous infusion of NTLA-2002 at one of three dose levels: 25, 50, or 75 mg. All participants were then monitored for long-term outcomes for a total of 104 weeks, or two years.

Results published in early 2024 showed that NTLA-2002 reduced kallikrein levels as designed — by up to 95% at the highest tested dose. Over a follow-up time of about six months to a year for most patients, the number of monthly swelling attacks decreased by a mean of 95% across all study participants.

More recent data, with a median follow-up time of more than 20 months, or longer than 1.5 years, showed the rate of monthly swelling attacks decreased by a mean of 98%. The monthly rate of attacks that required on-demand treatment also dropped by a mean of 97%, while that of moderate to severe attacks dropped by a mean of 99%. Reductions in the rate of swelling attacks were sustained over time, with eight patients remaining attack-free for at least 18 months.

In the Phase 2 part of the study, 27 people with HAE types 1 or 2 were given a single infusion of NTLA-2002 at one of two doses (25 or 50 mg) or a placebo. The main goal of this part of the trial was to evaluate the effect of treatment on rates of monthly swelling attacks over the first 16 weeks (about four months).

Results showed that, in the high-dose group, mean swelling attack rates decreased by about 80% over the course of four months compared with the placebo. Eight of the 11 patients given the high dose of the therapy were free from swelling attacks over the course of follow-up, whereas no patients given the placebo were free from such attacks. The rate of monthly swelling attacks also was reduced in the low-dose group compared with the placebo, though slightly less than the high-dose group.

HAELO Phase 3 trial

A Phase 3 study is also ongoing to further evaluate the safety and efficacy of NTLA-2002 in HAE patients. The study, called HAELO (NCT06634420), is expected to enroll about 60 adults with HAE types 1 or 2. Participants will be randomly assigned to receive a single intravenous infusion of NTLA-2002 at a dose of 50 mg, or a placebo.

The study’s main goal is to evaluate the effect of treatment on the rate of swelling attacks from week five through week 28 (about six months). After 28 weeks, patients initially assigned to the placebo will have the option to receive NTLA-2002. After the initial 28-week primary observation period, participants will enter a 76-week long-term observation period.

The trial began dosing in early 2025 and is expected to be completed in 2027.

Common side effects of NTLA-2002

No serious side effects related to NTLA-2002 were reported in the Phase 1/2 trial. In the Phase 1 part, the most commonly reported safety issues were infusion-related reactions, fatigue, and elevations in liver enzyme levels (possibly indicative of liver inflammation and damage). In the Phase 2 part, the most common safety issues were fatigue, headache, and cold-like symptoms.

Angioedema News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.