NTLA-2002 for hereditary angioedema

Last updated June 29, 2024, 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).

Intellia is planning to launch, in the second half of 2024, a pivotal Phase 3 trial to test the therapy’s safety and efficacy. The company now expects to submit an application to regulatory authorities in 2026 requesting NTLA-2002’s approval. The treatment is given as a one-time intravenous infusion directly into the bloodstream.

It’s 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 (FDA) has granted NTLA-2002 orphan drug and regenerative medicine advanced therapy (RMAT) designations, while the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) awarded the therapy an innovation passport. Regulators in the European Union gave NTLA-2002 orphan drug and priority medicines (PRIME) designations.

Therapy snapshot

How does NTLA-2002 work in hereditary angioedema?

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 hereditary angioedema?

In a Phase 1/2 trial involving people with HAE, NTLA-2002 was given at a dose level of 25, 50, or 75 mg via a single intravenous infusion lasting at least two hours.

NTLA-2002 in hereditary angioedema clinical trials

NTLA-2002 is being tested in a Phase 1/2 clinical trial (NCT05120830) that’s expected to involve approximately 30 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.

Interim data showed that nine of the 10 participants had no swelling attacks in the first year after treatment. 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 6 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.

The Phase 2 portion of the trial is comparing two doses of NTLA-2002 — 25 and 50 mg — against a placebo, with the main goal of assessing how the gene-editing therapy affects rates of swelling attacks in the first four months after treatment. This part of the study began dosing in mid-2023, and is still ongoing. Results from this part of the study are expected in late 2024.

Common side effects of NTLA-2002

No serious side effects related to NTLA-2002 were reported in the Phase 1 portion of the Phase 1/2 trial. The most commonly reported side effects of the therapy included infusion-related reactions, fatigue, and elevations in liver enzyme levels (possibly indicative of liver inflammation and damage).

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