CRISPR-based therapy shows promise for reducing hereditary angioedema attacks

LOUISVILLE, Ky. — All patients treated with one infusion of NTLA-2002 gene therapy have remained hereditary angioedema attack-free, according to data presented at American College of Allergy, Asthma & Immunology Annual Scientific Meeting.

Hereditary angioedema (HAE), a C1 inhibitor deficiency, is currently treated with prophylactic replacement C1 inhibitor, lanadelumab (Haegarda, CSL Behring), a monoclonal kallikrein inhibitory antibody, or berotralstat (Orladeyo, BioCryst) an oral kallikrein inhibitor, Hilary Longhurst, MA, MB BS, FRCP, PhD, FRCPath, consultant clinical immunologist at Barts Health NHS Trust, London, senior medical officer (immunology) at Auckland District Health Board and honorary associate professor at Auckland University, told Healio, adding that breakthrough attacks can be treated with icatibant (Firazyr, Takeda) or an additional IV C1 inhibitor.

“Where prophylactic treatments are not available, attenuated androgens or tranexamic acid are used for prophylaxis,” she said.

However, there is still a significant unmet need for patients with HAE, Longhurst added.

Hilary Longhurst

“Currently available prophylactics are unavailable in most countries and require parenteral administration in most cases,” she said. “Oral prophylactics are not effective for many. Attenuated androgens have many contraindications; are poorly tolerated, especially for the young women who tend to be worst affected by HAE; and have significant safety concerns, especially since they are required lifelong. Worries about treatment access compound the already significant symptom-related burden of anxiety that HAE patients experience.”

Thus, Longhurst and colleagues sought to evaluate the safety and efficacy evaluating NTLA-2002 (Intellia Therapeutics), an investigational CRISPR/Cas9-based therapy that targets KLKB1 — the gene that encodes the protease kallikrein — in hepatocytes. The goal of treatment is to achieve lifelong control of HAE attacks with only a single administration.

“We know that the angioedema of C1 inhibitor deficiency is caused by excess plasma kallikrein, and that genetic absence of prekallikrein (Fletcher’s syndrome) appears to be associated with normal health and life expectancy,” Longhurst said. “For these reasons a single treatment cure of HAE symptoms would be very desirable. We believe that NTLA-2002 gene editing treatment can deliver this.”

This first-in-human phase 1/2 study uses a single-ascending dose design, testing doses of 25 mg, 50 mg and 75 mg, to evaluate the safety of treatment and to identify up to two doses to advance to phase 2 testing.

The analysis included three patients treated with 25 mg NTLA-2002. All three treated patients showed a clinically significant reduction in plasma kallikrein levels at week 32 (mean, 64%).

Among four patients treated with the 50 mg dose, researchers observed an 81% mean plasma kallikrein reduction at day 22.

Also, three patients have been treated with 75 mg NTLA-2002, with these patients showing a mean 92% reduction in plasma kallikrein levels at week 16.

All six patients from the 25 mg and 75 mg cohorts have completed the 16-week observation period.

In the 25 mg group, patients at baseline experienced 1.1 to 7.2 attacks per month. However, by weeks 1 to 16, patients experienced a 91% reduction in attacks, with an 89% reduction at weeks 5 to 16.

Patients in the 75 mg group experienced four to 5.9 attacks per month at baseline, decreasing by 78% from weeks 1 to 16 and by 89% from weeks 5 to 16.

The duration of ongoing attack free interval ranged from 5.5 months to 10.6 months in the 25 mg cohort and from 2.3 months to 4.2 months in the 75 mg cohort.

Researchers noted that all three doses were generally well tolerated, with most adverse events being mild, infusion-related reactions.

Also, there have been no dose-limiting toxicities or clinically significant laboratory abnormalities.

“All patients are currently attack free, taking on activities and responsibilities that previously would not have been possible for fear of triggering attacks,” Longhurst said.

Overall, these results were not surprising, she added.

“The biological rationale, and a large body of preclinical data, all indicate that the treatment is likely to be safe and effective,” she said. “However, it’s extremely gratifying (especially for our volunteer patients) to see these initial results which are in line with this expectation.”

Reference:

Intellia Therapeutics presents new interim data from first-in-human study of NTLA-2002 for the treatment of hereditary angioedema (HAE) at the American College of Allergy, Asthma & Immunology 2022 Annual Scientific Meeting. https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-presents-new-interim-data-first-human. Published Nov. 12, 2022. Accessed Nov. 13, 2022.