Single-Dose In Vivo CRISPR Editing of KLKB1 Reduces Angioedema Attacks by Up to 97% in Phase 1 Trial
This phase 1 dose-escalation trial of NTLA-2002, a CRISPR-Cas9 therapy targeting KLKB1, demonstrated dose-dependent reductions in plasma kallikrein of up to 95% and a 95% reduction in monthly angioedema attacks across 10 patients with hereditary angioedema. No dose-limiting toxicities or serious adverse events were observed at any dose level. These results represent a milestone for in vivo CRISPR gene editing as a one-time treatment for genetic disease, with implications for laboratory monitoring of kallikrein and complement pathway biomarkers.
The original study
CRISPR-Cas9 In Vivo Gene Editing of
- Authors
- Longhurst HJ, Lindsay K, Petersen RS, Fijen LM, Gurugama P, Maag D, et al.
- Journal
- The New England journal of medicine
- Type
- Clinical Trial, Phase I, Journal Article
- PMID
- 38294975
Original abstract
BACKGROUND: Hereditary angioedema is a rare genetic disease that leads to severe and unpredictable swelling attacks. NTLA-2002 is an in vivo gene-editing therapy based on clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9. NTLA-2002 targets the gene encoding kallikrein B1 (KLKB1), with the goal of lifelong control of angioedema attacks after a single dose. METHODS: In this phase 1 dose-escalation portion of a combined phase 1-2 trial of NTLA-2002 in adults with hereditary angioedema, we administered NTLA-2002 at a single dose of 25 mg, 50 mg, or 75 mg. The primary end points were the safety and side-effect profile of NTLA-2002 therapy. Secondary and exploratory end points included pharmacokinetics, pharmacodynamics, and clinical efficacy determined on the basis of investigator-confirmed angioedema attacks. RESULTS: Three patients received 25 mg of NTLA-2002, four received 50 mg, and three received 75 mg. At all dose levels, the most common adverse events were infusion-related reactions and fatigue. No dose-limiting toxic effects, serious adverse events, grade 3 or higher adverse events, or clinically important laboratory findings were observed after the administration of NTLA-2002. Dose-dependent reductions in the total plasma kallikrein protein level were observed between baseline and the latest assessment, with a mean percentage change of -67% in the 25-mg group, -84% in the 50-mg group, and -95% in the 75-mg group. The mean percentage change in the number of angioedema attacks per month between baseline and weeks 1 through 16 (primary observation period) was -91% in the 25-mg group, -97% in the 50-mg group, and -80% in the 75-mg group. Among all the patients, the mean percentage change in the number of angioedema attacks per month from baseline through the latest assessment was -95%. CONCLUSIONS: In this small study, a single dose of NTLA-2002 led to robust, dose-dependent, and durable reductions in total plasma kallikrein levels, and no severe adverse events were observed. In exploratory analyses, reductions in the number of angioedema attacks per month were observed at all dose levels. (Funded by Intellia Therapeutics; ClinicalTrials.gov number, NCT05120830.).