First phase 3 trial of an in-vivo CRISPR therapy cuts hereditary angioedema attacks by 87 per cent

A single intravenous infusion of a CRISPR therapy reduced hereditary angioedema attacks by 87 per cent compared with placebo, according to the HAELO trial, published in the New England Journal of Medicine on 13 June 2026. It is the first randomised, placebo-controlled phase 3 trial of a gene-editing medicine given directly into the body to report results.

The therapy, lonvoguran ziclumeran, known as lonvo-z and formerly as NTLA-2002, is an in-vivo CRISPR-Cas9 treatment from Intellia Therapeutics. It is designed as a one-off infusion that knocks out the kallikrein B1 gene in liver cells, cutting off bradykinin production at source. Because the gene is disabled rather than supplemented, the treatment is intended to be given once. Hereditary angioedema is a rare autosomal-dominant disorder that causes recurrent, unpredictable swelling of the face, limbs, gut and airway, and laryngeal attacks can be fatal. Existing prophylaxis requires lifelong regular injections or twice-daily oral dosing.

HAELO, registered on ClinicalTrials.gov as NCT06634420, randomised 80 patients aged 16 years or older with hereditary angioedema due to C1-inhibitor deficiency. Allocation was double-blind and in a 2:1 ratio: 52 participants received a single 50 mg intravenous dose of lonvo-z and 28 received placebo.

The primary endpoint was investigator-confirmed attacks per month from week 5 through week 28. The least-squares mean monthly attack rate was 0.26 with lonvo-z (95% CI 0.15 to 0.45) against 2.10 with placebo (95% CI 1.55 to 2.86), a relative difference of minus 87 per cent (95% CI minus 93 to minus 78), P less than 0.001. The data cut-off was 10 February 2026. Median follow-up at publication was 7.5 months, with a range of 4.9 to 12.8 months.

Adverse events during or after infusion were common in both arms, occurring in 92 per cent of the lonvo-z group and 86 per cent of the placebo group. No serious adverse events and no grade 3 or higher adverse events were reported in the lonvo-z group. The adverse events that occurred more often with lonvo-z, each in more than 10 per cent of treated patients, were infusion-related reaction, headache, fatigue, back pain and upper respiratory tract infection.

The first author is Danny M. Cohn, of the Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, at Amsterdam University Medical Centers, University of Amsterdam. The investigator roster spans four continents. It includes Hilary J. Longhurst of Auckland City Hospital and the University of Auckland, New Zealand; Emel Aygören-Pürsün of University Hospital Frankfurt, Goethe University; Henriette Farkas of the Hungarian Angioedema Center of Reference and Excellence at Semmelweis University, Budapest; Markus Magerl of the Institute of Allergology, Charité-Universitätsmedizin Berlin; Jonny Peter of Groote Schuur Hospital, University of Cape Town, South Africa; Padmalal Gurugama of Cambridge University Hospitals NHS Foundation Trust; and Marc A. Riedl of the University of California, San Diego.

The trial was funded by Intellia Therapeutics. The paper carries the DOI 10.1056/NEJMoa2600931 and the PubMed identifier 42294842.

Earlier in-vivo CRISPR results, including the transthyretin amyloidosis programme and the bespoke base-editing treatment of an infant with a urea-cycle disorder in 2025, came from phase 1/2 or single-patient settings. HAELO is the first pivotal randomised readout for a systemically delivered gene-editing drug. The median follow-up of 7.5 months is the main limit on what it can say so far about how long a single dose holds.

Regulatory submission in the United States and Europe is the stated route from here. Longer follow-up will test whether one dose confers permanent protection.