Intellia files CRISPR drug after historic phase 3 readout
Intellia’s president and chief executive John Leonard.
Intellia Therapeutics has reported the first-ever phase 3 results with an in vivo gene-editing therapy, hereditary angioedema (HAE) therapy lonvoguran ziclumeran (lonvo-z), and moved ahead straight away with a rolling marketing application in the US.
The HAELO trial of lonvo-z, which is based on CRISPR/Cas9 gene editing technology, showed that a one-time treatment freed most patients with HAE from the unpredictable bouts of debilitating, painful, and potentially life-threatening swelling around the body that characterise the rare disease.
The results are a major milestone in CRISPR-based gene editing, which until now has mainly focused on ex vivo modification of cells outside the body. That is the approach deployed in CRISPR/Therapeutics/Vertex Pharma's Casgevy (exagamglogene autotemcel) for sickle cell disease and thalassaemia, which in 2023 became the first CRISPR-based therapy to be approved for marketing by the FDA.
Lonvo-z is designed to inactivate the kallikrein B1 (KLKB1) gene, which leads to elevated kallikrein and bradykinin levels in HAE, in a single outpatient infusion appointment.
In HAELO, the drug met its primary endpoint, a reduction in the number of Investigator-confirmed HAE attacks from week five to 28 after dosing, with an 87% reduction versus placebo.
Secondary efficacy endpoints were also met, including an attack-free rate of 62% with lonvo-z over six months of follow-up compared to 11% of the control group, and Intellia said the gene-editing therapy was associated with "favourable" safety and tolerability.
The safety data is particularly important, as last year Intellia's second in vivo CRISPR programme, nexiguran ziclumeran (nex-z) for transthyretin amyloidosis with cardiomyopathy (ATTR-CM) and polyneuropathy (ATTR-PN), was placed on clinical hold by the FDA while an investigation into liver toxicity played out. The hold was lifted last month.
The Cambridge, Massachusetts-based biotech, co-founded by Nobel Prize winner Jennifer Doudna, said it has started a rolling biologics license application (BLA) with the FDA that – if all goes to plan – could result in lonvo-z being approved and launched as the first one-shot HAE treatment in the first half of 2027.
Intellia's chief executive, John Leonard, said the readout is "a profound milestone for Intellia, the broader CRISPR and precision medicine fields and, most importantly, the HAE community."
That sentiment was echoed by HAELO investigator Aleena Banerji of Harvard Medical School and Massachusetts General Hospital, who said: "The results we are seeing from lonvo-z demonstrate its potential to eliminate the need for chronic medication and related challenges."
Current treatment for HAE relies on lifelong injectable or oral therapies to reduce the risk of attacks, in some cases requiring dozens of injections per year, which can place a considerable burden on patients and high costs for health systems.
