CRISPR genome editing trials paused due to liver toxicity

Two gene therapy trials run by Intellia Therapeutics have been paused after a study participant was hospitalised.

The US Food and Drug Administration has placed a clinical hold on two late-stage gene therapy clinical trials this week, after a participant exhibited severe signs of liver stress. The Phase III trial was testing Intellia's experimental CRISPR/Cas9-based gene therapy nexiguran ziclumeran, or nex-z, which was developed to treat transthyretin (ATTR) amyloidosis, a rare disease affecting the heart and nerves. The participant, a man in his 80s, is currently receiving medical treatment in hospital.

'In line with our commitment to patient safety, we have taken immediate action to temporarily pause enrolment in MAGNITUDE and MAGNITUDE-2 as we investigate this recent event,' said Dr John Leonard, president and CEO of Intellia. 'As we focus on ensuring the health of this patient, we are also engaging with regulatory authorities and other stakeholders globally to develop a strategy to resume enrolment as soon as appropriate.'

ATTR amyloidosis can lead to cardiomyopathy (ATTR-CM), or polyneuropathy (ATTR-PN), investigated by the MAGNITUDE and MAGNITUDE-2 trials, respectively. While the man who was hospitalised was taking part in the MAGNITUDE trial, both trials have been temporarily paused. Across both trials, 697 participants have been enrolled, with over 450 already having received doses of nex-z.

Patients with hereditary ATTR amyloidosis have mutations in the TTR gene, leading to the production of misfolded TTR proteins, which result in the disease. Intellia's nex-z therapy uses CRISPR/Cas9 to inactivate the TTR gene, preventing the faulty proteins from forming (see BioNews 1135 and 1167). However, CRISPR-based gene therapies are only one possible approach to treating diseases with a genetic basis. Recently, another gene therapy for ATTR amyloidosis showed promise in clinical trials, which functions by silencing the TTR gene using siRNA (see BioNews 1257).

This is the second time a participant in Intellia's MAGNITUDE study has experienced liver stress; however, this is the first time it has resulted in hospitalisation. Liver toxicity has also proved a problem for other gene therapies, after two patients died following treatment with Sarepta's Duchenne muscular dystrophy drug Elevidys (see BioNews 1282).

'This is not the first time Intellia has faced a regulatory hiccup,' Dr Debanjana Chatterjee, senior analyst at Jones Trading, who was not involved in the study, told Reuters. 'We remain optimistic that the trial might resume within a couple of months.'