Intellia earlier this year reported a similar grade 4 liver enzyme elevation associated with the gene therapy nexiguran ziclumeran, though analysts at BMO Capital Markets at the time brushed it off as a “non-concern.”
Adverse events in a patient have forced Intellia Therapeutics to put a hold on a pair of Phase III studies of the CRISPR-based therapy nexiguran ziclumeran, which is being tested for transthyretin amyloidosis.
The trials, MAGNITUDE and MAGNITUDE-2, are testing nexiguran ziclumeran (nex-z) for transthyretin amyloidosis with cardiomyopathy (ATTR-CM) and polyneuropathy (ATTR-PN), respectively. The patient in question was enrolled in MAGNITUDE and the adverse event—an episode of grade 4 elevations in liver transaminase and bilirubin levels—was documented on Sept. 30. The patient has since been hospitalized and is receiving medical care, according to a company announcement on Monday. Grade 4 adverse events are those that are life-threatening and require urgent medical attention.
Intellia has also informed regulatory authorities of the adverse event and is working with experts to determine the best way forward for nex-z, including potential risk mitigation strategies.
At $14.65 per share, Intellia is down nearly 43% before the opening bell on Monday. Its previous closing price was $25.60.
Using CRISPR editing, nex-z is an investigational gene therapy that targets and deactivates the TTR gene that encodes for the transthyretin protein. In patients with ATTR, transthyretin is wrongly folded and builds up in various tissues, in turn compromising the function of nerves or tissues in the heart. For $75 million upfront, Regeneron partnered with Intellia in April 2016 to develop gene therapies for ATTR and other diseases, expanding the partnership in October 2023.
In May this year, Intellia disclosed that one other patient who had been treated with nex-z experienced grade 4 liver enzyme elevations, though the company elected to not suspend dosing at the time. Analysts were largely unperturbed by that safety signal. In a May 29 note, Truist Securities said that the liver toxicity “does not cross the threshold for us to be concerned about the safety profile” of nex-z “just yet.”
BMO Capital Markets agreed, calling the enzyme elevation a “non-concern” in a note on the same day.
Nex-z was also linked to a “significant elevation in live enzymes” in a Phase I ATTR-PN study, according to an August 2022 release from Intellia. While the liver signal was asymptomatic and normalized without medical intervention after 28 days, the biotech at the time amended its study protocol and introduced a lower fixed-dose regimen of nex-z.
