In November 2025, one patient died after receiving Intellia Therapeutics’ investigational gene silencer for transthyretin amyloidosis.
A specific genetic variation appears to have driven the most severe liver enzyme elevations in patients treated with Intellia Therapeutics’ gene therapy nexiguran ziclumeran for transthyretin amyloidosis.
In particular, the biotech identified a specific allele of the HLA gene linked to the highest increases in liver transaminases, according to a Thursday second quarter earnings release. Intellia is presenting these findings to the FDA and other global health authorities, and plans to provide genotyping data to investigators across its trials.
“Each of the five highest elevations observed following dosing occurred in patients carrying this allele,” CEO John Leonard said in an investor call presenting the company’s Q2 earnings. That said, he noted that the “strong majority” of patients carrying this HLA allele did not display concerning increases in liver enzyme levels.
“So we continue to see the potential for a favorable benefit/risk profile even in this subgroup,” Leonard added.
That the liver risk is “isolated to carriers of a specific HLA allele” is good news for Intellia, William Blair wrote on Thursday, since it de-risks the biotech’s broader gene editing platform and minimizes the likelihood that these enzyme elevations will pose a problem to Intellia’s other therapies.
The HLA analysis could also help develop a risk mitigation strategy “that should de-risk an eventual label” for the gene therapy, if approved, the analysts added.
Nexiguran ziclumeran (nex-z) is an in vivo CRISPR-edited genetic medicine that targets and silences the TTR gene, in turn lowering the overall levels of the transthyretin protein in the body. In patients with transthyretin amyloidosis (ATTR), nex-z “offers the possibility of halting and reversing disease,” Intellia said Thursday. The biotech is advancing nex-z in partnership with Regeneron under a 2016 agreement.
In October last year, Intellia was forced to suspend two late-stage programs for nex-z—MAGNITUDE in ATTR-cardiomyopathy (CM) and MAGNITUDE-2 in ATTR-polyneuropathy (PN)—after detecting life-threatening elevations in liver transaminase and bilirubin concentrations in a MAGNITUDE patient.
A few days later, the patient died of liver complications. Intellia at the time attributed the fatality to “complicating comorbidities,” but enlisted its study investigators and outside experts to create a risk mitigation plan for nex-z.
In March, after signing off on Intellia’s enhanced safety monitoring and assessment strategy, the FDA lifted the clinical hold on the nex-z program.
Leonard on the Thursday call also addressed AstraZeneca and Ionis Pharmaceuticals’ failure in the Phase 3 CARDIO-TTRansform study, which last month showed that the partners’ Wainua was unable to elicit significant cardiovascular benefits in ATTR-CM patients versus placebo. Because Wainua is a TTR silencer, analysts expect the failure to be a headwind for this drug class. While not a TTR silencer, nex-z works similarly to Wainua.
“We believe, based on everything we know thus far, that the findings are likely specific to [Wainua] and not generally applicable to how we think about treatment of patients with TTR disease,” Leonard told investors. AstraZeneca and Ionis are expected to present full data from CARDIO-TTRansform later this month at the European Society of Cardiology congress.
Intellia’s MAGNITUDE and MAGNITUDE-2 studies continue to enroll participants, which the company expects to complete this year.
