Intellia Therapeutics announced on Aug. 7 that a specific genetic variation may be responsible for the most severe liver enzyme elevations seen in patients treated with its gene therapy, nexiguran ziclumeran, for transthyretin amyloidosis.
The company identified a particular allele of the HLA gene associated with the highest increases in liver transaminases, according to its second quarter earnings release. Intellia is sharing these findings with the Food and Drug Administration 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 during an investor call presenting Q2 earnings. He added that “the strong majority” of patients carrying this HLA allele did not show concerning increases in liver enzyme levels. “So we continue to see the potential for a favorable benefit/risk profile even in this subgroup,” Leonard said.
William Blair analysts wrote that isolating the liver risk to carriers of a specific HLA allele reduces concerns about Intellia’s broader gene editing platform and minimizes the likelihood that these enzyme elevations will affect other therapies. The analysis could also help develop a risk mitigation strategy, “that should de-risk an eventual label” for nexiguran ziclumeran if approved, they said.
Nexiguran ziclumeran is an in vivo CRISPR-edited genetic medicine designed to silence the TTR gene and lower transthyretin protein levels. In patients with transthyretin amyloidosis (ATTR), Intellia said it offers “the possibility of halting and reversing disease.” The therapy is being developed with Regeneron under a 2016 agreement.
Last October, Intellia suspended two late-stage programs—MAGNITUDE in ATTR-cardiomyopathy and MAGNITUDE-2 in ATTR-polyneuropathy—after detecting life-threatening increases in liver transaminase and bilirubin concentrations. A patient later died from liver complications; at that time, Intellia attributed the fatality to complicating comorbidities, but began working on a risk mitigation plan for nexiguran ziclumeran with study investigators and outside experts.
In March, after approving enhanced safety monitoring strategies from Intellia, the FDA lifted its clinical hold on nexiguran ziclumeran studies. The MAGNITUDE studies are continuing enrollment and are expected by Intellia to complete this year.
