Genetic variant tied to liver issues in ATTR gene therapy trial
Analysis of nex-z study offers way to identify patients more likely to be affected
Written by |
A specific genetic variant may have contributed to signs of severe liver problems observed in a few patients given nexiguran ziclumeran (nex-z), an investigational gene-editing therapy for hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and the related condition ATTR amyloidosis with cardiomyopathy (ATTR-CM).
That is the conclusion of a genetic analysis by the therapy’s developers, Intellia Therapeutics and Regeneron Pharmaceuticals, that involved samples from more than 600 treated patients across the nex-z clinical program. The companies are discussing the findings with the FDA and other global health authorities.
“What the finding gives us is valuable – a mechanistic explanation for a general signal we’d already flagged and a way to identify patients who are more likely to be affected before it happens,” John Leonard, MD, Intellia’s president and CEO, said in a recent webcast presenting the company’s latest earnings and business updates. “Investigators and patients will be informed about the [genetic] results … so that they can make more informed treatment decisions.”
These liver events, marked by elevations of liver enzymes, were “observed in less than 1% of [ATTR-CM] patients enrolled in” a Phase 3 clinical trial, called MAGNITUDE (NCT06128629), that is testing the therapy against a placebo in up to 1,200 ATTR-CM participants, Leonard said. “These were [temporary] and, in most cases, they resolved without any intervention.”
No such events were reported among hATTR-PN patients treated with nex-z so far in the parallel Phase 3 MAGNITUDE-2 trial (NCT06672237), which is enrolling up to 60 adult patients at sites in Argentina, Brazil, Mexico, Singapore, and Thailand.
Trials resume after being halted last year
Both trials were halted last year after life-threatening liver damage was reported in an older man with ATTR-CM after receiving nex-z in MAGNITUDE. The man, who already had other simultaneous health conditions, eventually died.
The U.S. Food and Drug Administration lifted the clinical hold earlier this year, following an agreement between Intellia and the FDA on study modifications and additional preventive measures, including closer monitoring of liver function.
“I’m excited to report today that we were able to resume enrollment and dosing in both trials [between April and June],” Leonard said.
Intellia also announced that recruitment in MAGNITUDE-2 is expected to be completed in the second half of this year. Enrollment in MAGNITUDE is currently ongoing at sites in the U.S. and several other countries.
“The second quarter [from March to June] was a momentous period for Intellia,” Leonard, said in a company press release. “We … resumed enrollment in our Phase 3 clinical trials in ATTR … and gained important new genomic insights that enhance our understanding of nex-z’s safety profile and its potential to deliver clinically meaningful outcomes for patients.”
Nex-z designed to inactivate the TTR gene in liver cells
hATTR-PN and ATTR-CM are forms of ATTR amyloidosis, a progressive disease caused by the buildup of toxic clumps of the transthyretin (TTR) protein in the body’s tissues, which can impair organ function.
In hATTR-PN, inherited mutations in the TTR gene cause abnormal TTR to form deposits that primarily damage nerves outside the brain and spinal cord, leading to neurological symptoms.
ATTR-CM, by contrast, occurs when TTR deposits build up mainly in the heart, making it harder for the heart to pump blood effectively. This form can be caused by TTR mutations in some cases.
Nex-z, previously known as NTLA-2001, is a gene-editing therapy designed to inactivate the TTR gene in liver cells, where TTR is mostly produced. Given as a one-time infusion into the bloodstream, nex-z is intended to provide consistent and potentially lifelong reduction in TTR production, which could potentially halt or even reverse the disease, according to Intellia.
We continue to see the potential for favorable benefit-risk profile, even in this subgroup, particularly with the mitigation strategy that is now in place.
In a Phase 1 trial (NCT04601051), which involved adults with hATTR-PN and ATTR-CM, nex-z led to deep reductions in blood TTR levels, lasting as long as three years in people with hATTR-PN. Most evaluable hATTR-PN patients also experienced clinically meaningful reductions in the Modified Neuropathy Impairment Score +7 (mNIS+7), a measure of nerve damage-related impairment.
“We look forward to presenting updated long-term durability data at future congresses,” Leonard said.
As the Phase 3 trials were resumed, the companies conducted a comprehensive genetic analysis of more than 600 patient samples collected across the nex-z clinical program.
“Our goal was to understand if there were subpopulations that might be most susceptible to [more severe liver enzyme elevations],” Leonard said. “This work focused on HLAs, which are proteins on the surface of cells that play a key role in [regulating] the immune system and helping to distinguish [self] and foreign [molecules].”
Data showed that patients carrying a specific genetic HLA variant, known as C*05:01, had “a significantly higher rate of [severe] transaminase elevations than the broader population,” Leonard said. “In fact, each of the five highest elevations observed following dosing occurred in patients carrying this [variant].”
The CEO emphasized that, because only 12% of all evaluated patients carried this variant, and most of them did not experience severe liver enzyme elevations, “we continue to see the potential for favorable benefit-risk profile, even in this subgroup, particularly with the mitigation strategy that is now in place.”
Leave a comment
Fill in the required fields to post. Your email address will not be published.