Intellia Therapeutics has acknowledged the death of the elderly patient hospitalized last week in its Phase III trial of assessing nexiguran ziclumeran (nex-z) in transthyretin amyloidosis with cardiomyopathy (ATTR-CM).
The patient, which Intellia described previously as a man in his early 80s with a high body mass index, succumbed to liver dysfunctions that included Grade 4 liver transaminases and increased total bilirubin after being dosed with nex-z in the Phase III MAGNITUDE trial (NCT06128629) on September 30.
In disclosing the hospitalization last week, Intellia said it learned of the patient’s condition approximately 24 days post-dosing and responded by voluntarily paused dosing and screening in the 650+-patient MAGNITUDE trial as well as a second 47-patient Phase III study of nex-z called MAGNITUDE-2 (NCT06672237).
Two days later, the FDA told Intellia it imposed a clinical hold on the Investigational New Drug (IND) applications of both trials. The company is expected to receive a formal letter to that effect from the agency.
“We have been advised by the treating physician that this is a case with complicating comorbidities, and it is being further evaluated,” Intellia president and CEO John Leonard, MD, said as part of the company’s press release announcing third quarter results. Intellia finished Q3 with a narrower $101.3 million net loss, improved from its $135.7 million net loss for the year-ago quarter, on collaboration revenue that grew 51% year-over-year, to $13.782 million from $9.111 million.
“As we await the FDA’s clinical hold letter, we are working with clinical investigators and external experts to better understand the liver-related events that have been observed within MAGNITUDE and to develop our risk mitigation plan,” Leonard stated. “We continue to believe in nex-z’s potential to address important unmet needs for patients with ATTR amyloidosis.”
Investors responded to news of the patient death with yet another stock selloff that sent Illumina shares tumbling about 21% Friday, to $9.77 as of 11 a.m. ET, from Thursday’s market closing price of $12.32—a 9% slide from $13.57 on Wednesday.
Intellia shares have plunged nearly 62% since disclosing news of the patient injury in the MAGNITUDE trial, falling from $25.60 on October 24.
Nex-z is a Regeneron Pharmaceuticals-partnered in vivo CRISPR-based therapy designed to treat ATTR-CM by inactivating the TTR gene. This gene encodes for the mutated transthyretin (TTR) protein that causes polyneuropathy.
Risk to broader TTR program
“Clearly this complicates the path for nex-z, heightens the safety overhang and puts the broader TTR program at risk,” Mani Foroohar, MD, a senior research analyst with Leerink Partners focused on genetic medicines, wrote Friday in a research note. “Despite investor skepticism, management continues to stand by the program, and we expect near-term headwinds as NTLA navigates a path to resume dosing.”
Maury Raycroft, PhD, equity analyst with Jefferies, said the best case scenario would be for Intellia to be able to restart the trials after identifying potential causes and aligning with the FDA on protocol amendments.
“We believe the liver injury situation is unique, given NTLA’s approach involves a 1x therapy and not chronic exposure to a drug. However, we acknowledge risk [with] FDA that can’t be fully ruled out yet, which could be detrimental,” Raycroft wrote Thursday in a research note.
Intellia executives have said that laboratory reports had shown the elderly patient to have had AST and ALT levels above three times the upper limit of normal, as well as bilirubin levels above two times the upper limit of normal. Those levels meet the criteria of Hy’s Law, which, according to an FDA guidance, holds that “pure hepatocellular injury sufficient to cause hyperbilirubinemia is an ominous indicator of the potential for a drug to cause serious liver injury.”
“If this event was not cardiovascular related and not triggered by the patient’s undisclosed comorbidities, then major concerns over DILI [drug induced liver injury]-related signals will be difficult to overcome, in our view,” Myles R. Minter, PhD, a partner and research analyst, healthcare covering biotech companies for William Blair, wrote Friday in a research note.
While MAGNITUDE, which dosed its first patient in March 2024, is assessing nex-z in ATTR-CM, the Phase III MAGNITUDE-2 trial is evaluating the therapy in transthyretin amyloidosis with polyneuropathy (ATTRv-PN). Intellia reasons that nex-z offers the potential to halt and reverse both diseases by through what it calls a deep, consistent, and potentially lifelong reduction in TTR protein after a single dose.
To date, according to Intellia, Grade 4 liver transaminase elevations have been reported in less than one percent of all patients enrolled in MAGNITUDE and no Grade 4 liver transaminase elevations have been reported in MAGNITUDE-2.
“The company continues to consult with clinical investigators and other experts to investigate the transaminase elevations and consider potential additional risk mitigation strategies while awaiting the FDA’s formal clinical hold letter,” Intellia said in its announcement.
Stepping up monitoring
In addition, Intellia has ordered all MAGNITUDE and MAGNITUDE-2 clinical sites to step up their monitoring of patient laboratory values in the weeks after dosing.
Before the dosing pause and clinical hold, Intellia expected to complete patient enrollment in the first half of 2026 for MAGNITUDE-2, which, according to ClinicalTrials.gov, had an estimated primary completion date of July 2027.
In light of the clinical hold, Intellia said, it has suspended its guidance to investors of the timing of clinical milestones for nex-z pending alignment with the FDA. Intellia plans to provide an update after it has finalized a plan with regulators on the path forward.
“Intellia plans to provide an update after it has finalized a plan with regulators on the path forward,” the company added.
In the meantime, Intellia said a researcher plans on Monday to present long-term safety and efficacy data for nex-z from a global Phase I trial (NCT04601051) evaluating the treatment in both ATTR-CM and ATTRv-PM patients through an ongoing open-label, multi-center, two-part study in adults.
The “late breaker” presentation will be presented at the 2025 American Heart Association (AHA) Scientific Sessions, being held today through Monday in New Orleans, by Julian Gillmore, MD, PhD, professor of medicine at the National Amyloidosis Centre, UCL Division of Medicine, Royal Free Hospital in the U.K.
MAGNITUDE and MAGNITUDE-2 are two of three Phase III studies Intellia is conducting of its two late-stage gene edited therapies. The third is the Phase III HAELO trial (NCT06634420) assessing lonvoguran ziclumeran (lonvo-z; formerly NTLA-2002), an in vivo CRISPR-based gene editing therapy being developed as a one-time treatment for hereditary angioedema (HAE).
Intellia expects to report HAELO topline data by mid-2026, submit a BLA in the second half of 2026, and prepare to launch lonvo-z in the first half of 2027 in the United States.
On Saturday at the American College of Allergy, Asthma & Immunology Annual Scientific Meeting (ACAAI), being held in Orlando through Monday, researchers working with Intellia plan to longer-term clinical data at an oral session from all patients who received a 50 mg dose of lonvo-z in Intellia’s ongoing Phase I/II trial (NCT05120830).
