FDA Places Clinical Hold on Intellia's CRISPR Trials Following Serious Liver Safety Event
Intellia Therapeutics has encountered a significant setback in its development of CRISPR-based gene therapies for transthyretin amyloidosis (ATTR), as the U.S. Food and Drug Administration (FDA) has placed a formal clinical hold on two of the company's Phase 3 trials. This decision comes in the wake of a serious liver safety event that led to the hospitalization of a study participant.
Trial Suspension and Safety Concerns
Intellia initially announced a voluntary pause in dosing and enrollment for its MAGNITUDE and MAGNITUDE-2 trials on October 27, 2025, after a patient in the ATTR with cardiomyopathy (ATTR-CM) study experienced grade 4 elevations in liver enzymes and bilirubin levels. The patient, a man in his 80s treated on September 30, was hospitalized on October 25 due to the severity of the adverse event.
The FDA's clinical hold, officially communicated to Intellia on October 30, affects both the ATTR-CM trial and a separate study for ATTR with polyneuropathy (ATTR-PN). Prior to the suspension, Intellia had enrolled over 650 participants in the ATTR-CM trial and 47 in the ATTR-PN study.
Mechanism and Potential Causes
Intellia's investigational therapy, nexiguran ziclumeran (nex-z), uses CRISPR gene editing to inactivate the TTR gene, which encodes the transthyretin protein responsible for ATTR. CEO John Leonard speculated that the safety issue might be tied to the specific gene target rather than the lipid nanoparticle delivery system, as the adverse event occurred weeks after treatment administration.
This incident marks the second time Intellia has reported a grade 4 liver enzyme elevation in its ATTR trials. A similar event occurred earlier in 2025, though it did not result in hospitalization. The company is now working with regulators and independent experts to develop new safety protocols and risk mitigation strategies.
Market Impact and Future Outlook
The news has had a significant impact on Intellia's stock, with shares plummeting by approximately 50% following the announcement. The clinical hold is expected to delay the potential market entry of nex-z, which Intellia had positioned as a long-lasting alternative to existing oral and injectable therapies for ATTR.
Intellia faces the challenge of addressing the FDA's concerns and providing a comprehensive response to the forthcoming formal letter, which the agency will issue within 30 days. The company has stated its intention to work "expeditiously" to resolve the clinical hold, but analysts anticipate that the study readout could be delayed by several quarters.
As the pharmaceutical industry closely watches these developments, the incident raises questions about the safety profile of CRISPR-based therapies and their potential long-term effects, particularly in relation to liver toxicity. The outcome of Intellia's efforts to address these safety concerns will likely have broader implications for the field of gene editing therapeutics.
References
- FDA places formal hold on two Intellia CRISPR trials
Two days after Intellia voluntarily paused dosing due to safety concerns, the regulator stepped in with an official hold that makes a longer halt more likely.
- FDA places Intellia phase 3 CRISPR trials on hold over raised liver enzymes
After Intellia Therapeutics paused a pair of phase 3 trials for its CRISPR therapy in response to a liver safety signal, the FDA has made things official by placing the studies under a clinical hold.
- Intellia Pauses Phase III ATTR Trials for CRISPR Gene Therapy After Life-Threatening Liver Toxicity
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.”
- Intellia pauses two CRISPR drug studies after safety scare
A study volunteer receiving Intellia’s transthyretin amyloidosis treatment was hospitalized due to severe signs of liver stress, prompting the company to pause enrollment and dosing while evaluating a new safety protocol.
- Intellia pauses phase 3 CRISPR trials after patient is hospitalized
Intellia Therapeutics has temporarily paused dosing and screening in a pair of phase 3 trials in response to a liver safety signal. Shares in Intellia fell 45% to $14.01 in premarket trading.
Explore Further
What steps is Intellia Therapeutics taking to address the FDA's concerns and develop improved safety protocols for its CRISPR-based therapies?
What are the current safety profiles and liver toxicity risks associated with CRISPR-based therapies in comparison to traditional treatments for ATTR?
Who are the major competitors offering oral and injectable therapies for ATTR, and how do their products compare in terms of efficacy and safety?
What impact could the delay in nexiguran ziclumeran's market entry have on Intellia's position in the ATTR treatment space and its financial performance?
What are the broader implications of liver safety events in gene-editing trials for the future of CRISPR-based therapeutics and their regulatory approval?