Intellia Halts Phase III CRISPR Trials Due to Severe Liver Toxicity

Intellia Therapeutics has paused two Phase III clinical trials of its CRISPR-based gene therapy for transthyretin amyloidosis (ATTR) following a serious liver safety event. The decision has sent shockwaves through the biotech industry, raising concerns about the safety of CRISPR therapies and causing Intellia's stock to plummet.

Safety Signal Prompts Trial Suspension

On September 30, a patient in the MAGNITUDE trial for ATTR with cardiomyopathy (ATTR-CM) experienced grade 4 elevations in liver enzymes and bilirubin levels, requiring hospitalization. This event triggered Intellia to halt enrollment and dosing in both the MAGNITUDE trial and the parallel MAGNITUDE-2 trial for ATTR with polyneuropathy (ATTR-PN).

The therapy in question, nexiguran ziclumeran (nex-z), uses CRISPR gene editing to target and deactivate the TTR gene, which encodes the transthyretin protein. In ATTR patients, misfolded transthyretin accumulates in tissues, compromising nerve and heart function.

Intellia CEO John Leonard stated, "We are working to develop a strategy to resume enrollment as soon as appropriate." The company is consulting with regulators and independent experts to implement new safety measures and determine the best path forward.

Previous Safety Concerns and Market Impact

This is not the first time nex-z has been associated with liver toxicity. In May 2025, Intellia reported a similar grade 4 liver enzyme elevation in another patient, though dosing was not suspended at that time. The company had also observed "significant elevation in liver enzymes" in a Phase I ATTR-PN study in August 2022, leading to protocol amendments and a lower fixed-dose regimen.

The market reaction to the latest safety event has been severe. Intellia's stock price plummeted by nearly 45% in early trading on Monday, opening at $14.34 per share, down from the previous close of $25.60.

Implications for CRISPR Technology and ATTR Treatment Landscape

The suspension of these trials raises questions about the broader application of CRISPR technology in gene therapies. Intellia is working to identify the cause of the liver toxicity, with CEO Leonard speculating that it may be tied to the specific gene target rather than the lipid nanoparticle delivery system.

This setback could potentially delay Intellia's entry into the ATTR treatment market, which is currently served by companies like Alnylam, BridgeBio, and Pfizer. Nex-z was positioned as a potential one-time alternative to existing therapies, but its future now depends on resolving these safety concerns.

As the biotech community awaits further updates, the incident serves as a reminder of the challenges and risks associated with developing cutting-edge gene therapies. The outcome of Intellia's investigation and subsequent actions will likely have far-reaching implications for the field of CRISPR-based treatments.