Intellia Halts Phase III CRISPR Trials Due to Severe Liver Toxicity

Intellia Therapeutics has announced a temporary pause in its Phase III clinical trials for nexiguran ziclumeran (nex-z), a CRISPR-based gene therapy targeting transthyretin amyloidosis (ATTR), following a life-threatening adverse event in a patient. The decision has sent shockwaves through the biotech industry, raising concerns about the safety of CRISPR-based therapies and their potential impact on liver function.

Safety Signal Prompts Trial Suspension

On September 30, a patient in the MAGNITUDE trial, which is testing nex-z for ATTR with cardiomyopathy (ATTR-CM), experienced grade 4 elevations in liver enzymes and bilirubin levels. The severity of the adverse event led to the patient's hospitalization and prompted Intellia to halt both the MAGNITUDE trial and its companion study, MAGNITUDE-2, which focuses on ATTR with polyneuropathy (ATTR-PN).

Intellia CEO John Leonard stated, "We are working diligently to develop a strategy to resume enrollment as soon as appropriate." The company is now collaborating with regulatory authorities and independent experts to evaluate the situation and determine the best path forward, including potential risk mitigation strategies.

Previous Safety Concerns and Market Reaction

This is not the first time Intellia has faced liver-related safety issues with nex-z. In May 2025, the company reported a similar grade 4 liver enzyme elevation in another patient, though that incident did not lead to a trial suspension. At the time, analysts from firms such as Truist Securities and BMO Capital Markets downplayed the significance of the event.

The market reaction to the latest news has been severe. Intellia's stock plummeted by nearly 45% in early trading on Monday, dropping from $25.60 to $14.34 per share. This dramatic decline reflects investor concerns about the future of nex-z and its potential impact on Intellia's pipeline.

Implications for CRISPR Technology and Competition

The safety signal in Intellia's trials raises questions about the broader application of CRISPR technology in gene therapies. While Leonard suggested that the issue might be specific to the TTR gene target, the incident could have implications for other CRISPR-based treatments in development.

Intellia's setback may also affect the competitive landscape in the ATTR treatment market. Companies like Alnylam, BridgeBio, and Pfizer, which have already established therapies for ATTR, may see reduced competition in the near term. However, the long-term potential of gene editing as a one-time treatment option for ATTR remains an attractive prospect, pending resolution of the safety concerns.

As the biotech community awaits further updates from Intellia, the incident serves as a reminder of the challenges and risks associated with developing cutting-edge gene therapies. The company's ability to address these safety concerns and resume its clinical trials will be crucial in determining the future of nex-z and potentially influencing the trajectory of CRISPR-based treatments in the pharmaceutical industry.