Intellia's CRISPR Trials on Hold as FDA Responds to Severe Liver Toxicity

Intellia Therapeutics has been forced to pause two Phase 3 clinical trials for its CRISPR-based gene therapy, nexiguran ziclumeran (nex-z), following a serious liver safety event. The U.S. Food and Drug Administration (FDA) has placed both studies under an official clinical hold, escalating the situation from Intellia's initial voluntary pause.

Severe Liver Toxicity Leads to Trial Suspension

The trials in question, MAGNITUDE and MAGNITUDE-2, were evaluating nex-z for the treatment of transthyretin amyloidosis with cardiomyopathy (ATTR-CM) and polyneuropathy (ATTR-PN), respectively. The decision to halt the studies came after a patient in the ATTR-CM trial experienced grade 4 elevations in liver enzymes and increased total bilirubin, necessitating hospitalization.

Intellia CEO John Leonard, M.D., explained that the combination of elevated liver enzymes and bilirubin "would meet the traditional definition of Hy's law," a benchmark used to assess the risk of drug-induced liver injury. This incident follows a similar grade 4 liver enzyme elevation reported earlier this year, which at the time was dismissed by some analysts as a "non-concern."

Regulatory Response and Next Steps

The FDA's decision to place the trials on clinical hold adds a layer of regulatory scrutiny to the situation. Intellia now faces the task of formally responding to the FDA's clinical hold letter and providing additional information before the trials can potentially restart.

Leonard stated, "The company intends to work with the FDA to address the clinical hold as expeditiously as possible." Intellia is collaborating with experts to determine the best path forward, including the development of potential risk mitigation strategies.

Impact on Intellia and the Broader CRISPR Field

The news has had a significant impact on Intellia's stock, with shares plummeting by nearly 45% in early trading following the announcement. This setback raises questions about the safety profile of CRISPR-based therapies, particularly those targeting the liver.

While Intellia believes the issue may be limited to its TTR program, the incident has broader implications for the field of gene editing. The company's other clinical-phase candidate, lonvoguran ziclumeran for hereditary angioedema, continues its studies unaffected.

As the biotech works to resolve these safety concerns, the timeline for nex-z's potential market entry – as a one-time alternative to existing therapies from companies like Alnylam, BridgeBio, and Pfizer – remains uncertain. The coming weeks will be crucial as Intellia develops new protective measures and seeks to identify the root cause of the liver toxicity events.