FDA Halts Intellia's Gene Therapy Studies Due to Severe Liver Toxicity

The U.S. Food and Drug Administration (FDA) has placed two of Intellia Therapeutics' Phase III studies under clinical hold following reports of life-threatening liver side effects in a patient. The regulatory action, disclosed in an SEC filing on Wednesday, impacts the MAGNITUDE and MAGNITUDE-2 trials evaluating the CRISPR-edited gene therapy nexiguran ziclumeran (nex-z) for transthyretin amyloidosis with cardiomyopathy (ATTR-CM) and polyneuropathy (ATTR-PN).

Safety Concerns Prompt Regulatory Action

The clinical hold comes on the heels of Intellia's voluntary suspension of enrollment and dosing in both studies earlier this week. On September 30, a patient in the MAGNITUDE trial developed severe elevations in liver transaminase and bilirubin concentrations, classified as a grade 4 or life-threatening event. The patient was subsequently hospitalized and received medical attention.

This incident is not isolated, as Intellia has previously encountered toxicity issues with nex-z. In May, another patient experienced grade 4 liver enzyme elevations after receiving the gene therapy. Additionally, in August 2022, the company reported "significant elevation in liver enzymes" in a Phase I study of nex-z, although that episode was asymptomatic and resolved after 28 days.

Market Impact and Industry Implications

The news has had a significant impact on Intellia's stock price, with shares dropping 15.6% in pre-market trading to $11.07, down from the previous closing price of $13.12.

These developments add to growing concerns about the safety of gene therapies across the pharmaceutical industry. Notable incidents this year include three deaths associated with Sarepta Therapeutics' products: two attributed to the Duchenne muscular dystrophy therapy Elevidys and one to an investigational asset for limb-girdle muscular dystrophy. Fatal outcomes have also occurred in trials of Rocket Pharmaceuticals' Danon disease asset and Capsida Biotherapeutics' treatment for STXBP1-related epileptic encephalopathy disorders.

Next Steps and Regulatory Process

The FDA has verbally communicated the clinical hold to Intellia and is expected to issue a formal letter within the next 30 days. In response to these events, Intellia is consulting experts to determine a path forward for nex-z, including the potential addition of risk mitigation mechanisms.

As the pharmaceutical industry grapples with these safety challenges, the outcome of Intellia's case may have far-reaching implications for the development and regulation of gene therapies. The incident underscores the critical importance of rigorous safety monitoring and the need for potential refinements in the design and implementation of gene therapy clinical trials.