FDA Places Clinical Hold on Intellia's CRISPR Trials Following Serious Liver Safety Event
Intellia Therapeutics has encountered a significant setback in its late-stage clinical trials for a CRISPR-based gene therapy targeting transthyretin amyloidosis (ATTR). The U.S. Food and Drug Administration (FDA) has officially placed a clinical hold on two Phase 3 trials of nexiguran ziclumeran (nex-z) following a serious liver safety incident that led to patient hospitalization.
Liver 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, necessitating hospitalization. This event triggered Intellia to voluntarily pause both the MAGNITUDE trial and its companion study, MAGNITUDE-2, which targets ATTR with polyneuropathy (ATTR-PN).
Intellia CEO John Leonard stated, "The elevated liver enzymes and bilirubin would meet the traditional definition of Hy's law," referring to a guideline used to assess the risk of drug-induced liver injury. This marks the second instance of severe liver enzyme elevation in the nex-z program, following a similar but less severe case reported earlier this year.
FDA Intervention and Regulatory Process
The FDA's formal clinical hold, announced on October 30, supersedes Intellia's voluntary pause. This regulatory action requires the company to respond to a formal letter from the FDA and provide additional information before trials can resume. William Blair analyst Myles Minter noted that this represents "a higher level of scrutiny than a sponsor electing to recommence a study on its own accord after a voluntary pause."
Intellia has stated its intention to work with the FDA to address the clinical hold "as expeditiously as possible." The company is collaborating with regulators and independent experts to develop new safety protocols and risk mitigation strategies.
Impact on Intellia and CRISPR Gene Therapy Landscape
The news has had a significant impact on Intellia's stock, with shares falling approximately 45% following the announcement. The clinical hold is expected to delay study readouts by several quarters, according to Leerink Partners analyst Mani Foroohar.
Prior to the suspension, Intellia had enrolled over 650 patients in the ATTR-CM trial and 47 in the ATTR-PN study. The company is developing nex-z as a potential long-lasting alternative to existing injectable and oral therapies for ATTR, in a field where competitors include Alnylam, BridgeBio, and Pfizer.
This setback raises questions about the broader implications for CRISPR-based therapies, particularly those targeting the liver. However, Leonard speculated that the issue might be specific to the TTR gene target rather than the lipid nanoparticle delivery system or the CRISPR technology itself.
As the pharmaceutical industry closely watches these developments, Intellia faces the challenge of addressing safety concerns while maintaining confidence in its innovative gene-editing approach to treating rare diseases.
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 specific safety protocols and risk mitigation strategies is Intellia developing to address the liver safety concerns?
How do the efficacy and safety profile of nexiguran ziclumeran compare to the existing therapies for ATTR like those from Alnylam, BridgeBio, and Pfizer?
What is the competitive landscape for CRISPR-based therapies targeting rare diseases like ATTR?
What implications does this clinical hold have for future CRISPR-based treatments, particularly in targeting the liver?
What additional data or information has the FDA requested from Intellia to lift the clinical hold on the nex-z trials?