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William Blair analysts said they were not surprised by the FDA putting a clinical hold on two Intellia Therapeutics trials “given the potential severity of triggering Hy’s Law and implications for potential drug-induced liver injury.”\n 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.The biotech was evaluating nex-z, a CRISPR therapy designed to inactivate the TTR gene, in two sets of patients with transthyretin amyloidosis (ATTR). One of the studies was focused on targeting ATTR with cardiomyopathy (ATTR-CM), with the other assessing ATTR with polyneuropathy (ATTR-PN).Intellia announced Monday that it had paused both trials after receiving a report of grade 4 liver enzymes and increased total bilirubin in a patient in the ATTR-CM trial. The patient was hospitalized, is being closely monitored and is undergoing treatment, the biotech said at the time.Wednesday, Intellia announced that the FDA had verbally informed the company that both trials were on clinical hold.“The company intends to work with the FDA to address the clinical hold as expeditiously as possible,” Intellia said in an Oct. 29 Securities and Exchange Commission filing.Talking to analysts on a call on Monday, Intellia CEO John Leonard, M.D., explained that—while the biotech has reported elevated liver enzymes in nex-z recipients in the past—a pause was needed this time because the combination of liver enzymes and total bilirubin above the threshold met the stopping criteria.Leonard said on the call that the elevated liver enzymes and bilirubin “would meet the traditional definition of Hy\'s law,” a rule of thumb for assessing the risk of drug-induced liver injury.In a note Wednesday evening, analysts at William Blair said they were not surprised by the FDA’s response “given the potential severity of triggering Hy’s Law and implications for potential drug-induced liver injury.”“The downside is that now Intellia will have to formally respond to the FDA in regard to the clinical hold letter and requests for additional information before the trials can restart,” the analysts explained. “This is a higher level of scrutiny than a sponsor electing to recommence a study on its own accord after a voluntary pause.” The analysts said they “continue to believe in the efficacy potential” of both nex-z and lonvo-z, Intellia’s CRISPR therapy designed to prevent hereditary angioedema attacks. “However, safety signals from the former give us caution, especially since therapeutic options are already approved for both ATTR-CM/PN and hereditary angioedema,” they wrote.Leonard speculated Monday that the problem is limited to Intellia’s TTR program. The analysts responded that “given the well-established safety of siRNA and ASO TTR silencers, we do not believe that this toxicity profile is due to removal/degradation of TTR transcript.”“However, we note nex-z’s CRISPR-mediated cuts in the TTR locus and indel formation is a different mechanism to achieve TTR reductions and may have a role in the delayed LFT signal,” the analysts concluded