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 44% to $14.34 in early trading Monday.
The pause affects trials of Intellia’s nex-z, a CRISPR therapy designed to inactivate the TTR gene, in two sets of patients with transthyretin amyloidosis (ATTR). One trial is targeting ATTR with cardiomyopathy (ATTR-CM). The other trial is focused on ATTR with polyneuropathy (ATTR-PN).
Intellia 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, according to the biotech.
The biotech has reported elevated liver enzymes in nex-z recipients in the past. As Intellia CEO John Leonard, M.D., told analysts on a call to discuss the update, a pause was needed this time because the combination of liver enzymes and total bilirubin above the threshold met the stopping criteria.
Leonard said 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.
Intellia is now working to develop a strategy that will allow it to resume enrollment. With the biotech only receiving news of the adverse event Friday, management is still early in the process of figuring out the causes of the liver safety signal.
“At this point, it's just premature to comment on any sort of predictors or patient populations at risk,” Leonard said. “Obviously, we're looking into that, and we're assembling a set of questions to pursue with our [data and safety monitoring board] and related parties.”
The patient had elevated liver enzymes more than three weeks after receiving nex-z. Leonard said there are similarities between the timing of the case and another patient who had asymptomatic elevated liver enzymes earlier in the phase 3 program. The patient who was hospitalized appears to have “a more pronounced manifestation” of the changes seen in the other patient, the CEO said.
The lag between administration of nex-z and the emergence of elevated liver enzymes suggests the lipid nanoparticles (LNPs) used to deliver the therapy are unlikely to have caused the adverse events. Patients can have small increases in liver enzymes in the day or two after receiving LNPs. The timing led Leonard to speculate that Intellia is facing another problem.
Leonard thinks the problem is limited to Intellia’s TTR program. Studies of lonvoguran ziclumeran, the biotech’s other clinical-phase candidate, in patients with hereditary angioedema are continuing.
It is unclear how long it will take Intellia to get the TTR trials back on track. Leonard said he can only speculate on the duration of the pause but added that work on the resolution will certainly take “some weeks.”
Any delay will push back Intellia’s potential entry into a space served by Alnylam, BridgeBio and Pfizer. If eventually approved, nex-z could be a one-time alternative to existing therapies.