RP-A501

iStock, Alex Sholom While an adverse event reported in Intellia’s gene therapy trial was a “non-concern” for analysts, it follows a handful of patient deaths in other trials for the modality and sent the company’s stock tumbling in pre-market trading. Intellia’s shares declined by 26% as the markets opened Thursday after disclosing a case of elevated liver enzymes in a late-stage study for its transthyretin amyloidosis gene editing therapy. Analysts brushed off the adverse event—the second disclosed for the candidate—considering both cases were asymptomatic and resolved without medication. The treatment, known as nexiguran ziclumeran (nex-z), is under development in partnership with Regeneron. The Phase III trial has enrolled 765 patients with ATTR, 200 of whom have been dosed so far, Intellia said in a regulatory filing posted after-market Wednesday. “The second grade 4 [liver function test] serious adverse event with nex-z is obviously disappointing and with the stock down 18% in aftermarket trading, there will be outstanding questions about safety moving forward,” William Blair analysts wrote to investors Wednesday evening. But Truist Securities analysts brushed off the adverse event, saying it “does not cross the threshold for us to be concerned about the safety pro one-and-done nex-z just yet.” BMO Capital Markets similarly called it a “non-concern.” The stock reaction was likely more due to recent patient deaths in the gene therapy space than the severity of this particular incident with Intellia, BMO said. “We believe [Intellia] post-market stock reaction to Phase III safety update reflects recent safety concerns raised in the broader gene therapy space from unfortunate patients deaths,” the group wrote. Earlier this week, Rocket reported the death of a patient in a Phase II trial of Danon disease gene therapy RP-A501. The study has been placed on hold by the FDA after the biotech voluntarily suspended it. Other deaths have occurred in studies conducted by Sarepta and Neurogene , BMO noted. But these were with different delivery vehicles and the analysts cautioned against comparisons. Treatment or Delivery? William Blair said Intellia’s adverse event raises a debate about whether the treatment, or the lipid nanoparticle (LNP) delivery mechanism, is to blame. Investigators have deemed the situation as likely related to nex-z. “[W]e believe that a single-time LNP administration is likely more safe/predictable/understood than a single-time AAV-based gene therapy,” BMO wrote. Rocket’s, Sarepta’s and Neurogene’s gene therapies all use AAV. William Blair noted that Verve Therapeutics’ recently released data for a next-gen candidate for cholesterol that uses LNP did not show signs of toxicity after a previous asset did. In the case of Intellia, reported adverse events, including asymptomatic liver transaminase elevations, have been in line with expectations based on earlier studies, the company said. A single patient exhibited grade 4 elevations based on lab tests, which Intellia said were resolving without hospitalization or medical intervention. The patient has since fallen to grade 3 alanine aminotransferase (ALT) and grade 2 aspartate transferase (AST) elevations. The new patient had normal ALT and AST at baseline, but they began to elevate a week post-infusion of nex-z. Intellia executives told analysts that the timing suggests it was not due to LNP toxicity. The ALT/AST elevations progressed to a grade 4 event at day 24, peaking at day 28. By day 36, the situation had fallen back down to a grade 3 for ALT and grade 2 for AST. The patient was never determined to be at risk of drug-induced liver injury. In the previous case that emerged in the Phase I trial of nex-z, the patient returned to normal levels about six to eight weeks after infusion. While Truist analysts were not overly concerned, they said “it’s certainly a reason to stay vigilant, especially as it appears to be a recurring theme from Phase I and Phase III MAGNITUDE.” William Blair noted that the rate of this particular adverse event, given about 305 patients treated across the clinical program so far, is about 0.66%. “We will be keeping an eye on this but it is an objectively low rate, and we do not believe at this time it should have broader read-through to other LNP-delivered genetic medicines.” Given the low incidence, William Blair is still confident in nex-z’s risk/benefit pro ATTR. With that said, the indication has seen a surge of interest of late with several new mechanisms of action entering the market, “so safety will be a consideration moving forward.” Truist noted that Intellia’s Phase III trial is proceeding without any changes to protocol with enrollment on track to wrap up by early 2027. The next data from the nex-z program will be a two-year update from the Phase I trial, which BMO noted is due in the second half of this year.