Intellia Therapeutics (NASDAQ: NTLA) found out this past week what other genetic medicine developers have learned in recent weeks: Any safety issue that arises in a clinical trial is enough to send investors scrambling to sell their shares.
Intellia saw its stock tumble 23% Thursday to $7.45 from $9.66 at Wednesday’s closing bell. In between, Intellia filed a Form 8-K on Wednesday evening revealing that one of about 365 patients enrolled in the company’s global Phase III MAGNITUDE trial (NCT06128629) developed severe liver toxicity which apparently later abated.
That news sparked a double-digit post-market drop in Intellia’s stock price that dragged down shares through Thursday and into Friday, when the stock price fell another roughly 8% to $6.87.
“There has been a single, recent, asymptomatic patient with grade 4 liver transaminase elevations based on laboratory tests, which appear to be resolving without hospitalization or medical intervention and have fallen to grade 3 ALT [alanine aminotransferase] and grade 2 AST [aspartate transaminase] elevations,” Intellia reported. “We continue to monitor these events as the MAGNITUDE study progresses.”
MAGNITUDE, which dosed its first patient in March 2024, is assessing nexiguran ziclumeran (nex-z, formerly NTLA-2001), a Regeneron Pharmaceuticals-partnered in vivo CRISPR-based therapy designed to treat transthyretin amyloidosis with cardiomyopathy (ATTR-CM) by inactivating the TTR gene. This gene encodes for the mutated transthyretin (TTR) protein that causes polyneuropathy.
As Adam Feuerstein of STAT News reported on X and several analysts later confirmed in their research notes, Intellia issued the regulatory filing after initially disclosing the safety issue selectively at investor meetings. The company then discussed the news with analysts Wednesday evening on a conference call.
Mani Foroohar, MD, a senior research analyst with Leerink Partners focused on genetic medicines, opined that Intellia’s post-market stock drop was expected given the broader issue raised by the company’s safety disclosure—though he and other analysts continue, for now, to maintain a generally positive view of the CRISPR-based gene editing therapy developer.
‘Not surprised’
“While this one occurrence comes in the context of hundreds of treated patients across NTLA trials, we are not surprised to see shares down 15% after hours, with investor sensitivity high in the wake of unexpected safety events in Genetic Medicines,” Foroohar wrote Wednesday.
He cited as a recent example Rocket Pharmaceuticals (NASDAQ: RCKT), which on Tuesday disclosed that one of its patients dosed with its Danon disease gene therapy candidate RP-A501 died in a pivotal Phase II trial, which the FDA has placed on clinical hold. The patient, whose age was not disclosed, suffered an unexpected serious adverse event involving clinical complications related to capillary leak syndrome, following dosing with RP-A501 in early May, Rocket’s CEO Gaurav Shah, MD, told analysts.
Another tragedy linked to a gene therapy took place in March, when Sarepta Therapeutics (NASDAQ: SRPT) acknowledged the sudden death of a 16-year-old patient with Duchenne muscular dystrophy (DMD) following treatment with Elevidys® (delandistrogene moxeparvovec-rokl), the only gene therapy approved by the FDA to treat DMD.
In Intellia’s case, the patient with liver toxicity showed no transaminase elevations after one week, which according to Foroohar suggested that the event was not driven by nex-z’s lipid nanoparticle (LNP) formulation, since such elevations would have appeared after ~4-5 days had there been LNP toxicity. The Grade 4 elevation was detected at Day 24, with transaminase peaking at Day 28. The patient showed “high normal” bilirubin at baseline, and increased marginally, but never exceeded 2x the upper limit of normal.
“While this incremental color has us feeling more reassured on this patient’s course, and on the impact of this event on the fundamentals of the company (virtually nil), we expect bears to argue this disclosure could slow enrollment or deter patient interest—a thesis unsupported by brisk enrollment to date, low rate of occurrence for this (reversible and asymptomatic) event, and robust patient interest suggested by our recent TTR physician treater survey,” Foroohar added.
Myles R. Minter, PhD, a partner and analyst covering biotechnology companies for William Blair, added additional details shared by Intellia during the analysts call in his research note Thursday:
- By the last update on day 36 following infusion, lab tests had fallen to grade 3 for ALT and grade 2 for AST without hospitalization or medication.
- The patient’s liver issue did not qualify as Hy’s Law, since there was no evidence of liver damage.
- ALT and AST levels are expected to return to baseline within 6-8 weeks post-infusion if the liver tox case is similar to a grade 4 liver function test (LFT) case seen in a Phase I study of nex-z.
Remaining positive
Because the profiles were similar among the two patients who showed grade 4 LFT, Intellia presumes that the safety issues were related to nex-z, though Intellia remains blinded to study results.
“Although there are outstanding questions here, we remain positive on the risk/benefit given the two reported grade 4 LFT events with nex-z have been asymptomatic to date, avoided hospitalization, and are likely to resolve without medication, in our view,” Minter wrote.
Intellia said MAGNITUDE had reached enrollment of 365 patients as of the analysts’ conference call, 48% of the target enrollment of approximately 765 patients after about 17 months. Trial enrollment is expected to be completed by early 2027.
More than 200 patients have been dosed with nex-z in the MAGNITUDE trial, according to Intellia.
“If we assume about 240 patients treated in MAGNITUDE (2:1 randomization) and 65 patients treated in the Phase I study (polyneuropathy and cardiomyopathy) with nex-z, then the grade 4 LFT elevation incidence is 0.66%,” Minter wrote. “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.”
Minter cited as an example Verve Therapeutics (NASDAQ: VERV), which announced positive initial data on April 14 from the Phase 1b Heart-2 trial (NCT06164730) assessing VERVE-102 in heterozygous familial hypercholesterolemia (HeFH) and/or premature coronary artery disease. Among 14 participants across three dose levels, a single VERVE-102 infusion yielded dose-dependent decreases in blood PCSK9 protein levels and low-density lipoprotein cholesterol (LDL-C), with a mean reduction in blood LDL-C of 53% and a maximum of 69% seen among four participants in the 0.6 mg/kg dose cohort.
Yet last year, investors punished Verve by sending its shares nosediving 35% after the company reported a serious adverse event in one patient during its Phase 1b Heart-1 trial (NCT05398029), a grade 3 drug-induced transient elevation of serum alanine aminotransferase (ALT) and grade 3 drug-induced thrombocytopenia. After pausing Heart-1 which assessed VERVE-101 in heterozygous familial hypercholesterolemia (HeFH), Verve pivoted its development effort toward VERVE-102.
Outstanding safety questions
“[Intellia’s] second grade 4 LFT 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. However, we believe the asymptomatic nature of these elevations and low incidence still plays out for a favorable risk/benefit for nex-z in TTR amyloidosis,” Minter asserted.
He continued: “Yes, there are other effective treatment options here with TTR stabilizers and silencers, so safety will be a consideration moving forward in this indication, but with enrollment timelines for MAGNITUDE on track, we continue to see nex-z’s TTR knockdown profile as impressive and derisking a positive clinical outcome.”
Minter reiterated William Blair’s “Outperform” rating on Intellia shares, “but expect the stock to be weak in response to this safety update.” Also holding fast are H.C. Wainwright analyst Mitchell Kapoor, who reiterated his firm’s “Buy” rating and $30 price target on Intellia shares; analyst Silvan Tuerkcan of Citizens JMP, who maintained his firm’s “Market Perform” rating; and Rick Bienkowski of Cantor Fitzgerald, who reiterated his firm’s “Overweight” rating and $65 price target.
However, Greg Harrison at BofA Securities trimmed his firm’s price target on Intellia shares 9%, from $43 to $39.
Jefferies equity analyst Maury Raycroft, PhD, noted in his report that in addition to high-normal bilirubin, the patient also was shown to have 3 grams of paracetamol (the equivalent of Tylenol sold outside the U.S.) per day for about 8 days before receiving nex-z, “which we believe could be an additional/supportive explanation for the Gr[ade] 4 LFT event, since acetaminophen can induce liver damage on its own and may have induced an exaggerated response to NTLA’s gene editing therapy.”
After noting an 18% post-market drop in the stock as of his report deadline, Raycroft offered some investment advice favorable to Intellia: “We would accumulate on weakness.”
Leaders and laggards
- InflaRx (NASDAQ: IFRX) shares plummeted 60% from $1.82 to 73 cents Wednesday after the company announced it intends to end development of vilobelimab in pyoderma gangrenosum (PG), halting a Phase III trial (NCT05964413) at the recommendation of its Independent Data Monitoring Committee due to futility. Vilobelimab will remain available in the U.S. under FDA emergency use authorization to treat COVID-19 in hospitalized adults within 48 hours of receiving invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO). Vilobelimab is also marketed under exceptional circumstances in the European Union as Gohibic® for certain adults with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS). InflaRx said it will pivot resources toward developing INF904, which is expected this summer to read out Phase IIa data in chronic spontaneous urticaria (CSU) and hidradenitis suppurativa (HS).
- Prothena (NASDAQ: PRTA) shares slumped 30% from $6.58 to $4.58 Tuesday after the company said it will end development of birtamimab in amyloid light-chain (AL) or primary amyloidosis, including stopping an open label extension study evaluating its Phase III AFFIRM-AL trial (NCT04973137). Prothema acted after birtamimab failed AFFIRM-AL by missing the primary endpoint of time to all-cause mortality as well as the study’s secondary endpoints. AFFIRM-AL was a global, double-blind, placebo-controlled, time-to-event clinical trial that enrolled 207 newly diagnosed, treatment naïve patients with Mayo Stage IV AL amyloidosis. As a result of the development halt, Prothema said, it will lower ongoing operating expenses, and expects to make a “substantial” reduction in organizational size, with a further update planned for June.
- Savara (NASDAQ: SVRA) shares nosedived 32% from $2.84 to $1.94 Tuesday after the company acknowledged receiving a refusal-to-file (RTF) letter from the FDA for the Biologics License Application (BLA) seeking approval for Molbreevi as a treatment for autoimmune pulmonary alveolar proteinosis (PAP). After a preliminary review, Savara said, the FDA determined that the BLA submitted in March was not complete enough to allow substantive review. The agency also requested additional Chemistry, Manufacturing, and Controls (CMC) data. The RTF was not the result of safety concerns, and the FDA did not request or recommend additional efficacy studies, Savara said. “We are confident we can thoroughly address the Agency’s request and expect to resubmit our BLA in the fourth quarter of 2025,” Savara Chair and CEO Matt Pauls stated.
- Summit Therapeutics (NASDAQ: SMMT) shares skidded 30.5% from $26.21 to $18.22 Friday after the company disappointed investors with its data from the Phase III HARMONi trial (NCT05184712) evaluating ivonescimab plus platinum-doublet chemotherapy vs. placebo plus chemo in epidermal growth factor receptor (EGFR)-mutated, locally advanced or metastatic non-squamous non-small cell lung cancer who have progressed after treatment with a third generation EGFR tyrosine kinase inhibitor. Ivonescimab-chemo reduced the risk of disease progression or death by 48% vs. placebo-chemo—but showed only a “positive trend” in overall survival without achieving a statistically significant benefit, Summit acknowledged. Summit cited FDA guidance that “a statistically significant overall survival benefit is necessary to support marketing authorization, which will weigh into Summit’s considerations regarding the timing of a potential BLA [Biologics License Application] filing,” while adding it intends to file for a BLA for ivonescimab, engineered by Akeso (HKEX: 9926).
