Addressing analysts in August, Intellia Therapeutics (NASDAQ: NTLA) president and CEO John Leonard, MD, announced that, given greater-than-expected patient enrollment in a Phase III trial assessing nexiguran ziclumeran (nex-z) in transthyretin amyloidosis with cardiomyopathy (ATTR-CM), the company would increase enrollment to approximately 1,200 patients.
“We expect that we will enroll more patients this year in our cardiomyopathy program than originally planned,” Leonard predicted.
Those lofty expectations crashed to earth starting October 27 when Intellia voluntarily paused dosing and screening in the 650+-patient global trial, called MAGNITUDE (NCT06128629), and a second 47-patient Phase III study of nex-z called MAGNITUDE-2 (NCT06672237).
The pauses followed hospitalization of a MAGNITUDE patient who experienced Grade 4 liver transaminases and increased total bilirubin after being dosed with nex-z.
The patient was a man in his early 80s with a high body mass index who was dosed with nex-z on September 30. Intellia learned of his condition approximately 24 days post-dosing, the company disclosed during a conference call with analysts held to discuss the dosing pauses.
During that conference call, Intellia executives disclosed that laboratory reports had shown AST and ALT levels above 3x the upper limit of normal, as well as bilirubin levels above 2x the upper limit of normal. Those levels met the criteria of Hy’s law, which, according to an FDA guidance, holds that “pure hepatocellular injury sufficient to cause hyperbilirubinemia is an ominous indicator of the potential for a drug to cause serious liver injury.”
The hospitalized patient—reported by Intellia to be in stable condition after experiencing abdominal pain—was among more than 450 patients dosed with nex-z across both trials.
The FDA responded to the safety issue and resulting dosing pauses by taking the not-unexpected step of imposing a clinical hold on the Investigational New Drug (IND) applications of both the MAGNITUDE and MAGNITUDE-2 trials—holds that Intellia disclosed only in a regulatory filing, rather than via press release as it did in announcing its voluntary pauses.
MAGNITUDE, which dosed its first patient in March 2024, is assessing nex-z (formerly NTLA-2001), a Regeneron Pharmaceuticals (NASDAQ: REGN)-partnered in vivo CRISPR-based therapy designed to treat ATTR-CM by inactivating the TTR gene. This gene encodes for the mutated transthyretin (TTR) protein that causes polyneuropathy.
While MAGNITUDE is assessing nex-z in ATTR-CM, the Phase III MAGNITUDE-2 trial is evaluating the therapy in transthyretin amyloidosis with polyneuropathy (ATTRv-PN). Before the dosing pause and clinical hold, Intellia expected to complete patient enrollment in the first half of 2026 for MAGNITUDE-2, which, according to ClinicalTrials.gov, had an estimated primary completion date of July 2027.
Intellia “intends to work with the FDA to address the clinical hold as expeditiously as possible,” the company stated in its regulatory filing.
“We are not surprised.”
One analyst commented that the FDA clinical hold was expected—and will stretch out Intellia’s timeframe for completing the affected trials. The company previously told investors that MAGNITUDE was expected to enroll at least 650 patients by the end of 2025 and complete its enrollment by 2027, with the study’s primary completion date reported as December 2027 on ClinicalTrials.gov.
Intellia also previously told investors that it expected by year’s end to present long-term safety and efficacy data for nex-z from a global Phase I trial (NCT04601051) evaluating the treatment in both ATTR-CM and ATTRv-PM patients through an ongoing open-label, multi-center, two-part study in adults.
The company offered positive two-year follow-up data in May: “Patients are getting better. Their TTR is not continuing to accumulate.” Intellia CSO Birgit Schultes, PhD, said last month at the European Society of Gene and Cell Therapy (ESGCT)’s Annual Congress in Seville, Spain, characterizing the TTR reduction as “rapid, deep, consistent, and durable.”
Myles R. Minter, PhD, a partner and research analyst, healthcare covering biotech companies for William Blair, wrote Wednesday in a research note that: “Given the potential severity of triggering Hy’s Law and implications for potential drug-induced liver injury, we are not surprised by the FDA’s response, even though the MAGNITUDE program was placed on voluntary pause.”
As a result of the FDA clinical holds, Minter observed, Intellia will have to formally address the agency in a letter expected to be sent within 30 days, as well as respond to any requests for additional information from regulators before the studies can restart. The FDA will have 30 days to review Intellia’s formal response before deciding whether to issue a decision.
Among topics the agency will likely want to discuss with Intellia, Minter wrote, is concerns about the safety of nex-z—especially in light of a May incident in which one of about 365 patients then enrolled in MAGNITUDE developed severe liver toxicity, which apparently later abated.
“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 at the time.
That news sparked a 23% slide in Intellia’s stock on May 29, the day after Intellia disclosed the incident via regulatory filing.
Focus on TTR locus
“Management’s current logic is that the safety signal is not lipid nanoparticle related, given the delayed timing of LFT [liver function test] elevations, but could be due to the underlying patient population or to editing the TTR locus itself,” Minter wrote. “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,” Minter added.
Two days earlier, Minter predicted how investors would likely react to the safety questions raised by nex-z:
“Despite management arguing the LFT and bilirubin elevations are specific to the ATTR patient population and/or nex-z target gene, investors will have outstanding questions as to whether this is a platform risk, and the company will need to prove these safety considerations are applicable to nex-z alone,” Minter wrote. “We continue to believe in the long-term efficacy of CRISPR-based knockdown strategies and view the RNA silencer class as providing meaningful clinical de-risking to nex-z (and lonvo-z) if the adverse events can be mitigated.”
MAGNITUDE and MAGNITUDE-2 are two of three Phase III studies Intellia is conducting of its two late-stage gene edited therapies. The third is the Phase III HAELO trial (NCT06634420) assessing lonvoguran ziclumeran (lonvo-z; formerly NTLA-2002), an in vivo CRISPR-based gene editing therapy being developed as a one-time treatment for hereditary angioedema (HAE).
Intellia has kept intact, for now, what it told investors over the summer—namely that it expected to complete randomization during the third quarter of this year, submit a BLA in the second half of 2026, and potentially launch lonvo-z in 2027 in the United States.
“We continue to see HAE as a more meaningful driver of NTLA fundamentals than TTR in the next 18 months and look to pivotal HAELO data as a key catalyst for NTLA and the gene editing space as a whole,” Mani Foroohar, MD, senior managing director, genetic medicines with Leerink Partners, wrote in a research note.
Investors responded to the double dose of bad news by punishing Intellia with a selloff that sent the company’s shares nosediving 51% from $25.60 on October 24 to $12.62 at Friday’s closing bell. The dosing pause triggered a 42% plunge to $14.79 on October 27, followed by shares slumping another 17% over the following three days to $12.27. But Intellia shares rebounded 3% Friday as the broader NASDAQ market rose on strong Q3 results from Amazon (NASDAQ: AMZN), the expectation of growth by other high-tech stocks, and momentum from Wednesday’s benchmark interest rate cut by the Federal Reserve.
The one-week decline is a far cry from the 19% surge in Intellia’s stock price from October 6–10 on news of positive clinical data in hereditary angioedema (HAE) and transthyretin amyloidosis (ATTR) that, in turn, lifted the shares of other gene editing companies. Shares rose another 4% the following week, and indeed had more than doubled, soaring 109% in the month through October 15.
Two days earlier, upon the initial news of the dosing pauses, Minter downgraded Blair’s rating on Intellia shares from “Outperform” to “Market Perform.”
Blair was one of at least six firms to have downgraded Intellia shares this past week. The other four:
- Bernstein (William Pickering, MD): From “Outperform” to “Market Perform.” Pickering also raised the firm’s price target about 4% from $14 to $14.50 on expectations of better market performance, according to published reports.
- BofA Securities (Alec Stranahan): From “Buy” to “Neutral.” Stranahan more than halved the firm’s price target 53% to $14 from $30—four days after BofA’s Greg Harrison cut that price target 17% from $36 while keeping the “Buy” rating.
- Guggenheim Partners (Debjit Chattopadhyay, PhD): From “Buy” to “Neutral.” Chattopadhyay reduced the firm’s price target 18%, from $55 to $45.
- RBC Capital Markets (Luca Issi, PhD): From “Outperform” to “Sector Perform.” Issi chopped the firm’s price target 33% from $21 to $14.
- Wells Fargo Securities (Yanan Zhu, PhD): From “Overweight” to “Equal-Weight” on October 28, then a second downgrade to “Hold” on Thursday. Zhu slashed the firm’s price target 62% from $45 to $17.
At least four other investment firms lowered their price targets on Intellia shares:
- H.C. Wainwright (Mitchell Kapoor): Down 40%—first a 17% drop from $30 to $25 on Tuesday, then down another 28% from $25 to $18 on Thursday, maintaining “Buy” rating.
- Chardan Capital Markets (Geulah Livshits, PhD): Down 20% from $60 to $48, maintaining “Buy” rating.
- Citizens JMP (Silvan Tuerkcan, PhD): Down 12% from $33 to $29, maintaining “Market Outperform” rating.
- Barclays (Gena Wang, PhD, CFA): Down about 8% from $26 to $24, maintaining “Overweight” rating.
Not all analysts and investors have been bearish on Intellia. David Nierengarten, PhD, a senior analyst with Wedbush Securities, doubled his firm’s price target on Intellia shares from $7 to $14, while maintaining its “Neutral” rating. Nierengarten covers small- and mid-capitalization stocks, with a heavy focus on oncology, rare disease, and gene therapy.
Small-cap stocks have market caps from $250 million to $2 billion, and mid-caps, between $2 billion to $10 billion in market cap. (Market cap is the product of the share price and the number of outstanding shares.)
Among investors, ARK Investment Management (ARK Invest), led by chief investment officer and portfolio manager Catherine D. (Cathie) Wood, bucked the trend away from the company’s stock by snapping up 750,115 shares valued at $19.2 million on October 27, followed by another 479,411 shares on Tuesday.
Both stock purchases were divided between two of ARK Invest’s exchange transfer funds, ARK Genomic Revolution ETF (CBOE Global Markets: ARKG) and ARK Innovation ETF (CBOE Global Markets: ARKK).
Illumina jumps 25% on Q3 surge
Illumina (NASDAQ: ILMN) shares leaped 25% from $99.01 to $123.54 on Friday as the longtime sequencing giant delivered third-quarter results that surpassed analyst expectations and included better-than-expected guidance to investors for full-year 2025 results.
Illumina reported non-GAAP net income for Q3 of $206 million, up 14% from $181 million a year earlier, on revenue that barely rose 0.4% from July-September 2024, to $1.084 billion from $1.08 billion.
The Q3 non-GAAP profit translated to $1.34 per share, up nearly 15% above the $1.17 per share consensus estimates from analysts cited by Reuters and Jefferies.
“While the beat suggests that end-markets have bottomed, patience is required as we await clarity on China, A&G [academic and government] funding, and Roche, all of which are likely ’26 stories,” Tycho Peterson, equity analyst with Jefferies, wrote in a research note.
A&G sales have reeled from federal research funding cuts, while Roche has emerged as a potentially significant challenge to Illumina after unveiling its sequencing by expansion (SBX) technology in February at the Advances in Genome Biology and Technology (AGBT) meeting, followed last month by major updates to SBX revealed at the American Society of Human Genetics (ASHG) 2025 Annual Meeting in Boston.
At ASHG, Illumina offered mapped reads and multiomics announcements. One was early results from a pilot study by GeneDx using Illumina’s Constellation mapped read technology through an early access program. The other was the broad release of its 5-base solution for multiomics analysis, designed to support simultaneous detection of both genomic variants and DNA methylation from a single sample in a streamlined workflow.
GAAP net income, however, fell 79% year over year, to $150 million from $705 million.
Illumina lowered its forecast for total company constant currency revenue decline to between 1.5% and 0.5%, improved from 2.5% to 1.5%. The forecast for instrument sales decline was reduced to 4% from 6%. However, the company raised its guidance on:
- Non-GAAP operating margin—To between 22.75% and 23%, from 22%-22.5%.
- Non-GAAP diluted earnings per share (EPS)—To between $4.65 and $4.75, from $4.45-$4.55.
- Sequencing consumables—To between 2.5% and 3%, from 1%-3%.
- Operating profit margin (OPM)—To between 22.8% and 23%, from 22%-22.5%.
