Intellia’s Gene Therapy Nex-z Faces Safety Concern but Analysts Remain Positive

Analysts Maintain Support Amid Intellia's Stock Drop

Highlights

• Intellia Therapeutics reported a grade 4 asymptomatic liver enzyme elevation in its phase 3 ATTR-CM trial for gene therapy candidate nex-z.
• The adverse event was resolved without medical intervention, yet led to a 23% drop in Intellia's stock during premarket trading.
• Analysts from William Blair remain optimistic, citing a favorable risk/benefit profile for nex-z despite the safety concern.
• Previous trials also noted enzyme elevations, leading to dose adjustments in 2022.
• Nex-z competes with multiple approved therapies for ATTR from companies like Alnylam, Ionis, AstraZeneca, and Pfizer.
• Intellia aims to file for FDA approval of nex-z for ATTRv-PN in 2028, and for hereditary angioedema as early as 2026.

Adverse Event Reported in Phase 3 ATTR-CM Trial

Intellia Therapeutics faced a sharp decline in its stock value following the disclosure of a grade 4 adverse event in a phase 3 clinical trial. Despite this, industry analysts remain cautiously optimistic about the safety profile of the company’s gene therapy candidate, nex-z.

According to a Securities and Exchange Commission filing on May 28, Intellia provided updates on three late-stage trials of nex-z, including one focused on transthyretin amyloid cardiomyopathy (ATTR-CM). The company reported that more than 200 patients have been dosed in this trial so far.

"So far, the reported adverse events have been 'similar in nature' to a phase 1 trial of the drug in ATTR-CM, Intellia said. These events have included infusion-related reactions and asymptomatic liver transaminase elevations, a term for raised levels of the ALT and AST enzymes that can be a sign of liver stress."

Grade 4 Adverse Event Triggers Market Reaction

A single case of elevated liver enzymes was identified as a grade 4 adverse event—the most severe classification for nonfatal effects. Intellia stated that this event was asymptomatic, discovered via laboratory testing, and resolved without hospitalization or medical treatment. The patient's ALT and AST levels have since decreased to grade 3 and 2, respectively.

Despite the benign nature of the incident, investor sentiment took a hit. "Still, the details appeared to trigger a sell-off of Intellia’s stock, which was 23% in the red in premarket trading Thursday morning."

Analysts Reassess, But Stay Confident

Analysts from William Blair described the grade 4 event as “obviously disappointing” and acknowledged that it raised ongoing concerns about the safety of nex-z. However, they emphasized the rarity and asymptomatic nature of these enzyme elevations.

"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," the analysts noted. "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 … we continue to see nex-z’s TTR knockdown profile as impressive and de-risking a positive clinical outcome."

Historical Context and Competitive Landscape

Enzyme level increases were previously observed during Intellia’s phase 1 trial of nex-z in ATTR, prompting the company to introduce a lower fixed dose in the polyneuropathy trial arm in 2022. The ATTR therapeutic space is already populated by competitors including Alnylam’s Onpattro and Amvuttra, Ionis Pharmaceuticals' Tegsedi, and Wainua, developed in partnership with AstraZeneca. These treatments target polyneuropathy associated with ATTR. Pfizer’s Vyndaqel is another major player, approved for cardiomyopathy treatment in TTR patients.

Regulatory Outlook and Future Plans

Intellia reaffirmed its commitment to bringing nex-z to market. The company stated its intent to file for FDA approval of nex-z for transthyretin amyloid polyneuropathy (ATTRv-PN) in 2028, with a targeted commercial launch in the U.S. in 2029.

Additionally, Intellia plans to seek FDA approval as early as next year for nex-z in hereditary angioedema. The gene therapy is currently undergoing phase 3 evaluation in both ATTRv-PN and hereditary angioedema, alongside the ongoing ATTR-CM study.