Intellia’s CRISPR Gene Editor Early Promise Strong Biomarker Benefit in ATTR Amyloidosis

 

Analysts appear optimistic for Intellia’s gene editor nex-z, which showed a greater serum TTR reduction than Alnylam’s Amvuttra.

Intellia Therapeutics over the weekend released Phase I data for its investigational gene editor nexiguran ziclumeran, touting promising biomarker improvements in patients with transthyretin amyloidosis, pointing to the disease-modifying potential of the therapy.

The Phase I results, presented Saturday at the American Heart Association’s 2024 Scientific Sessions in Chicago, showed that nex-z resulted in “rapid, deep and durable” reductions in serum levels of TTR, according to Intellia’s press announcement.

In patients with transthyretin amyloidosis (ATTR) with cardiomyopathy, a single dose of nex-z led to a sustained decrease in serum TTR level, with the mean reduction hitting 90% at 12 months. All 11 patients with follow-up data through 24 months were able to maintain response to nex-z, showing no signs of waning treatment effect over time.

According to Intellia, consistent reductions in serum TTR could potentially suppress the formation of amyloid, in turn allowing for amyloid clearance and symptomatic improvement in patients. In this vein, the Phase I study also detected signals of disease-modifying effects for cardiac disease, with patients at 12 months showing signs of stabilization or improvement—despite many being enrolled with advanced or severe disease.

At 12 months, 81% of treated patients showed stability or improvement in N-terminal prohormone of brain natriuretic peptide levels, an indicator of heart problems. Meanwhile, 94% and 77% of patients saw stable or better high-sensitivity Troponin T levels and six-minute walk test results, respectively. All three cardiac disease markers either stabilized or improved in 66% of patients.

Nex-z also showed strong efficacy for patients with hereditary ATTR amyloidosis with polyneuropathy. In the 33 treated patients, mean reduction in serum TTR levels was 91% at 12 months, with all 16 patients followed through 24 months showing sustained response and no signs of waning effect. As in the case of cardiomyopathy, nex-z also showed disease-modifying potential for ATTR amyloidosis with cardiomyopathy, showing “favorable trends” for various clinical measures, according to Intellia’s announcement.

The gene editor was generally well-tolerated across both cardiomyopathy and polyneuropathy cohorts. The most common side effects were infusion-related reactions, which were largely mild or moderate in severity.

Intellia CEO John Leonard in a statement called nex-z’s effects on cardiac markers “remarkable,” adding that the gene editor showed “similarly positive and consistent trends” in polyneuropathy, underscoring its disease-modifying potential. “These results from the ongoing Phase 1 study increase our belief in the likelihood of success of our active Phase 3 studies based on our hypothesis that greater TTR reduction may lead to greater clinical benefit,” Leonard added.

Analysts also appear to be optimistic about nex-z. BMO Capital Markets’ Kostas Biliouris in a Sunday note called the readout “robust,” adding that the early findings “are supportive of a strong profile, suggesting a successful PhIII outcome.”

“We believe a nex-z profile that confers improved convenience/cost-effectiveness/efficacy would be attractive to certain patients/physicians, conferring significant value to NTLA,” Biliouris added.

Meanwhile, Truist Securities’ Joon Lee called Intellia’s data “impressive,” pointing out that nex-z resulted in a stronger serum TTR reduction than Alnylam’s Amvuttra (vutrisiran), alongside a “faster onset of action,” which in turn “should lead to numerically superior benefit” in Intellia’s ongoing Phase III study.

https://www.biospace.com/drug-development/intellias-crispr-gene-editor-shows-early-promise-with-strong-biomarker-benefit-in-attr-amyloidosis