Novel CRISPR-Cas9 Therapy Slows ATTR-CM Progression

CHICAGO, IL—A novel in vivo gene-editing therapy based on CRISPR-Cas9 that targets inactivation of the transthyretin (TTR) gene could slow disease progression in patients with cardiomyopathy caused by transthyretin amyloidosis (ATTR-CM), according to phase I data.

The investigational therapy, nexiguran ziclumeran (nex-z; Intellia Therapeutics), is given as a single IV infusion and targets the TTR gene in the patient’s liver cells. It has previously shown promise in a first-in-human study, as reported by TCTMD.

Other drugs in this space that reduce and silence levels of TTR, respectively, include tafamidis (Vyndaqel and Vyndamax; Pfizer), which was approved by the US Food and Drug Administration in 2019, and vutrisiran (Amvuttra; Alnylam), which has shown encouraging findings.

“Administration of a single dose of nex-z demonstrated favorable safety and tolerability, and resulted in deep, rapid, and durable reductions in serum TTR with very low variability among the patients in the study,” said Marianna Fontana, MD, PhD (University College London, Royal Free Hospital, England), who presented the findings here at the American Heart Association (AHA) 2024 Scientific Sessions. “Reductions in TTR were accompanied by stability or improvement of several disease markers in an ATTR-CM population with advanced disease who are expected to have rapid disease progression and high mortality rates.”

Sarah Cuddy, MD (Brigham and Women’s Hospital, Boston, MA), who discussed the findings during the AHA session, reviewed all the “cutting edge” therapeutic developments in the ATTR-CM field over the past several decades and argued that the advantage of nex-z is that it targets the liver directly. The study shows “really promising and effective data,” she continued. “This has opened up the door for gene editing, a permanent approach to therapy.”

The results were published simultaneously in the New England Journal of Medicine.

‘Deep, Rapid, and Durable’ Effect

For the two-part analysis, Fontana and colleagues enrolled 36 patients (mean age 78 years; 97% male) with hereditary (31%) or wild-type (69%) ATTR-CM with NYHA class I-III symptoms (50% class III). The median NT-proBNP level was 2,052 ng/L, the median peak VO₂ level was 12.7 mL/kg/min, and the median baseline CMR extracellular volume was 58%. No tafamidis was used at baseline.

In the dose-finding analysis, patients either received a nex-z dose of 0.7 mg/kg (n = 9) or 1 mg/kg (n = 3). In the second part, the researchers enrolled 24 patients to receive a dose of 55 mg, which is the fixed-dose equivalent of 0.7 mg/kg.

In her talk, Fontana reported that nex-z was associated with a “deep, rapid, and durable” decrease in serum TTR (primary endpoint) across all patients from baseline to 28 days, with a mean reduction of 89%, reaching a mean absolute serum level of 18.9 μg/mL. TTR levels remained “low and virtually unchanged” through 24 months.

The secondary endpoints of NT-proBNP, troponin T, and functional capacity as assessed by the 6-minute walk test showed “evidence of disease stabilization at 12 months,” she said. Notably, 83% and 47% of patients with NYHA class I/II and III symptoms, respectively, showed no worsening of any of these markers at 1 year.

Almost all patients (92%) reported either no change or improvement in NYHA class at 1 year, with 72% of patients with baseline NYHA class III symptoms showing improvement. Median change in Kansas City Cardiomyopathy Questionnaire overall score at 12 months was 7.8 points. Functional capacity remained stable.

A total of 34 patients reported at least one adverse event, including five transient infusion-related reactions and two transient liver-enzyme elevations that were deemed treatment-related. The rate of serious adverse events was 39%. The rate of cardiac hospitalization events at 0.16 per patient per year was “low for this population,” Fontana said.

Next, the researchers are planning to further evaluate nex-z in the global, placebo-controlled MAGNITUDE trial.