A single dose of nexiguran ziclumeran (nex-z) in patients with transthyretin amyloidosis cardiomyopathy (ATTR-CM) was associated with a substantial reduction in serum transthyretin (TTR) levels, according to a phase 1, single-group, open-label ongoing study presented at AHA 2024 and simultaneously published in NEJM.

Marianna Fontana, MD, et al., treated 36 patients with ATTR-CM with a single two-hour intravenous infusion of nex-z (also known as NTLA-2001), an investigational therapy based on CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease). Participants were predominantly older (median age 78 years), men (97%) and White (78%). One-half were in NYHA class III and 31% had variant ATTR-CM. The trial's dual primary objectives were assessing safety and pharmacodynamics including the serum TTR level.

Results showed that mean percent change in serum TTR level from baseline was –89% at 28 days (95% CI, −92 to −87) and −90% at 12 months (95% CI, −93 to −87). Of the 36 participants, 34 experienced adverse events (including cardiac failure, upper respiratory tract infection, COVID-19, atrial fibrillation and urinary tract infection), with 14 of those being serious adverse events and five determined to be transient infusion-related reactions. Of those reactions, one was severe and four were mild to moderate. Two patients had increased levels of aspartate aminotransferase also determined to be related to the infusion. During a safety follow-up of 27 months, one patient died from ischemic heart disease considered unrelated to treatment.

Of the secondary endpoints, geometric mean change in NT-proBNP level from baseline to 12 months was 1.02 (95% CI, 0.88 to1.17) and mean change in high-sensitivity cardiac troponin T level was 0.95 (95% CI, 0.89 to 1.01). Median change from baseline to 12 months in six-minute walk distance was 5 m, and in Kansas City Cardiomyopathy Questionnaire score was 8 points, with 61% of patients reporting at least a 5-point increase. In addition, 92% of patients had either improvement or no change in their NYHA class.

The authors write that the single dose of nex-z in this trial "appeared to be safe and associated with consistently deep, rapid, and durable reductions in serum TTR levels, accompanied by evidence of limited disease progression" during this 12-month follow-up. Clinical outcomes with this drug are being studied in the phase 3 MAGNITUDE trial.