Key Takeaways:
- A single dose of nexiguran ziclumeran (nex-z), a CRISPR-Cas9-based therapy, achieved a 90% reduction in serum transthyretin (TTR) levels at 12 months (95% CI, −93 to −87).
- NT-proBNP levels showed stability with a geometric mean factor change of 1.02 (95% CI, 0.88 to 1.17), while high-sensitivity cardiac troponin T had a mean factor change of 0.95 (95% CI, 0.89 to 1.01).
- Of the 14 patients with serious adverse events, 7 had an event leading to hospitalization associated with cardiac failure (4 patients), arrhythmia (2 patients), or both (1 patient). The observed rate of cardiac events was 0.16 per patient per year (95% CI, 0.08 to 0.36).
Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is a progressive, life-threatening disease caused by the accumulation of amyloid fibrils derived from misfolded transthyretin protein. Current treatments involve stabilizing or silencing TTR protein production but require lifelong administration. Nex-z employs CRISPR-Cas9 gene editing to achieve a one-time, precise knockout of the TTR gene, aiming to significantly reduce TTR levels and improve outcomes in ATTR-CM.
This phase 1, open-label trial included 36 patients with wild-type or variant ATTR-CM who received a single intravenous dose of nex-z. The trial primarily assessed the safety and pharmacodynamic effects of nex-z, with serum TTR levels as the key pharmacodynamic measure. Secondary endpoints evaluated changes in NT-proBNP, high-sensitivity troponin T, 6-minute walk distance, and quality of life measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ). On November 16, 2024 the primary results were presented at AHA Scientific Sessions 2024 with simultaneous publication in the New England Journal of Medicine.
A total of 36 patients received nex-z and completed at least 12 months of follow up. Of these patients, 50% were in NYHA class III and 31% had variant ATTR-CM. The mean percent change from baseline in the serum TTR level was −89% (95% confidence interval [CI], −92 to −87) at 28 days and −90% (95% CI, −93 to −87) at 12 months.
Nex-z resulted in a significant reduction in serum TTR levels, achieving a 90% decrease at 12 months (95% CI, −93 to −87) at 28 days with absolute levels dropping to 16.5 μg/mL (95% CI, 13.4 to 19.7). NT-proBNP levels remained stable over 12 months, with a geometric mean factor change of 1.02 (95% CI, 0.88 to 1.17), while high-sensitivity cardiac troponin T levels also showed stability with a factor change of 0.95 (95% CI, 0.89 to 1.01). Functional capacity, as measured by the 6-minute walk distance, showed a median increase of 5 meters (IQR, −33 to 49). Additionally, patient-reported outcomes demonstrated improvement, with KCCQ scores increasing by a median of 8 points (IQR, −0.5 to 15), and 61% of patients achieving clinically meaningful improvements (≥5 points). Moreover, 47% of patients experienced an improvement in NYHA functional class, while 44% remained stable through the study period.
At least one adverse event was reported in 34 of 36 of participants. Of the 14 patients with serious adverse events, 7 had an event leading to hospitalization associated with cardiac failure (4 patients), arrhythmia (2 patients), or both (1 patient). The observed rate of cardiac events was 0.16 per patient per year (95% CI, 0.08 to 0.36). Infusion-related reactions occurred in 5 patients, and transient liver enzyme elevations were noted in 2 patients, both resolving without intervention. No permanent treatment discontinuation was reported, and only one treatment-related serious adverse event (a severe infusion reaction) required overnight observation.
The authors concluded that “these results represent the first clinical evidence of in vivo CRISPR/Cas9 gene editing in cardiomyopathy showing that targeted inactivation of the TTR gene may favorably impact disease progression in ATTR-CM.” In addition, they highlighted that “A single dose of nex-z appear to be safe and was associated with consistently deep, rapid, and durable reductions in serum TTR levels, accompanied by evidence of limited disease progression during the initial 12 months after treatment.” Nex-z offers a promising one-time therapy for ATTR-CM, and its evaluation in the phase 3 MAGNITUDE trial will provide further insights into its long-term safety and efficacy.