Interim results from a Phase 1 trial of nexiguran ziclumeran (nex-z), a CRISPR-based gene-editing therapy, have demonstrated early success in treating transthyretin amyloidosis cardiomyopathy (ATTR-CM). The study, involving 36 patients, showed a single infusion of nex-z reduced serum TTR levels by approximately 90% over 12 months, potentially offering a one-time treatment for this progressive and often fatal disease. The findings were presented at the American Heart Association (AHA) Scientific Sessions 2024.
Deep and Durable TTR Reduction
Marianna Fontana, MD, PhD, a professor of cardiology at University College London and primary investigator of the trial, noted the significant impact of nex-z. "After a single infusion of nex-z, there was a deep, rapid, and durable reduction in the circulating TTR levels, and the reduction was similar across patients, with all patients achieving a similar level, despite the genotype or the TTR at baseline," she told HCPLive.
Impact on Disease Progression
The trial included patients with ATTR-CM, with 50% having advanced heart failure (NYHA class III). Participants experienced stabilization in biomarkers of disease progression, including NT-proBNP and hsTroponin-T, and a median increase of 5 meters in a 6-minute walk distance. Furthermore, 92% of patients either maintained or improved their NYHA class over the 12 months of the study.
Safety Profile
The most common adverse events were mild-to-moderate infusion-related reactions, with no major safety concerns reported. These results suggest that nex-z could potentially alter the natural course of ATTR-CM by slowing or halting disease progression.
Future Directions
Larger trials are needed to confirm these findings. "The Phase 3 study, which is a randomized, multicenter, placebo-controlled trial, are sensing the efficacy and safety of nex-z in a large population of patients with ATTR-CM," Fontana stated. "Hopefully, very soon, the enrollment will be completed, and we’ll see the results of the Phase 3 trials."
If confirmed in larger trials, nex-z could become the first CRISPR-based therapy to successfully treat a cardiovascular condition, providing new hope for patients with limited treatment options.
