Interim Phase 1 Update Shows Favorable Effect of Nex-z for ATTR-CM

Interim 12-month Phase 1 data demonstrated the favorable impact of a single dose of nexiguran ziclumeran (nex-z), an investigational in vivo CRISPR-Cas9 gene editing therapy, for patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM).¹

Presented as late-breaking science at the American Heart Association (AHA) Scientific Sessions 2024, nex-z achieved rapid and durable reductions in serum TTR levels, while maintaining promising tolerability, despite a link to transient infusion-related reactions, over 12 months.

“The Phase 1 data presented today offer compelling evidence that deep and persistently low levels of TTR reduction achieved with nex-z, an investigational in vivo CRISPR-based gene editing therapy, may favorable impact disease progression for people living with ATTR amyloidosis,” John Leonard, MD, president and chief executive officer of Intellia, said in a statement.²

ATTR-CM is a rare, progressive, and often fatal disease—it is defined by a progressive decline in cardiac structure and function, with a further impact on functional capacity and quality of life.³ Despite therapeutic achieving clinical benefits in cardiac outcome trials, these patients remain at risk for cardiac events and mortality, especially in light of advanced disease stages.

In this Phase 1 clinical trial, the first and largest gene editing study in cardiovascular disease, investigators evaluated the safety and efficacy of a single intravenous infusion of nex-z for patients with ATTR-CM.⁴ Primary objectives for the study included the measurement of the effect of nex-z on safety and pharmacodynamics, including serum TTR levels.

Secondary objectives involved the effect on N-terminal pro–B natriuretic peptide (NT-proBNP) levels, high-sensitivity cardiac troponin T levels, the 6-minute walk distance, and the New York Heart Association (NYHA) class.

Overall, 36 patients received a single dose of nex-z and completed ≥12 months of follow-up. Approximately half (50%) of patients were in NYHA class III and 31% had variant ATTR-CM. Upon analysis, nex-z led to consistently rapid and sustained serum TTR reductions, irrespective of baseline levels.

At 12 months, the mean serum TTR reduction from baseline was 90% (95% CI, –93 to –87), with a mean absolute residential serum TTR concentration of 17 µg/mL.¹ Among 11 patients who completed 24-month follow-up, all showed a sustained response and no evidence of a diminishing effect over time.

Furthermore, the geometric mean factor change from baseline to Month 12 was 1.02 (95% CI, 0.88–1.17) in the NT-proBNP level and 0.95 (95% CI, 0.89–1.01) in the high-sensitivity cardiac troponin T level. Median change from baseline to Month 12 in the 6-minute walk distance was +5 meters (interquartile range [IQR], –33 to 49) and +8 points in the KCCQ score (95% CI, –0.5 to 15).

“The stability or improvement observed after a single dose of nex-z in multiple markers of cardiac disease progression is remarkable, especially considering the high proportion of patients with cardiomyopathy who had advanced heart failure,” Leonard said.²

Safety data showed the general well-tolerated profile of nex-z, with adverse events reported in 34 patients.⁴ Approximately 5 patients had transient infusion-related reactions and 2 had transient liver-enzyme elevations determined to be treatment-related. Meanwhile, serious adverse events consistent with ATTR-CM were reported in 14 patients.

“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.²

References

1. _{Fontana M, Taubel J, Gane E, Pilebro B, Adam D et al. Nexiguran ziclumeran (nex-z, also known as NTLA-2001), an investigational in vivo CRISPR-based therapy for patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM): interim report of the Phase 1 study. Presented at the American Heart Association (AHA) Scientific Sessions 2024. Chicago, Illinois. November 16-18, 2024.}
2. _{Intellia announces first clinical evidence from ongoing phase 1 study that nexiguran ziclumeran (nex-Z), an in vivo CRISPR/cas9-based gene editing therapy, may favorably impact disease progression in transthyretin (ATTR) amyloidosis. Intellia Therapeutics. November 16, 2024. Accessed November 16, 2024. https://ir.intelliatx.com/news-releases/news-release-details/intellia-announces-first-clinical-evidence-ongoing-phase-1-study.}
3. _{Jain A, Zahra F. Transthyretin Amyloid Cardiomyopathy (ATTR-CM) [Updated 2023 Apr 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK574531/}
4. _{Fontana M, Solomon SD, Kachadourian J, Walsh L et al. CRISPR-Cas9 Gene Editing with Nexiguran Ziclumeran for ATTR Cardiomyopathyr. NEJM. November 16, 2024. Accessed November 16, 2024. https://www.nejm.org/doi/full/10.1056/NEJMoa2403664.}