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

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Key Takeaways

  • Nexiguran ziclumeran (nex-z) achieved rapid, durable serum TTR reductions in ATTR-CM patients, with a mean reduction of 90% at 12 months.
  • The therapy showed a favorable safety profile, with transient infusion-related reactions and liver-enzyme elevations in a few patients.
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A single dose of nex-z achieved consistent and rapid reductions in serum TTR levels over 12 months of follow-up in patients with ATTR-CM.

Interim Phase 1 Update Shows Favorable Effect of Nex-z for ATTR-CM | Image Credit: Intellia

John Leonard, MD

Credit: Intellia

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.
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