CRISPR-Cas9 Gene Editing with Nexiguran Ziclumeran for ATTR Cardiomyopathy

Authors, Journal, Affiliations, Type, DOI

• Authors: Marianna Fontana, Scott D. Solomon, Jessica Kachadourian, Liron Walsh, Ricardo Rocha, David Lebwohl, Derek Smith, Jörg Täubel, Edward J. Gane, Björn Pilebro, David Adams, Yousuf Razvi, Joy Olbertz, Alexandra Haagensen, Peijuan Zhu, Yuanxin Xu, Adia Leung, Alison Sonderfan, David E. Gutstein, Julian D. Gillmore
• Journal: New England Journal of Medicine 2024;391:2231–41
• Affiliations: National Amyloidosis Centre UCL/Royal Free Hospital (London); Brigham and Women's Hospital (Boston); Intellia Therapeutics (Cambridge MA); Richmond Pharmacology (London); University of Auckland; Umeå University; CHU de Bicêtre/University Paris-Saclay; Regeneron Pharmaceuticals (Tarrytown NY)
• Type: Phase 1, open-label, single-group, dose-escalation + dose-expansion trial
• Funded by: Intellia Therapeutics and Regeneron Pharmaceuticals
• DOI: 10.1056/NEJMoa2412309 (ClinicalTrials.gov NCT04601051)

Overview

This Phase 1 open-label trial enrolled 36 patients with ATTR-CM (50% NYHA class III; 31% variant ATTR-CM) who received a single intravenous infusion of nexiguran ziclumeran (nex-z/NTLA-2001), a CRISPR-Cas9 gene editing therapy packaged in a hepatotropic lipid nanoparticle. Serum TTR was reduced by −89% at 28 days and −90% at 12 months, with suppression maintained through 24 months in all 11 patients who completed 2 years of follow-up. Safety was manageable with predominantly mild infusion-related reactions and transient liver enzyme elevations; disease biomarkers and functional capacity appeared stable in most patients at 12 months in the absence of concurrent TTR-targeted therapy. This is the first clinical trial of in vivo CRISPR-Cas9 gene editing for ATTR-CM, providing proof-of-principle for a one-time permanent knockdown strategy as an alternative to lifelong TTR stabilizers or RNAi; the Phase 3 MAGNITUDE trial is ongoing.

Keywords

ATTR cardiomyopathy, CRISPR-Cas9, nexiguran ziclumeran, NTLA-2001, transthyretin, gene editing, lipid nanoparticle, TTR knockdown, heart failure, amyloidosis, gene therapy

Key Takeaways

Study Design

• Phase 1, single-group, open-label, two-part study: Part 1 = dose escalation (0.7 mg/kg in 9 patients; 1 mg/kg in 3 patients); Part 2 = dose expansion (55 mg fixed dose in 24 patients — fixed-dose equivalent of 0.7 mg/kg)
• Single-site study (National Amyloidosis Centre, UK); data cut August 21, 2024; median follow-up 18 months (range 12–27)
• 36 patients: 50% NYHA class III; 31% variant ATTR-CM including 7 patients (19%) with p.Val142Ile (2 homozygous); median baseline NT-proBNP 2,052 ng/L
• No patients were on TTR stabilizer therapy at baseline (limited UK availability during study period)
• All patients received premedication: oral dexamethasone 8 mg (8–24h prior) + glucocorticoid + H1 + H2 antagonist (~1h prior) to mitigate infusion-related reactions
• 15-year safety surveillance planned per regulatory guidance for cell and gene therapies

Mechanism and Delivery

• Nex-z (NTLA-2001): hepatotropic lipid nanoparticle (LNP) delivering (1) single-guide RNA targeting the TTR gene and (2) human-codon–optimised mRNA encoding Streptococcus pyogenes Cas9 endonuclease
• LNP delivers components to hepatocytes — the primary source of circulating TTR — where NHEJ-mediated permanent knockout of the TTR gene is induced
• Unlike AAV-based gene therapies: LNP is rapidly cleared after administration; no AAV immunogenicity; allows broad patient eligibility without pre-existing antibody exclusion
• A single infusion theoretically produces permanent heritable reduction in hepatic TTR synthesis

Primary Endpoint — Pharmacodynamics (Serum TTR)

• Mean serum TTR reduction: −83% at 14 days; −89% (95% CI −92 to −87) at 28 days; −90% (95% CI −93 to −87) at 12 months
• Every patient achieved serum TTR <50 μg/mL by 28 days; 78% achieved <25 μg/mL
• Deep and consistent knockdown regardless of baseline TTR level, nex-z dose received, or TTR genotype (ATTRwt vs ATTRv)
• Serum TTR suppression maintained through 24 months in all 11 patients who completed 2 years

Secondary Endpoints (12 months)

• NT-proBNP: Geometric mean factor change 1.02 (95% CI 0.88–1.17) — stable
• hs-cardiac troponin T: Geometric mean factor change 0.95 (95% CI 0.89–1.01) — stable
• 6-minute walk distance: Median change +5 m (IQR −33 to 49) — stable
• KCCQ overall score: Median change +8 points (IQR −0.5 to 15); 61% achieved ≥5-point improvement (minimal clinically important difference)
• NYHA class: Improved ≥1 class in 47%; unchanged in 44%; worsened in 8%
• Cardiac imaging (echo/CMR): Consistent pattern of structural stability including myocardial extracellular volume (marker of amyloid load)
• Cardiopulmonary exercise: Median peak VO₂max change −0.3 ml/kg/min (IQR −2.3 to 1.4); VE/VCO₂ slope −0.6 (IQR −5.6 to 1.2) — stable

Post Hoc Analysis — Disease Progression Markers

• 66% had no worsening on any prognostic marker (NT-proBNP, hs-TnT, 6MWT) at 12 months
• By baseline NYHA: 83% of NYHA I/II patients had no worsening; 47% of NYHA III patients had no worsening
• Stability in individual markers at 12 months: NT-proBNP 81%; hs-TnT 94%; 6MWT 77%

Safety

• At least one adverse event in 34/36 patients (94%)
• Most common events: cardiac failure (36%); upper respiratory tract infection (19%); COVID-19 (19%); atrial fibrillation (17%); urinary tract infection (17%)
• Treatment-related AEs: Infusion-related reactions in 5 patients (14%) — 4 mild/moderate, 1 severe (hypotension → overnight observation; treated with IV saline); transient AST elevation in 2 patients (6%; peak 133/146 U/L; ALT 66/142 U/L; resolved ~10 days without intervention)
• Serious adverse events: 14 patients (39%); only the severe infusion reaction was treatment-related; remainder consistent with ATTR-CM disease progression
• Cardiac SAEs: Heart failure hospitalization (4); arrhythmia (2); HF + arrhythmia same event (1); cardiac event rate 0.16/patient/year (95% CI 0.08–0.36)
• Mortality: 1 death (day 506; 77-year-old man; ischemic heart disease; investigator-assessed as not treatment-related; baseline NT-proBNP 19,624 ng/L)
• Vitamin A: Persistently decreased throughout follow-up (expected — TTR transports retinol-binding protein complex); no clinical vitamin A deficiency; no thyroid hormone abnormalities (TTR also transports T4; thyrotropin levels normal)

Limitations of the Document

• No control group — clinical efficacy cannot be established; open-label design introduces assessment bias for functional/patient-reported endpoints
• Small sample size (n=36); single-site study limits generalizability
• Safety data limited to 27 months; TTR suppression data to 24 months; 15-year surveillance ongoing
• No concurrent TTR stabilizer use (atypical of global clinical practice — UK availability limited during study)
• Concomitant heart failure therapies (SGLT2i, MRA) may have independently contributed to biomarker stability
• Interim, unplanned analysis; all patients had ≥12 months but not all ≥24 months

Key Concepts Mentioned

• concepts/CRISPR-Cas9-in-Channelopathies — CRISPR-Cas9 gene editing technology; this paper represents first clinical application in ATTR-CM
• entities/ATTR-Amyloidosis — disease entity and indication
• entities/Nexiguran-Ziclumeran — the investigational therapy described in this paper
• concepts/TTR-Stabilizer-Therapy — comparator drug class requiring lifelong dosing vs single-dose gene editing

Key Entities Mentioned

• entities/Nexiguran-Ziclumeran — CRISPR-Cas9 LNP investigational TTR gene knockout therapy; sponsor Intellia Therapeutics/Regeneron
• entities/ATTR-Amyloidosis — disease entity; both ATTRwt and ATTRv included
• entities/Vutrisiran — comparator RNAi agent (referenced for TTR knockdown magnitude comparison)
• entities/Patisiran — comparator RNAi agent (referenced for TTR knockdown magnitude comparison)

Wiki Pages Updated

• Created wiki/sources/nexz-crispr-attrcm-nejm-2024.md
• Created wiki/entities/Nexiguran-Ziclumeran.md
• Updated wiki/entities/ATTR-Amyloidosis.md — added nex-z section to Disease-Modifying Therapy; updated Contradictions
• Updated wiki/concepts/CRISPR-Cas9-in-Channelopathies.md — added clinical translation section; updated source count
• Updated wiki/sourceindex.md
• Updated wiki/wikiindex.md