CMR outcomes following one-time in vivo CRISPR editing with nexiguran ziclumeran in patients with ATTR-CM: phase 1 results
Y Razvi, S D Solomon, J Taubel, E Gane, B Pilebro, A Echaniz Laguna, J Kachadourian, R Rocha, D Smith, A Haagensen, J Olbertz, D E Gutstein, L Walsh, J Gillmore, M FontanaAbstract
Introduction
Nexiguran ziclumeran (nex-z) is an investigational in vivo CRISPR-based, one-time therapy designed to achieve lifelong suppression of hepatic TTR production. In the Phase 1 trial in patients with transthyretin amyloid cardiomyopathy (ATTR-CM), a single dose of nex-z was associated with rapid, deep and durable TTR knockdown with favourable biomarker and functional trajectories (eg, NT-proBNP, hs-TnT, 6-MWT) and was generally well tolerated (1). Cardiovascular magnetic resonance (CMR), including extracellular volume (ECV) mapping, provides a sensitive method to quantify amyloid burden and treatment response; changes in ECV <5% are associated with clinical stability (2).
Purpose
We evaluated the impact of nex-z on cardiac structure, function and myocardial amyloid load.
Methods
Thirty-six patients received a weight-based (0.7 or 1.0 mg/kg) or a fixed dose (55 mg) of nex-z as a one-time IV infusion. Participants who met appropriate criteria underwent prospective serial CMR with ECV mapping through 24 months after dosing, per trial protocol.
Results
29 participants (55% NYHA class III; 34% variant ATTR-CM) underwent baseline CMR; 27 and 24 completed 1- and 2-year follow-up CMR, respectively, after a single open-label dose of nex-z. Baseline CMR characteristics were consistent with advanced ATTR-CM. Across the cohort, a single dose of nex-z was associated with stability of cardiac structure, function and amyloid burden over 24 months. Median (IQR) changes at 1- and 2-years in ECV (2% [0, 5], 3.0% [0.0, 6.2]; Figure 1), left ventricular mass (-12 g [-23, -5], -28.5g [-40, -17]; Figure 2), left and right ventricular ejection fractions (LVEF: 0% [-5, 6], 0% [-7, 4.5]; RVEF: -1% [-8, 4], 2% [-4.5, 8.5]), and left ventricular stroke volume (2.0mL [-9, 11], 8.0mL [-2, 17]) showed stable trajectories over the 2 years, in contrast to the progressive decline usually seen in ATTR-CM. Stability was observed irrespective of baseline NYHA class.
Conclusions
In this Phase 1 cohort with a high proportion of hereditary ATTR-CM (including genotypes typically associated with rapid CMR progression), a single dose of nex-z was associated with stability of cardiac structure, function and amyloid burden over 2 years. These findings support the potential of gene editing to alter the natural history of amyloid deposition and disease progression in ATTR-CM.Figure 1For image description, please refer to the figure legend and surrounding text.Figure 2For image description, please refer to the figure legend and surrounding text.