Abstract
Introduction: Transthyretin amyloidosis (ATTR amyloidosis) is a progressive fatal disease characterized by accumulation of amyloid fibrils composed of misfolded transthyretin (TTR) protein in tissues, resulting in cardiomyopathy and heart failure. Approximately 50,000 people have hereditary ATTR amyloidosis, and up to 500,000 have wild-type ATTR amyloidosis globally, leading to poor quality of life and high morbidity, resulting in death within a median of 2 to 6 years after diagnosis. However, data on the prevalence of ATTR-CM is limited and poorly characterized. NTLA-2001, an in vivo gene-editing therapeutic agent designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum by knocking out the TTR gene, has been shown to be effective, presenting a new therapeutic strategy. However, the safety, tolerability, and pharmacodynamic response to IV NTLA-2001 administration has not been yet demonstrated. Study and results: The first-in-human in vivo CRISPR/Cas9 trial of TTR Gene editing by NTLA-2001 in patients with Transthyretin Amyloidosis and cardiomyopathy was designed to evaluate the safety, tolerability, efficacy, and pharmacokinetic and pharmacodynamic responses to IV NTLA-2001 administration and its effect on serum transthyretin (TTR) levels in patients with ATTR amyloidosis and cardiomyopathy. Twelve subjects received NTLA-2001 (three NYHA I/II subjects at 0.7 mg/kg, three subjects at 1.0 mg/kg, and six NYHA III subjects at 0.7 mg/kg). Serum TTR levels were reduced from the baseline in all subjects (mean>90% after 28 days). Mean % reductions (+/-SEM) from baseline to day 28 were: NYHA I/II at 0.7 mg/kg = 92% (1%), at 1.0 mg/kg = 92% (2%), and for NYHA III at 0.7 mg/kg = 94% (1%) maintained through 4-6 months. Two of the 12 patients (16.7%) reported a transient infusion reaction. One patient experienced a grade 3 infusion-related reaction that resolved without any clinical sequelae. Lessons learned: This study showed a significant and consistent reduction in serum TTR protein levels after a single admission, while being generally well tolerated, representing a potential new option for the treatment and improvement of the prognosis of cardiac ATTR amyloidosis. Further research into the long-term safety and efficacy of NTLA-2001, particularly in higher-risk patients, including continued monitoring of whether knockout of the TTR gene results in sustained TTR reduction over the long term, is essential. Evaluation of the potential effects of markedly reduced TTR levels on patients' clinical outcomes, with a focus on functional capacity, quality of life, and mortality benefits are essential. The analysis of the use of this technology for an array of other diseases is vital.