First-in-Human in vivo Crispr/Cas9 Editing of the TTR Gene by NTLA-2001 in patients with Transthyretin Amyloid Cardiomyopathy

By Leah Kosyakovsky on

Key Points:

  • Transthyretin Amyloidosis (ATTR) is a highly morbid and often fatal cause of cardiomyopathy. Existing therapies targeting TTR protein reduction have been effective, but have not managed to achieved complete or sustained knockdown of TTR levels.
  • This was a Phase I study of a novel in vivo Crisp/Cas9 editing system (NTLA-2001) to reduce TTR. The primary objective was to assess safety, tolerability and PK and PD, and the secondary objective was to evaluate efficacy on clinical measures of cardiac disease.
  • NTLA-2001 was generally well tolerated, with largely mild-moderate adverse events reported. Patients receiving NTLA-2001 achieved sustained, >90% reduction in TTR up to 4-6 months after infusion.

Transthyretin Amyloidosis (ATTR) is a disease characterized by systemic deposition of amyloid fibrils composed of misfolded transthyretin (TTR) protein. Current therapies aim at decreasing amyloid formation, but they have not been able to accomplish complete knockdown of TTR production and function. Earlier this year, an in-vivo gene editing technique using CRISP-Cas9 technology (NTLA-2001) was tested in a small group of patients with ATTR and was demonstrated to be safe and capable of sustained TTR knockdown. In a breaking presentation at the 2022 AHA Scientific Sessions today, Dr. Julian D. Gillmore (University College London) and his team presented their study: “First-in-Human in vivo Crispr/Cas9 Editing of the Ttr Gene by Ntla-2001 in Patients with Transthyretin Amyloidosis With Cardiomyopathy.”

This was two part, open-label, multi-center Phase I randomized clinical trial which evaluated the safety, tolerability, and pharmacokinetics and pharmacodynamics of NTLA-2001, with secondary outcomes assessing the efficacy of TTR reduction. Part I involved a single ascending dose administered via an IV iron infusion, and Part 2 involved a dose expansion to 55mg. A total of 12 participated in this study. The median age was 75, and 100% of patients were male. 50% of patients were NYHA III at the outset, and the media NT-proBNP was 2461 ng/L.

The primary outcome was safety and tolerability. Twenty five percent of patients reported no adverse events, and 67% reported mild or moderate adverse events. Two patients experienced infusion-related reactions. There were no clinically significant laboratory findings observed with infusion. Secondary outcomes included TTR reduction; all patients achieved >90% reduction in TTR levels by day 28 post initial infusion, with a sustained reduction achieved through 4-6 months. The results were similar regardless of baseline NYHA class.

When discussing the clinical implications of the study at AHA, Dr. Gillmore stated: “These results indicate that IV NTLA-2001 is a potential new treatment option that may stop disease progression in patients with ATTR amyloid cardiomyopathy…however, further research is needed to establish long-term safety  and to continue to monitor and evaluate the potential effects on patients’ clinical outcomes.”