Intellia’s CRISPR Therapy for ATTR-CM First to Enter Late-Stage Trials


Intellia Therapeutics plans to initiate the phase 3 trial of NTLA-2001 by the end of 2023.

The FDA has cleared Intellia Therapeutics’ investigational new drug (IND) application to initiate a phase 3 trial of NTLA-2001 in patients with transthyretin (ATTR) amyloidosis with cardiomyopathy (CM).1

The trial, which is set to start by the end of 2023, will represent the first late-stage clinical trial to evaluate an in vivo CRISPR-based gene editing therapy. It uses Intellia’s proprietary non-viral platform to deploy lipid nanoparticles to deliver guide RNA and Cas9-encoding mRNA to the liver. The program is a collaboration between Intellia and Regeneron and a phase 1 trial (NCT04601051) is evaluating the therapy in patients with hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN) or ATTR with CM. Patients with ATTR amyloidosis experience serious complications due to a buildup of structurally abnormal transthyretin (TTR) protein which leads to death.

“The FDA clearance of the NTLA-2001 IND application allows us to initiate a pivotal Phase 3 trial in the United States, marking the first in vivo CRISPR-based candidate to begin late-stage clinical development. This is another important step forward for Intellia and our collaborator, Regeneron, as we aim to establish a new standard of care for the treatment of ATTR amyloidosis,” John Leonard, MD, President and Chief Executive Officer, Intellia, said in a statement.1 “We are thrilled to further advance NTLA-2001 and our pipeline of investigational gene editing therapies as we embark on a new era in medicine. We look forward to sharing additional information about the Phase 3 study at our upcoming quarterly earnings webcast, being held on Thursday, November 9.”

READ MORE: Intellia’s CRISPR Gene Editing Therapy Significantly Reduces Swelling in Hereditary Angioedema, New Data Show

Clinical Takeaways

  1. The FDA has cleared Intellia Therapeutics to begin a first-of-its-kind phase 3 trial of NTLA-2001, an in vivo CRISPR-based gene editing therapy, for patients with ATTR amyloidosis with cardiomyopathy.
  2. NTLA-2001 demonstrated promising reductions in TTR protein levels and a favorable safety profile in a phase 1 trial, suggesting its potential as a single-dose treatment to address the underlying cause of ATTR amyloidosis.
  3. This collaborative effort between Intellia and Regeneron marks a significant advancement in research for gene editing therapies in general and in the disease.

The most recent data from the phase 1 trial of NTLA-2001 showed that patients in the low-dose cohort (0.7 mg/kg; n=9) who had either Class I/II or Class III New York Heart Association (NYHA) heart failure had a mean TTR serum reduction by day 28 of 93%, with a mean reduction of 92.5% in the high-dose cohort (1.0 mg/kg; NYHA Class I/II; n=3).2 These reductions were sustained through follow-up, which ranged from 2 to 6 months as of the July 1, 2022 data cutoff. In terms of adverse events (AEs), 2 of 12 patients treated reported transient infusion reactions, one of which was grade 3 and resolved without consequence. Notably, no significant liver findings were observed in patients in either dose level.

“Together with the previously reported data from the polyneuropathy arm of this landmark study, these results strongly suggest that NTLA-2001 could serve as a single-dose treatment regardless of disease manifestation. At these deep and consistent levels of protein reduction, we believe NTLA-2001 has the potential to halt and even reverse the underlying cause of ATTR amyloidosis," Leonard said in a statement at that time.2 "Given the similarly robust TTR reductions observed at the 2 doses tested, we have selected a fixed dose comparable to the 0.7 mg/kg level for evaluation across both arms in the ongoing dose-expansion portion of the study. We look forward to completing the Phase 1 study as we advance closer to a potential pivotal trial, which we expect will include patients in the US.”

1. Intellia Therapeutics announces FDA clearance of Investigational New Drug (IND) application to initiate a pivotal phase 3 trial of NTLA-2001 for the treatment of Transthyretin (ATTR) Amyloidosis with cardiomyopathy. News release. Intellia Therapeutics. October 18, 2023.
2. Intellia and Regeneron Announce Initial Data from the Cardiomyopathy Arm of Ongoing Phase 1 Study of NTLA-2001, an Investigational CRISPR Therapy for the Treatment of Transthyretin (ATTR) Amyloidosis. News release. Intellia Therapeutics. September 16, 2022.
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