Latest Results in ATTR Amyloidosis CRISPR Trial Bolsters Potential of In Vivo Gene Editing


The therapy was well-tolerated in 15 patients and no clinically relevant liver findings were observed.

Updated data on NTLA-2001, Intellia and Regeneron’s investigational CRISPR-Cas9 therapy, showed deep and sustained reductions of transthyretin (TTR) protein in patients with hereditary transthyretin (ATTR) amyloidosis with polyneuropathy(ATTRv-PN) in the phase 1 study (NCT04601051), according to an announcement from Intellia.1 The findings build on prior positive data that were published back in June 2021 in the New England Journal of Medicine and simultaneously presented at the 2021 Peripheral Nerve Society Annual Meeting.2

The positive interim data further support the systemic administration of a CRISPR-Cas9 gene-editing therapy. The investigational agent, which is delivered via a single intravenous infusion, targets the TTR gene in liver cells to effectively inactivate it in order to prevent the production of misfolded TTR protein, the accumulation of which is associated with serious and potentially fatal central and autonomic nervous system complications.

The latest data are from 15 participants in the study with ATTRv-PNtreated across 4 single-ascending dose cohorts of NTLA-2001 0.1 mg/kg, 0.3 mg/kg, 0.7 mg/kg, and 1.0 mg/kg via intravenous infusion. Investigators observed dose-dependent reductions in serum TTR, with peak reductions by day 28. Mean reductions were 52%, 87%, and 86% in 3 patients each in the first 3 cohorts and 93% in the 6 patients in the highest cohort.

Mean serum TTR reductions were durable throughout patient follow-up, which ranged from 2 to 12 months. Reductions were also consistent across all dose levels greater than 0.1 mg/kg. All patients at the highest dose level had over an 80% serum TTR reduction and most (n = 4) had an over 90% reduction by day 28. All patients in this cohort had sustained reductions in TTR.

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“These observations are consistent with animal data indicating potential life-long serum TTR suppression,” investigatorEd Gane, MD, professor of medicine, University of Auckland, New Zealand, and chief hepatologist, transplant physician, and deputy director, New Zealand Liver Transplant Unit, Auckland City Hospital, said in a statement.1 “Importantly, these early results suggest NTLA-2001 has the potential to deliver profound benefits for patients around the world.”

The ongoing phase 1 clinical trial is primarily assessing safety, as measured by adverse events (AEs) and efficacy as measured by serum biomarker levels. Secondary outcome measures include change from baseline in Familial Amyloid Polyneuropathy Stage, Polyneuropathy Disability score, Modified Body Mass Index, Neuropathy Impairment score, 10-Meter Walk Test, Norfolk Quality of Life-Diabetic Neuropathy, and EuroQOL-5D-5L. The CRISPR gene-editing therapy, which received orphan drug designation from the FDA in October 2021, was generally well-tolerated at all dose levels. Most AEs were mild, with 73% (n = 11) of patients experiencing a grade 1 AE. These included headache, infusion-related reactions, back pain, rash, and nausea. A serious, treatment-related AE of grade 3 vomiting did occur in a participant with concomitant medical history of gastroparesis treated with 1.0 mg/kg of NTLA-2001. A serious, unrelated AE of COVID-19 pneumonia also occurred in a patient in the 0.7 mg/kg dose group. Investigators did not observe any clinically significant liver AEs.

Part 2 of the study, a single-dose expansion cohort, is expected to begin in the first quarter of 2022 to evaluate the fixed dose of 80 mg, which should be similar to the 1.0 mg/kg dose. The study continues to dose and evaluate participants in the ATTR-cardiomyopathy arm with 0.7 mg/kg with plans to escalate the dose to 1.0 mg/kg. Enrollment for both arms should be completed in 2022 and more data will be presented later this year at medical meetings.

“These data suggest that treatment with a one-time, systemically delivered CRISPR-based investigational therapy has the potential to substantially reduce levels of a disease-causing protein. Data from the ongoing, first-in-human study of NTLA-2001 demonstrated rapid, deep and durable reduction of serum TTR protein... We believe this deep and consistent reduction shows promise for halting and even reversing disease progression in people with ATTR amyloidosis,” John Leonard, MD, president and chief executive officer, Intellia, said in a statement.1 “The NTLA-2001 proof-of-concept further validates our CRISPR technology platform and also supports the continued development of our genome editing approaches for a variety of diseases. Based on the safety and activity data generated to date, we believe we have increased the probability of success for our broader pipeline. Intellia looks forward to advancing our second in vivo clinical candidate, NTLA-2002, for the treatment of hereditary angioedema and additional in vivo candidates in 2022 in our pursuit of harnessing the full potential of genomic medicines.”

Intellia developed the therapy using their proprietary nonviral platform that uses lipid nanoparticles to deliver NTLA-2001. The CRISPR therapy consists of guide RNA and mRNA encoding the Cas9 enzyme.

Intellia also recently announced that the first patient with acute myeloid leukemia has been dosed in their phase 1/2a trial (NCT05066165) of NTLA-5001, a CRISPR T-cell receptor T-cell therapy.3 The FDA approved the investigational new drug application for NTLA-5001 in October 2021, paving the way the investigate the company’s first ex vivo CRISPR therapy that targets the Wilms’ Tumor 1 antigen. The study will evaluate the therapy’s safety, tolerability, cell kinetics, and anti-tumor activity with dose escalation and expansion phases in 2 arms stratified according to disease burden, with a planned enrollment of up to 54 participants.

1. Intellia and Regeneron announce updated phase 1 data demonstrating a single dose of NTLA-2001, an investigational CRISPR therapy for transthyretin (ATTR) amyloidosis, resulted in rapid, deep and sustained reduction in disease-causing protein. News release. Intellia Therapeutics. February 28, 2022.
2. Gillmore JD, Gane E, Taubel J, et al. CRISPR /Cas9 in vivo gene editing for transthyretin amyloidosis. N Engl J Med. Published online June 26, 2021. doi: 10.1056/NEJMoa2107454
3. Intellia Therapeutics announces first patient dosed in phase 1/2a clinical trial of NTLA-5001 for the treatment of acute myeloid leukemia. News release. Intellia Therapeutics. March 1, 2022.
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