Amyloidosis Gene Therapy Demonstrates Durable Reductions in Transthyretin


A 93% reduction in serum TTR remained consistent in 6 patients at 6 months.

Intellia’s NTLA-2001, an investigational gene therapy for the treatment of transthyretin (ATTR) amyloidosis has demonstrated durable efficacy after a single dose.1

These updated data, from 15 patients with hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN), were presented at the European Association for the Study of the Liver (EASL) International Liver Congress 2022, held June 22-26 in London.

The 6 patients treated at the highest dose of 1.0 mg/kg achieved a 93% mean and 98% maximum reduction in disease-causing serum transthyretin (TTR) at 28 days after treatment. Reductions remained consistent in these patients at 6 months, with 3 patients showing no loss in TTR reductions at 9 months post-treatment. Patients in the lower dose cohorts also showed durable TTR reductions, with an 86% mean serum TTR reduction remaining durable at 6 months in the 0.7 mg/kg cohort and an 89% mean reduction sustained at 12 months in the 0.3 mg/kg cohort.

“Notably, the higher doses yielded even deeper serum TTR reduction, with doses of 0.3 mg/kg and above achieving mean reductions of more than 85% and the highest dose of 1 mg/kg leading to a 93% mean reduction by day 28,” David Lebwhol, MD, chief medical officer, Intellia Therapeutics, said in a conference call regarding the data that was held on June 24, 2022.2 “With this profound level of TTR reduction, it is our judgment that there is limited benefit of assessing doses beyond 1 mg/kg.”

NTLA-2001, developed in collaboration with Regeneron, was generally well-tolerated, with 73% of patients reporting a maximal adverse event (AE) severity of grade 1. A serious grade 3 AE of vomiting in the 1.0 mg/kg dose group in a patient with a concomitant medical history of gastroparesis was deemed possibly related to treatment. Common AEs included infusion-related reactions, all of which were mild, and headache, back pain, rash, and nausea.

The on-going, 2-part, phase 1 clinical trial (NCT04601051) is open to adults with either ATTRv-PN or ATTR amyloidosis with cardiomyopathy (ATTR-CM). The ATTRv-PN arm, for which Part 1 is now completed, was open to patients aged 18 to 80, with a diagnosis of polyneuropathy due to ATTR amyloidosis, who had a bodyweight of at least 45 kg at screening. Patients who had amyloidosis not attributable to the TTR protein or known leptomeningeal transthyretin amyloidosis were excluded from the study.

The study’s UK-only ATTR-CM arm is still ongoing and is open to patients aged 18 to 90 with a diagnosis of ATTR-CM, classified as hereditary ATTR amyloidosis with cardiomyopathy (ATTRv-CM) or wild type cardiomyopathy (ATTRwt-CM). Patients in this arm must be at least 45 kg at screening, have at least 1 prior hospitalization for heart failure and/or clinical evidence of heart failure, and must be able to complete ≥150 meters on the 6-minute walk test during the screening period. Patients with amyloidosis not attributable to the TTR protein, those with known leptomeningeal transthyretin amyloidosis, and patients with heart failure that the investigators determine is caused by ischemic heart disease, hypertension, or uncorrected valvular disease and not primarily due to ATTR-CM will be excluded from the study.

In part 1 of the ATTRv-PN arm, participants were assigned to 1 of 4 dose-escalation cohorts and received a single dose of NTLA-2001. According to the results from this part and pharmacokinetic modeling and simulation data, patients will receive an optimal biologically active dose of 80 mg in part 2 and will be followed for up to 24 months. In part 1 of the ATTR-CM arm, patients will be assigned to 1 of 2 dose-escalation cohorts and receive a single dose of NTLA-2001. In part 2 they will receive the dose identified in part 1 and will be followed for up to 24 months. Primary end points include the number of participants with treatment-emergent AEs, the number of participants with clinically significant clinical laboratory test findings, and the percent change from baseline in serum TTR.

For the ATTRv-PN arm, secondary end points include the changes from baseline in Familiar Amyloid Polyneuropathy Stage, Polyneuropathy Disability Score, and modified Body Mass Index. For the ATTR-CM arm, secondary end points include changes from baseline in N-terminal prohormone of brain natriuretic peptide, hs Troponin T, and magnetic resonance imaging.

“Based on the interim data shared today, we believe NTLA-2001’s potential to be a transformational treatment for patients with ATTR amyloidosis is becoming clearer. The safety, depth of serum TTR reduction and durability profile demonstrated thus far highlights its potential for halting and reversing the disease after a single dose,” Intellia president and chief executive officer John Leonard, MD, said in a statement.1 “These data further underscore the power of genomic medicines and bolster the probability of success across our broader in vivo genome editing platform. We look forward to progressing the clinical development of the first-ever systemically administered in vivo CRISPR investigational therapy.”

Enrollment for both arms is expected to be completed in 2022, and the companies plan to present interim data from the ATTR-CM arm in the second half of the year.

1. Intellia and Regeneron present updated interim data from phase 1 study of CRISPR-based NTLA-2001 for the treatment of transthyretin (ATTR) amyloidosis demonstrating that deep serum TTR reductions remained durable after a single dose. News release. Intellia Therapeutics, Inc. and Regeneron Pharmaceuticals, Inc. June 24, 2022. 
2. NTLA-2001 for ATTR amyloidosis: Interim clinical results from ongoing phase 1 trial. Webcast. Intellia Therapeutics, Inc. June 24, 2022.
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