Phase 3 trial of NTLA-2001 for ATTR-CM to launch by year’s end

FDA clears gene-editing therapy to enter late-stage clinical development

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

Share this article:

Share article via email
An illustration shows a bottle labelled 'clinical trials.'

Intellia Therapeutics is launching a pivotal Phase 3 clinical trial in the U.S. to evaluate the safety and effectiveness of its investigational gene-editing therapy NTLA-2001 in people with ATTR amyloidosis with cardiomyopathy (ATTR-CM).

The study, which is expected to start by the end of the year, follows the recent approval of an investigational new drug application for NTLA-2001 by the U.S. Food and Drug Administration (FDA). A pivotal trial is one where its findings, should they be positive, are used to support an application seeking the therapy’s approval.

The FDA’s decision makes NTLA-2001, which is being co-developed by Intellia and Regeneron Pharmaceuticals, the first CRISPR-based gene therapy to enter late-stage clinical development, according to a company press release.

“The FDA clearance … 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, Intellia’s president and CEO, said in the release.

Recommended Reading
An illustration of a health professional working at a computer while a person seated alongside the desk speaks.

Machine learning could help ID those with need for FAP genetic test

Intellia to share additional information about trial on Nov. 9 webcast

“The Intellia team has done tremendous work as part of its mission to bring forth a new era of medicine. This decision by the FDA to allow us to initiate a pivotal Phase 3 trial for ATTR amyloidosis with cardiomyopathy (ATTR-CM) is not only a key moment for Intellia, but an exciting moment for the field of genome editing as the first in vivo CRISPR-based treatment to reach late-stage clinical development,” Intellia said in an emailed statement to FAP News Today.

Additional information on the trial will be shared on a company earnings webcast, to be held Nov. 9, Leonard said.

In addition to the trial in ATTR-CM, Intellia is preparing for the launch of another pivotal Phase 3 trial that will test NTLA-2001 in people with familial amyloid polyneuropathy (FAP), also known as hereditary ATTR amyloidosis with polyneuropathy.

“We are thrilled to advance this candidate for ATTR-CM and look forward to progressing NTLA-2001 for the treatment of ATTR with polyneuropathy (ATTRv-PN) for which we are currently preparing a global Phase 3 study,” Intellia said in the statement.

The company is in discussions with regulatory authorities about this global trial.

These pivotal trials are supported by data from an ongoing Phase 1 trial (NCT04601051), which is testing the safety and preliminary efficacy of NTLA-2001 in people with FAP or ATTR-CM. Additional trial results are expected by year’s end, Intellia stated to FAP News Today.

ATTR amyloidosis is a group of disorders characterized by the accumulation of toxic clumps of misfolded transthyretin (TTR) protein in tissues.

… an exciting moment for the field of genome editing as the first in vivo CRISPR-based treatment to reach late-stage clinical development.

FAP is a specific form of ATTR amyloidosis that is caused by mutations in the TTR gene, which provides instructions for making the TTR protein, and characterized mostly by nerve damage.

ATTR-CM, a form of ATTR amyloidosis marked by the buildup of TTR clumps in the heart, can be caused by TTR mutations.

NTLA-2001 uses the gene-editing technology CRISPR-Cas9 to disrupt the TTR gene in liver cells — the main producers of TTR in the body — and halt TTR protein production. This is expected to reduce the accumulation of the toxic protein aggregates, thereby lessening disease symptoms.

NTLA-2001 has received orphan drug designation in the U.S. and Europe, which is meant to accelerate the therapy’s clinical development and regulatory review.

The ongoing two-part Phase 1 trial enrolled 72 adults with FAP or ATTRCM. The group of ATTR-CM patients was added to the study’s protocol in late 2021.

In the trial’s first part, participants receive a single infusion of NTLA-2001 at different doses to identify the optimal dose to be tested in its second, dose-expansion part. All participants will be followed for up to two years.

Findings from the first 15 FAP patients showed that a single infusion of NTLA-2001 led to dose-dependent reductions in blood TTR levels after about 30 days. Low TTR protein levels were sustained for up to six months.

Recommended Reading
An illustration depicting a man skateboarding in Philadelphia for the banner image of Ezekiel Kim's column

My philosophy for family caregivers instills patient dignity, self-worth

NTLA-2001 found to be generally well tolerated in participants

The therapy was generally well tolerated, with common side effects that included back pain, rash, nausea, headaches, and infusion-related reactions.

A dose of 55 mg of NTLA-2001 was chosen as the best dose for FAP patients to be evaluated in the second, dose-expansion phase of the trial, which started dosing patients in May 2022.

In addition, three FAP patients given the lowest dose of the gene therapy (0.1 mg/kg) in the first part are currently being re-treated with the optimal dose.

Among the ATTR-CM group, nine men were treated at a dose of 0.7 mg/kg and three at a dose of 1 mg/kg within the study’s first part. Interim data has shown similar findings to the FAP patients, with marked reductions in blood TTR levels detected after a month and sustained for up to six months.

Enrollment of ATTR-CM patients for the study’s second part was completed in December.