RARE Daily

FDA Clears Intellia’s Pivotal Trial of ATTR-CM In Vivo Gene Editing Therapy

October 18, 2023

Rare Daily Staff

The U.S. Food and Drug Administration has Intellia Therapeutics’ application to conduct a global phase 3 study of its experimental in vivo gene editing therapy for the treatment of transthyretin amyloidosis with cardiomyopathy.

Intellia expects to begin the study by the end of 2023.

“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,” said Intellia President and Chief Executive Officer John Leonard. “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.”

Transthyretin amyloidosis, or ATTR amyloidosis, is a rare, progressive, and fatal disease. Hereditary ATTR (ATTRv) amyloidosis occurs when a person is born with mutations in the TTR gene, which causes the liver to produce structurally abnormal transthyretin (TTR) protein with a propensity to misfold. These damaged proteins build up as amyloid in the body, causing serious complications in multiple tissues, including the heart, nerves and digestive system. ATTRv amyloidosis predominantly manifests as polyneuropathy (ATTRv-PN), which can lead to nerve damage, or cardiomyopathy (ATTRv-CM), which can lead to heart failure. Some individuals without the genetic mutation produce non-mutated, or wild-type TTR proteins that become unstable over time, misfolding and aggregating in disease-causing amyloid deposits. This condition, called wild-type ATTR (ATTRwt) amyloidosis, primarily affects the heart. There are an estimated 50,000 people worldwide living with ATTRv amyloidosis and between 200,000 and 500,000 people with ATTRwt amyloidosis.

Based on CRISPR/Cas9 technology, NTLA-2001 could potentially be the first single-dose treatment for ATTR amyloidosis. NTLA-2001 is the first investigational CRISPR therapy candidate to be administered systemically, or through a vein, to edit genes inside the human body. Intellia’s proprietary non-viral platform deploys lipid nanoparticles to deliver to the liver a two-part genome editing system: guide RNA specific to the disease-causing gene and messenger RNA that encodes the Cas9 enzyme, which carries out the precision editing. Robust preclinical and clinical data, showing deep and long-lasting transthyretin (TTR) reduction following in vivo inactivation of the target gene, supports NTLA-2001’s potential as a single-administration therapeutic. Intellia leads development and commercialization of NTLA-2001 as part of a multi-target discovery, development, and commercialization collaboration with Regeneron. The global phase 1 trial is an open-label, multi-center, two-part study of NTLA-2001 in adults with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) or transthyretin amyloidosis with cardiomyopathy (ATTR-CM). The trial is now closed for enrollment.

Photo: John Leonard, president and CEO of Intellia

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