Intellia Doses First Patient in MAGNITUDE-2 Phase 3 Nexiguran Trial

Intellia Therapeutics, Inc, a leading clinical-stage gene editing company focused on revolutionizing medicine with CRISPR-based therapies, announced the first patient has been dosed in MAGNITUDE-2, a global, pivotal phase 3 trial of nexiguran ziclumeran (nex-z) for the treatment of hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN).

“We are pleased to have dosed the first patient with a treatment that has such strong potential to redefine the treatment paradigm for those living with ATTR with polyneuropathy. This is a debilitating, progressive disease that leaves people feeling increasingly helpless,” said Dr. Paulo Sgobbi, medical director, PSEG Clinical Research Center. “Through nex-z’s potential to favorably impact disease progression, patients living with ATTR polyneuropathy could experience life-changing benefit while being freed from the existing chronic treatment regimen of pills, injections and infusions.”

“This milestone marks important progress toward our goal of completing the MAGNITUDE-2 clinical programme and we are optimistic the study will enable us to demonstrate nex-z’s potential to be the first to halt or reverse disease progression with a single dose in hereditary ATTR with polyneuropathy,” said John Leonard, president and chief executive officer of  Intellia.

The phase 3 MAGNITUDE-2 study is informed by Intellia’s phase 1 data, showing that a single dose of nex-z led to consistently rapid, deep and durable reduction in serum TTR. Intellia expects to present longer-term data from the phase 1 studies of nex-z for both polyneuropathy and cardiomyopathy later this year. The company plans to submit a biologics licensing application for ATTRv-PN by 2028.

MAGNITUDE-2 study is a pivotal phase 3 MAGNITUDE-2 clinical trial is a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of nexiguran ziclumeran (nex-z) in approximately 50 patients with transthyretin amyloidosis with polyneuropathy (ATTRv-PN). The primary endpoint of the study includes a modified neuropathy impairment score and change in serum TTR levels. Adult patients with ATTRv-PN will be randomized 1:1 to receive a single 55 mg infusion of nex-z or placebo.

Based on Nobel Prize-winning CRISPR/Cas9 technology, nex-z has the potential to become the first one-time treatment for transthyretin (ATTR) amyloidosis. Nex-z is an investigational in vivo CRISPR-based therapy designed to inactivate the TTR gene that encodes for the mutated transthyretin (TTR) protein causing the polyneuropathy. Interim phase 1 clinical data showed the administration of nex-z led to consistent, deep and long-lasting TTR reduction. Nex-z has been granted Regenerative Medicine Advanced Therapy designations by the US FDA for both cardiomyopathy and polyneuropathy. Nex-z has also been granted Orphan Drug Designation by the US FDA and European Commission. Intellia leads development and commercialization of nex-z as part of a multi-target discovery, development and commercialization collaboration with Regeneron.

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. There is no known cure for ATTR amyloidosis and currently available medications are limited to slowing accumulation of misfolded TTR protein.

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