FDA Lifts Hold on Intellia’s Experimental Gene-Editing Therapy for ATTR-CM

Rare Daily Staff

The U.S. Food and Drug Administration has removed a clinical hold on Intellia Therapeutics’ application to conduct a phase 3 trial of its experimental gene-editing therapy nexiguran ziclumeran in transthyretin amyloidosis with cardiomyopathy.

The FDA had imposed clinical holds on the MAGNITUDE and MAGNITUDE-2 phase 3 programs in October, after a MAGNITUDE patient who received nexiguran ziclumeran experienced Grade 4 liver transaminase elevations and increased total bilirubin that triggered protocol-defined pausing criteria.

Intellia said it has now agreed with the FDA on mitigation measures for both studies, including enhanced monitoring of liver laboratory tests, guidance on short-term steroid treatment if elevated liver enzymes are seen soon after dosing, and exclusion of patients with certain liver abnormalities. For MAGNITUDE, the company is adding further exclusion criteria for patients with a recent history of cardiovascular instability and those with an ejection fraction below 25 percent at screening.

John Leonard, Intellia’s president and CEO, said the company’s focus now turns to completing enrollment in both ongoing phase 3 trials, while it works with clinical investigators, ethics committees, international regulators, and other stakeholders to resume enrollment.

Transthyretin amyloidosis with cardiomyopathy is a form of amyloidosis in which misfolded transthyretin protein builds up in the heart, leading to a stiff, thickened myocardium, progressive heart failure symptoms, and an increased risk of serious cardiovascular events. The disease can arise in people with hereditary transthyretin variants or in those who develop the condition later in life, and it is associated with significant morbidity, reduced quality of life, and early mortality if not effectively treated.

Nexiguran ziclumeran, also known as nex-z, is an experimental, one-time, in vivo CRISPR/Cas9 gene-editing therapy designed to inactivate the TTR gene that encodes the transthyretin protein. By knocking down transthyretin production, the therapy aims to reduce or prevent amyloid deposition in patients with transthyretin amyloidosis with cardiomyopathy and hereditary ATTR with polyneuropathy. Nex-z is being studied in the MAGNITUDE and MAGNITUDE-2 phase 3 trials, and earlier-stage data have shown that administration of the therapy can lead to consistent, deep, and long-lasting reductions in transthyretin levels, according to the company.

Nex-z is based on CRISPR/Cas9 gene-editing technology and has the potential to become the first one-time treatment for transthyretin amyloidosis with cardiomyopathy and hereditary ATTR with polyneuropathy, the company said. Nex-z has received Orphan Drug and Regenerative Medicine Advanced Therapy designations from the FDA, as well as Orphan Drug Designation from the European Commission. Intellia is leading development and commercialization of nex-z under a multi-target discovery, development, and commercialization collaboration with Regeneron Pharmaceuticals.

Photo: John Leonard, Intellia president and CEO