The FDA has liberated the second of two Intellia Therapeutics clinical trials that were put on hold last October following a report of serious liver toxicity that later led to death.
The agency has lifted the hold on Magnitude, a phase 3 trial of Intellia’s Regeneron-partnered CRISPR gene therapy nexiguran ziclumeran (nex-z) in patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM). Magnitude and a related phase 3 trial, Magnitude-2, were both halted after a patient in the Magnitude study experienced elevated levels of liver enzymes that later led to death.
The newly lifted hold comes with some safety caveats, Intellia announced in a March 2 release. The biotech will now exclude patients from Magnitude if they have certain liver issues, a heart ejection fraction of less than 25% or a “recent history of cardiovascular instability,” according to the release. For both trials, the company will also monitor liver enzymes more closely and provide guidance on short-term steroid treatments for patients who experience the potentially dangerous side effect.
“We are very pleased to have aligned with the FDA on the path forward for our Magnitude clinical trial, with measures designed to further enhance patient safety and allow us to continue to investigate nex-z in a broad ATTR-CM population,” Intellia President and CEO John Leonard, M.D., said in the release.
Combined with the January lifting of the hold on Magnitude-2, which is testing nex-z in hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN), “our attention now turns to completing enrollment in both ongoing trials,” he added.
Analysts from Evercore ISI called the safety adjustments “modest” in a March 2 note, noting that the hold was lifted relatively quickly and “probably comes with minimal disruption to the clinical timeline.”
Related
However, the analysts also flagged that the reason behind the liver toxicity is still unknown. Until more clarity comes, doctors and patients may take a “wait and see” approach, they wrote, even if the drug delivers positive data and eventually wins FDA approval.
Nex-z is designed to be a one-time treatment for ATTR-CM and ATTRv-PN by using CRISPR gene editing to disrupt the gene that makes the transport protein transthyretin. In these conditions, mutations in the transthyretin gene cause the protein to be misshapen and form clumps that damage the heart and other organs.
Intellia’s stock unsurprisingly ticked up in the wake of the news, from $13.78 per share at Friday’s close to $14.12 at 10:00 a.m. ET today.
Liver toxicity is a recurring issue for gene therapies, which often target the organ. While Intellia’s nex-z uses a lipid nanoparticle to deliver the CRISPR gene editing machinery, many other biotechs have faced issues using adeno-associated viruses (AAVs) as vectors.
Recently, uniQure paused some dosing in a phase 1/2 Fabry disease trial after two patients given its AAV gene therapy experienced elevated liver enzymes. And Sarepta Therapeutics navigated a safety controversy last summer when its AAV-based muscular dystrophy therapies, including the approved Elevidys, caused three liver-related patient deaths.