CRISPR-based genome editing therapy may help ATTR amyloidosis with cardiomyopathy

November 5, 2022

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Source:

Gillmore JD, et al. LBS.02. Late-Breaking Science: Breakthrough Methods in the HF Journey. Presented at: American Heart Association Scientific Sessions; Nov. 5-7, 2022; Chicago (hybrid meeting).

Disclosures:
The study was funded by Intellia and Regeneron. Gillmore reports receiving grants from Alnylam and consulting fees from Alnylam, AstraZeneca, ATTRalus, Intellia, Ionis, Novo Nordisk, and Pfizer.


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CHICAGO — A new CRISPR-based in vivo gene editing therapy reduced transthyretin levels in patients with hereditary transthyretin amyloidosis with cardiomyopathy, researchers reported at the American Heart Association Scientific Sessions.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an “aggressive and fatal disease,” in which amyloid deposits cause impaired systolic and diastolic function and conduction disorders, Julian D. GillmoreMBBS, MD, PhD, director of the Center for Amyloidosis and Acute Phase Proteins at University College London, said at a press conference. He said ATTR-CM is usually fatal within 3 to 10 years if left untreated.

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A novel CRISPR-based in vivo gene editing therapy reduced transthyretin levels in patients with hereditary transthyretin amyloidosis with cardiomyopathy.
Source: Adobe Stock

“There remains a large unmet medical need in ATTR cardiomyopathy,” he said. “Current treatments only slow the progression of the disease and require lifelong medication, and due to cost, access to treatment is limited.”

In a first-in-human study, the researchers evaluated NTLA-2001 (Intellia/Regeneron), a novel CRISPR/Cas9-based in vivo gene editing therapy. The primary objectives were safety, tolerability, pharmacokinetics, pharmacodynamics and effect on serum transthyretin (TTR) levels. Secondary endpoints were efficacy on clinical measures including cardiac imaging, biomarkers, cardiopulmonary exercise test, and 6-minute walk.

The study included 12 patients (median age, 75 years; 100% male) with hereditary ATTR-CM or ATTR with wild-type cardiomyopathy and NYHA class I to III HF who received a single intravenous dose of NTLA-2001.

“This is a group where reductions in serum TTR have recently been shown to have clinical benefit,” Gillmore said. “The expectation is that a greater reduction will result in a greater clinical benefit.” The knockout hypothesis on TTR genes to achieve deep sustained TTR reduction is attractive.”

Six patients with NYHA class III received a dose of 0.7 mg/kg. Three patients with NYHA class I or II received a dose of 0.7 mg/kg and three with NYHA class I or II received a dose of 1 mg/kg.

Three patients reported no side effects and eight reported mild or moderate side effects, according to Gillmore. One patient with NYHA class III who received the 0.7 mg/kg dose had a grade 3 infusion-related reaction, which resolved without any clinical sequelae, Gillmore said.

There were no clinically significant laboratory findings, Gillmore said.

Serum TTR was reduced by 93% at 6 months in patients with NYHA class I or II receiving the 0.7 mg/kg dose, by 92% at 4 months in patients with NYHA class I or II receiving the 1 mg/kg dose. and about 94% in patients with NYHA class III who received the 0.7 mg/kg dose, Gillmore said. All patients achieved a reduction in serum TTR of at least 90% after 28 days.

The results are similar to those of patients with polyneuropathy who received NTLA-2001 in a separate arm of the study, Gillmore said.

“Profound, stable, and durable reductions in TTR were achieved at both the 0.7 and 1 mg/kg doses, with more than 90% reduction in TTR at both doses at day 28 and up to the latest follow-up between 4 and 6 months,” said Gillmore. “NTLA-2001 was generally well tolerated at both doses and had similar outcomes in patients with NYHA class I/II and NYHA class III.” These data show … promise for CRISPR and Cas9-based in vivo gene editing in humans.

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