CRISPR-based genome editing therapy may help in ATTR amyloidosis with cardiomyopathy
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CHICAGO — A novel 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 a “progressive and fatal disease,” during which amyloid deposits cause impaired systolic and diastolic function and conduction disorders, Julian D. Gillmore, MBBS, MD, PhD, director of the Centre for Amyloidosis at University College London, said during a press conference. He said ATTR-CM is usually fatal within 3 to 10 years if untreated.
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“There remains a major unmet medical need in ATTR cardiomyopathy,” he said. “Current treatments only slow disease progression and require lifelong administration, 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. The secondary objectives were efficacy on clinical measures including cardiac imaging, biomarkers, cardiopulmonary exercise testing and 6-minute walk distance.
The study included 12 patients (median age, 75 years; 100% men) with hereditary or wild-type ATTR-CM and NYHA class I to III HF who were administered a single dose of NTLA-2001 via IV infusion.
“This is a cohort in whom reduction in serum TTR protein concentration has recently been shown to be of clinical benefit,” Gillmore said. “The anticipation is that greater reduction will translate into greater clinical benefit. The hypothesis of knockout of the TTR gene to achieve deep sustained TTR reduction is an attractive one.”
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 adverse events and eight reported mild or moderate adverse events, according to Gillmore. One patient with NYHA class III who received a dose of 0.7 mg/kg 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 declined by 93% at 6 months in patients with NYHA class I or II who received a dose of 0.7 mg/kg, by 92% at 4 months in patients NYHA class I or II who received a dose of 1 mg/kg and by 94% in patients with NYHA class III who received a dose of 0.7 mg/kg, Gillmore said. All patients achieved a serum TTR reduction of at least 90% by 28 days.
The results are similar to those of patients with polyneuropathy who received NTLA-2001 in a separate arm of the trial, Gillmore said.
“Deep, consistent and durable TTR reductions were achieved at both the 0.7 and 1 mg/kg doses, with a TTR reduction of greater than 90% achieved at both doses by day 28 and out to the latest follow-up between 4 and 6 months,” Gillmore said. “NTLA-2001 was generally well tolerated at both doses and had similar results in patients with NYHA class I/II and NYHA class III. These data demonstrate the promise of CRISPR and Cas9-based in vivo gene editing in humans.”
Perspective
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Alex Reyentovich, MD
This was a relatively small study focused on biological efficacy and safety in a population with more sickness from a CV perspective, as opposed to the original study which looked at patients with more of a neurologic manifestation.
The therapy was able to demonstrate safety in a small cohort of patients and was able to suppress transthyretin production for up to 1 year, demonstrating biological efficacy and safety. Hepatocytes turn over, so the question is how frequently you would need to repeat the therapy.
This is the first study using CRISPR technology for gene therapy in the CV realm. It is an amazing first step for the entire field, not just the management of amyloidosis. Clearly, the ability to take a therapy once or very infrequently and not have to come back for repeated infusions would be the main benefit. Right now, tafamidis (Vyndamax, Pfizer), the only approved therapy for cardiac amyloidosis, is fairly safe pill that has limitations in efficacy. It is not a silencer and does not prevent production of transthyretin. The therapy in this study is completely different, and the question is whether it will improve outcomes. The main benefit is to potentially have a one-time infusion to suppress transthyretin production in the long term as opposed to coming back repeatedly.
This is a disease with a very high morbidity and mortality. Even in the treatment arm of ATTR-ACT, the pivotal trial for tafamidis, 30% of patients died at 30 months. What we really need to see is a clinical benefit as measured by morbidity and mortality, because the therapy is expected to come at a very high cost.
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Gillmore JD, et al. LBS.02. Late-Breaking Science: Breakthrough Strategies in the HF Journey. Presented at: American Heart Association Scientific Sessions; Nov. 5-7, 2022; Chicago (hybrid meeting).
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