Novel CRISPR-Cas9-Based Promising in ATTR Cardiomyopathy

CHICAGO – A CRISPR-Cas9-based investigational therapy was linked with a drop in serum transthyretin (TTR) levels in patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM), according to phase I data.

A single IV infusion of nexiguran ziclumeran (nex-z), a therapy that targets production of TTR in the liver, was delivered to patients (n=36) with ATTR-CM, explained Marianna Fontana, MD, PhD, of University College London, and the mean percentage change from baseline in serum TTR levels decreased 89% (95% CI -92 to -87) at 28 days and 90% (95% CI -93 to -87) at 12 months.

Disease progression seemed to stop over the course of 12 months, with very little change from baseline in NT-proBNP and hs-Troponin T levels, or in the 6-minute walk test (6MWT), she said in a presentation at the American Heart Association (AHA) annual meeting. Study data were simultaneously published in the New England Journal of Medicine.

“These results represent the first clinical evidence of in vivo CRISPR/Cas9 gene editing in cardiomyopathy showing that targeted inactivation of the TTR gene may favorably impact disease progression in ATTR-CM,” Fontana said. “These results also support the hypothesis that rapid, deep, and durable reductions in serum TTR result in meaningful clinical benefits,” adding that deep serum TTR reductions were observed in every patient, regardless of baseline TTR level or genotype.

She noted that the phase III MAGNITUDE trial will assess safety and efficacy of nex-z in patients with ATTR-CM.

The progressive and fatal ATTR-CM results from accumulation of wild type or variant TTR amyloid fibrils in the heart. It is often an underdiagnosed cause of heart failure and is estimated to impact 200,000-500,000 patients globally, Fontana said.

Nex-z is a 4-hour infusion that aims to inactivate the TTR gene, whether wild-type or variant. “The CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease) investigational therapy packaged in a proprietary lipid-nanoparticle delivery system with liver tropism…was designed as a one-time therapy to induce a rapid, deep, and durable reduction in the serum TTR level,” according to Fontana and colleagues.

Christopher Kramer, MD, vice president of the American College of Cardiology, told MedPage Today that findings in the early-phase trial were “promising. We know that a reduction of serum TTR is associated with clinical improvement.”

But Kramer, who was not involved in the study, cautioned that “what we don’t know about this drug is how long it will last, and whether there are any long-term adverse events [AEs].” He also noted that the patients were heavily pretreated with steroids and antihistamines — oral dexamethasone, glucocorticoid, a histamine H₁ receptor antagonist (RA), and a histamine H₂ RA — to reduce the impact of infusion site reactions, which were frequent in the study.

AEs “were reported in 34 patients. Five had transient infusion-related reactions, and two had transient liver enzyme elevations that were assessed as treatment-related,” according to Fontana and colleagues. AEs occurring in ≥15% of patients included cardiac failure and COVID-19. As for serious AEs, which were seen in 14 patients, they were generally consistent with ATTR-CM, and included hospitalization tied to cardiac failure and arrhythmia. The observed rate of such cardiac events was 0.16 per patient per year (95% CI 0.08-0.36), according to the authors.

“During the 27 months of safety follow-up, one patient died from ischemic heart disease, which was not considered by the investigator to be treatment-related. This death occurred on study day 506 in a 77-year-old man who had a history of ischemic heart disease, in addition to ATTR-CM,” the authors said.

Kramer, who is at the University of Virginia in Charlottesville, said MAGNITUDE will likely provide more answers. He also suggested that earlier administration of nex-z might allow patients to show improvement in quality of life because when given at a later stage, disease control and slowing progressing are likely to be the most achievable outcomes.

Eligible patients had a diagnosis of variant or wild-type ATTR-CM; 50% were in New York Heart Association (NYHA) class III and 31% had variant ATTR-CM. Median age was 78, the majority were men, 78% were white, and 89% were on a loop diuretic.

Fontana’s group reported that the geometric mean factor change from baseline to month 12 was 1.02 (95% CI 0.88-1.17) in the NT-proBNP level and 0.95 (95% CI 0.89-1.01) in the high-sensitivity cardiac troponin T level. The median change from baseline to month 12 in the 6MWT distance was 5 m. And 92% of the patients had either improvement or no change in NYHA class, although they highlighted that “[b]ecause the trial was open-label, the characteristics of the patients…including NYHA class…and results for the 6-minute walk distance…are subject to bias and should be interpreted with caution.”