A novel CRISPR-Cas9-based therapy, nexiguran ziclumeran (nex-z), has shown promising results in reducing serum transthyretin (TTR) levels in patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM). The phase I data, presented at the American Heart Association (AHA) annual meeting and published in the New England Journal of Medicine, indicate that a single IV infusion of nex-z led to a significant and sustained reduction in TTR levels, potentially halting disease progression.
Deep Reduction in TTR Levels
Marianna Fontana, MD, PhD, of University College London, reported that patients (n=36) with ATTR-CM experienced a mean percentage change from baseline in serum TTR levels of -89% (95% CI -92 to -87) at 28 days and -90% (95% CI -93 to -87) at 12 months following nex-z administration. This substantial reduction in TTR, a protein implicated in the formation of amyloid fibrils in the heart, is a key indicator of the therapy's potential efficacy.
Stabilization of Disease Progression
Over the 12-month study period, there were minimal changes from baseline in NT-proBNP and high-sensitivity cardiac troponin T levels, both markers of cardiac stress and damage. The 6-minute walk test (6MWT) distance also remained relatively stable. According to Fontana, "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."
Mechanism of Action and Administration
Nex-z is administered as a 4-hour infusion and is designed to inactivate the TTR gene, regardless of whether it is the wild-type or a variant. The therapy utilizes a CRISPR-Cas9 system packaged in a lipid-nanoparticle delivery system with liver tropism, aiming for a one-time treatment that induces a rapid, deep, and durable reduction in serum TTR levels.
Safety and Tolerability
Adverse events (AEs) were reported in 34 patients, with five experiencing transient infusion-related reactions and two having transient liver enzyme elevations assessed as treatment-related. Common AEs (≥15% of patients) included cardiac failure and COVID-19. Serious AEs, observed in 14 patients, were generally consistent with ATTR-CM, such as hospitalization due to cardiac failure and arrhythmia. The rate of such cardiac events was 0.16 per patient per year (95% CI 0.08-0.36). One patient with a history of ischemic heart disease died from the condition, but it was not considered treatment-related.
Expert Commentary
Christopher Kramer, MD, vice president of the American College of Cardiology, described the early-phase trial findings as "promising," noting that "a reduction of serum TTR is associated with clinical improvement." However, he cautioned about the long-term durability of the treatment effect and potential long-term adverse events. He also pointed out that patients received pretreatment with steroids and antihistamines to mitigate infusion site reactions.
Future Directions
The phase III MAGNITUDE trial will further evaluate the safety and efficacy of nex-z in patients with ATTR-CM. Kramer suggested that earlier administration of nex-z might lead to improvements in quality of life, whereas later-stage administration may primarily focus on disease control and slowing progression.
Study Population
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. The median age was 78, with a majority being men (78%) and white (78%). Most patients (89%) were on a loop diuretic. The open-label nature of the trial warrants caution in interpreting NYHA class and 6-minute walk distance results due to potential bias.
