Novel CRISPR-Cas9 Therapy Slows ATTR-CM Progression

 A novel CRISPR-Cas9-based therapy shows promise in slowing disease progression for cardiomyopathy caused by transthyretin amyloidosis (ATTR-CM).

This therapy, nexiguran ziclumeran (nex-z), directly targets the TTR gene in liver cells via a single IV infusion.

Phase I data revealed deep, rapid, and durable reductions in serum TTR levels among study participants.

The investigational therapy builds on previous advancements, such as tafamidis and vutrisiran, which reduce TTR levels through other mechanisms.

The therapy demonstrated favorable safety and tolerability, with minimal variability in outcomes across patients.

Nex-z also showed stability or improvement in disease markers, especially in patients with advanced ATTR-CM and high mortality risks.

This gene-editing approach offers a potential permanent treatment for ATTR-CM by directly targeting the liver.

A two-part analysis included 36 patients, with 24 receiving a fixed dose of 55 mg in the second phase.

Serum TTR levels dropped by 89% from baseline to 28 days, remaining low and stable for up to 24 months.

Secondary endpoints, including NT-proBNP, troponin T, and functional capacity, indicated disease stabilization.

Over 12 months, 83% of NYHA class I/II patients and 47% of class III patients showed no worsening of key markers.

Most patients (92%) reported either no change or improvement in NYHA class, with significant functional and quality-of-life benefits.

Adverse events included transient infusion reactions and liver-enzyme elevations, but serious events were relatively low at 39%.

The researchers plan to evaluate nex-z further in the MAGNITUDE trial, a global placebo-controlled study.

Take-Home Points:

1. Nexiguran ziclumeran represents a novel CRISPR-Cas9 therapy targeting TTR gene in the liver.
2. It offers durable reductions in serum TTR and potential permanent treatment for ATTR-CM.
3. Phase I results show disease stabilization and functional improvement over 12 months.
4. The safety profile is favorable, with low serious adverse event rates.
5. Further evaluation will occur in the global MAGNITUDE trial.