Single-Dose Gene Editing Shows Promising Results for Fatal Amyloidosis

LONDON, UK – A multinational research team led by University College London’s National Amyloidosis Center has reported highly promising 24-month results for an investigational, one-time, in vivo gene-editing therapy called nexiguran ziclumeran in treating hereditary transthyretin (ATTR) amyloidosis with polyneuropathy.

The single infusion produced rapid, deep, and durable reductions in the misfolded transthyretin (TTR) protein, with measures of the debilitating disease largely stable or showing improvement through two years. The findings from the Phase 1 trial were published in The New England Journal of Medicine.

Targeting the Root Cause

Nexiguran ziclumeran (nex-z) is a lipid nanoparticle (LNP)-based therapy that delivers a CRISPR-Cas9 gene editing construct to the liver to treat ATTR. Hereditary ATTR amyloidosis with polyneuropathy is a rare, progressive, and fatal disease where misfolded TTR protein accumulates in peripheral nerves and other tissues. The average survival time from disease onset is only six to 12 years. Current treatments require repeated, lifelong administration and often fail to halt disease progression entirely.

Nexiguran ziclumeran is designed to address the root cause of the disease: the production of the unstable TTR protein by the liver.

In the Phase 1, single-group, open-label trial, researchers assessed the safety and pharmacodynamics of the therapy in 36 patients across four international sites.

Sustained Protein Reduction and Clinical Stability

The primary measure of the study was the level of TTR in the serum. Key results demonstrate the therapy’s potent effect:

• Protein Reduction: A single infusion achieved a mean reduction in serum TTR levels of -90% by day 28 and -92% at month 24. This profound reduction was sustained through month 36 in participants with available data.
• Neurologic Function: At month 24, the Polyneuropathy Disability Score remained stable in 27 participants (75%), improved in five, and worsened in two.
• Disease Progression: The Familial Amyloid Polyneuropathy stage remained stable in 29 patients and improved in two.

Biomarkers and patient-reported measures largely shifted in the direction of clinical benefit according to prespecified scales.

Safety Profile

Adverse events were reported in all patients, with the most frequent being infusion-related reactions (21 patients), headache (10), and diarrhea (8). Decreased thyroxine was reported in eight patients but did not result in hypothyroidism.

Eleven patients reported serious adverse events. One death occurred from cardiac amyloidosis on study day 273, and one participant discontinued due to motor decline, both of which were judged by the investigators to be unrelated to the gene-editing therapy.

The authors concluded that the one-time administration of nexiguran ziclumeran provides “profound and durable transthyretin lowering,” strongly supporting further investigation of the therapy for hereditary ATTR with polyneuropathy.