Gene-editing Therapy NTLA-2001 Found to Reduce TTR Protein Levels

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A one-time treatment with NTLA-2001, Intellia Therapeutics’ experimental gene-editing therapy for people with familial amyloid polyneuropathy (FAP) and other types of ATTR amyloidosis, continued to demonstrate reduced levels of the disease-driving transthyretin (TTR) protein for at least six months, new data show.

“Based on the interim data shared today, we believe NTLA-2001’s potential to be a transformational treatment for patients with ATTR amyloidosis is becoming clearer,” John Leonard, MD, Intellia’s president and CEO, said in a press release.

“The safety, depth of serum TTR reduction and durability profile demonstrated thus far highlights its potential for halting and reversing the disease after a single dose,” he said.

ATTR amyloidosis is characterized by the buildup of toxic clumps of misfolded TTR protein in body tissues. FAP is a specific form of the disease, caused by genetic mutations, in which these toxic clumps mainly accumulate in peripheral nerves found outside the brain and spinal cord.

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NTLA-2001, which Intellia is co-developing with Regeneron Pharmaceuticals, aims to reduce the production of TTR protein by removing the gene that encodes it in liver cells. Those cells are the main TTR producers in the body. The therapy is administered via an infusion into the bloodstream, and it uses specialized spheres made up of fatty molecules called lipid nanoparticles to deliver CRISPR-Cas9 gene editing machinery that functionally deletes the gene.

Intellia is sponsoring a Phase 1 trial (NCT04601051) to test NTLA-2001 in people with FAP. In the first part of the study, 15 FAP patients were given a single infusion of the investigational therapy at one of four doses: 0.1, 0.3, 0.7, and 1 mg/kg.

Interim data previously reported by Intellia showed the treatment was able to lower TTR levels in the blood within a month following infusion. The strongest effect was seen with the highest dose, resulting in an average 93% reduction in TTR levels by day 28.

The new data presented by Intellia is a follow-up update on all 15 of these patients, who were monitored for at least six months.

Results showed that TTR reductions seen after one month have been largely sustained at six months: in the highest dose group, the average reduction in TTR levels at six months was 93%. Three of the six patients in the highest dose group have been followed for at least nine months, and the average reduction in TTR levels seen in these individuals at the same time point also was 93%.

In lower-dose groups, most patients have been followed for at least a year, and data generally suggest that reductions in TTR levels are sustainable.

“These data further underscore the power of genomic medicines and bolster the probability of success across our broader in vivo [in living organisms] genome editing platform. We look forward to progressing the clinical development of the first-ever systemically administered in vivo CRISPR investigational therapy,” Leonard said.

The new data showed no new safety findings concerning NTLA-2001 treatment. The most common adverse events reported in the study included headache, infusion-related reactions, back pain, rash, and nausea; most of these were mild in severity.

Just one serious adverse event that was possibly related to NTLA-2001 was reported: an instance of severe vomiting in a patient who had an underlying stomach condition called gastroparesis. The only other serious event documented was pneumonia due to COVID-19 infection, which was not related to the experimental treatment.

“We’re pleased to share updated data that enhance the safety and durability profile of NTLA-2001, increasing our confidence in its potential as a one-time, systemically delivered and long-lasting CRISPR-based therapy. Single-dose in vivo gene editing could one day help patients with a variety of hard-to-treat genetic diseases, making it one of the most exciting medical breakthroughs on the horizon today,” said George D. Yancopoulos, MD, PhD, Regeneron’s president and chief scientific officer.

The Phase 1 trial recently launched its second part, which will test a single infusion of NTLA-2001 at a fixed dose of 80 mg. Simulations indicate that dose will be functionally equivalent to 1 mg/kg. A parallel part of the study, also ongoing, is testing NTLA-2001 in people with heart disease related to ATTR amyloidosis.