2nd Part Launches in Phase 1 Trial of Gene-editing Therapy NTLA-2001

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by Steve Bryson PhD |

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The first patient has been dosed in the second part of a Phase 1 trial evaluating NTLA-2001, Intellia Therapeutics’ investigational gene-editing therapy for people with familial amyloid polyneuropathy (FAP) and other forms of ATTR amyloidosis.

The first part of the study exposed patients to single ascending doses of NTLA-2001 to identify the optimal biologically active dose. The therapy uses the gene-editing tool CRISPR-Cas9 to remove the mutated TTR gene.

This gene encodes a protein called transthyretin (TTR) that, when defective, forms toxic deposits that build up and damage different tissues. FAP is an inherited form of ATTR amyloidosis, in which TTR deposits mainly accumulate and damage peripheral nerves — those found outside the spinal cord and brain — leading to a condition known as polyneuropathy.

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Co-developed by Regeneron Pharmaceuticals and administered by intravenous (into-the-vein) infusion, NTLA-2001 uses microscopic spheres of fatty molecules called lipid nanoparticles to deliver the CRISPR-Cas9 machinery specifically to liver cells, where TTR is primarily produced.

Recently shared interim efficacy data of 15 FAP patients from the first part of the study showed that a single dose of NTLA-2001 led to a dose-dependent drop in blood TTR levels after about one month, with mean reductions of 86% at 0.7 mg/kg and 93% at 1.0 mg/kg dose.

The maximum TTR reduction was 98% with the highest dose. Such decreases were maintained through patient follow-up, ranging from two months to one year.

NTLA-2001 was generally well-tolerated at all doses, with the most frequent adverse events being headache, back pain, rash, nausea, and infusion-related reactions.

“Intellia is successfully executing on its 2022 strategic priorities as we advance our proprietary CRISPR-based drug discovery and development platform,” John Leonard, MD, Intellia’s president and CEO, said in a press release. “We recently shared updated interim data from our landmark study of NTLA-2001, which demonstrated that treatment with NTLA-2001 in people with ATTR amyloidosis with polyneuropathy was generally well-tolerated and delivered rapid, consistent, dose-dependent reductions in [blood] TTR.”

“In addition to achieving a mean reduction of 93% at the 1.0 mg/kg dose, we were particularly pleased that reductions in serum TTR levels persisted, further bolstering our confidence in NTLA-2001 as a potentially durable, one-time treatment for ATTR amyloidosis,” Leonard added.

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Based on part 1 data, Intellia is now evaluating a fixed dose of 80 mg in the second part of the Phase 1 trial (NCT04601051), which is presumed to provide a similar exposure to the 1.0 mg/kg dose. The company plans to present additional data from the first portion of the trial at the European Association for the Study of the Liver – International Liver Congress, to be held June 2226.

“In June, we plan to share additional durability data from the dose-escalation portion of the polyneuropathy arm and data supporting our fixed dose selection for Part 2,” Leonard said.

In addition, dosing continues in patients with ATTR amyloidosis-associated cardiomyopathy, a form of the disease in which TTR deposits damage heart tissue. These participants were recently added to the study’s protocol, also evaluating increasing doses of NTLA-2001. The company expects to share initial safety and TTR reduction data from part 1 in this group in the second half of the year.

Recruitment is ongoing for both arms of the Phase 1 study at sites in New Zealand, Sweden, and the U.K. and is expected to be completed this year.