Experimental Gene-editing Therapy NTLA-2001 Safe, Effective, Early Trial Data Shows

Marta Figueiredo PhD avatar

by Marta Figueiredo PhD |

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A single dose of NTLA-2001, Intellia Therapeutics’ investigational gene-editing therapy, safely and effectively leads to rapid and sustained reductions in the levels of the damaging transthyretin (TTR) protein in people with familial amyloid polyneuropathy (FAP), according to interim data from a Phase 1 trial.

Notably, maximum TTR reductions were observed after about one month, and in a dose-dependent manner, with the highest dose tested (1 mg/kg) resulting in a 93% drop in TTR levels.

Based on findings recently detailed in the company’s webcast, Intellia anticipates launching the second part of the trial in the second quarter of this year. In this part, the potential optimal fixed dose of the therapy will be tested in a larger number of FAP patients, pending feedback from regulatory agencies.

“Data from the ongoing, first-in-human study of NTLA-2001 demonstrated rapid, deep and durable reduction of [blood] TTR protein,” John Leonard, MD, Intellia’s president and CEO, said in a press release. “We believe this deep and consistent reduction shows promise for halting and even reversing disease progression in people with ATTR amyloidosis.”

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ATTR amyloidosis comprises a group of conditions in which the TTR protein forms toxic deposits that build up in different tissues and organs. FAP is a hereditary form of ATTR amyloidosis characterized by progressive polyneuropathy, or damage to peripheral nerves — those found outside the brain and spinal cord — and variable involvement of other organs, such as the heart. It is caused by mutations in the TTR gene, which provides instructions for making the TTR protein.

Co-developed by Regeneron Pharmaceuticals, NTLA-2001 uses the power of the CRISPR-Cas9 gene-editing system to completely remove the TTR gene from patients’ liver cells, the main producers of TTR, thereby lowering the protein’s levels.

Adapted from a natural defense mechanism of bacteria, CRISPR-Cas9 allows researchers to add, remove, or change specific sections of a person’s DNA.

Administered directly into the bloodstream, NTLA-2001 uses microscopic spheres of fatty molecules that are stable in the bloodstream and can easily enter cells to deliver the CRISPR-Cas9 machinery specifically to liver cells.

By preventing TTR production, a single dose of the therapy is expected to halt or delay nerve cell and heart damage in all forms of ATTR amyloidosis.

Previous studies in nonhuman primates showed that a single dose of NTLA-2001 was able to reduce TTR levels by more than 95% and keep them low for at least one year.

The therapy received orphan drug designation in the U.S. and Europe, which is meant to accelerate its clinical development and regulatory review.

The two-part Phase 1 trial (NCT04601051) is evaluating NTLA-2001’s safety, tolerability, pharmacokinetics, and pharmacodynamics in up to 38 adults with FAP and 36 adults with ATTR amyloidosis with cardiomyopathy (ATTR-CM), or heart disease. The group of ATTR-CM patients was added to the study’s protocol in late 2021.

Pharmacokinetics refers to the therapy’s movement into, through, and out of the body, while pharmacodynamics comprises its effects on the body. Patients are currently being recruited at sites in New Zealand, Sweden, and the U.K.

In the trial’s first part, participants of both groups will receive a single infusion of one of several doses of NTLA-2001 to determine its optimal dose, which will be evaluated in more participants in its second expansion part. All participants will be followed for up to two years.

Newly presented data concerned the 15 FAP patients (nine men and six women) given the therapy — at four different doses (0.1, 0.3, 0.7, and 1 mg/kg) — in Part 1. Their median age was 55, and they were followed for at least two months and up to one year.

Results showed that NTLA-2001 led to dose-dependent reductions in blood TTR levels, ranging from 52% in the lowest dose group to 93% in the highest dose group after 28 days (nearly one month).

Notably, TTR level drops greater than 80% (considered clinically meaningful) were observed with doses greater than 0.1 mg/kg at 28 days and at the last follow-up visit (up to nine months), with no major changes in TTR levels over time.

By day 28, all six patients in the highest dose group (1 mg/kg) had achieved greater than 80% reduction in TTR levels, with four attaining a greater than 90% drop. Such reductions were sustained through the last visit for all six patients, ranging from two to six months.

NTLA-2001 was generally well-tolerated across all dose levels, with most adverse events being mild in severity. A treatment-related severe adverse event of vomiting was reported in a patient given the highest dose of the therapy, who had been previously diagnosed with delayed stomach emptying.

The most commonly reported adverse events included headache, infusion-related reactions, back pain, rash, and nausea. No clinically significant laboratory findings were observed and the maximally tolerated dose was not reached.

Based on these findings, a fixed dose of 80 mg — expected to deliver a similar exposure to 1 mg/kg — has been selected for evaluation in the trial’s second expansion part.

Intellia plans to continue enrolling ATTR-CM patients, who are receiving either 0.7 or 1 mg/kg of NTLA-2001 in the trial’s first part to determine the best dose for testing in Part 2.

The company expects to complete recruitment of patients for both groups this year, as well as to present additional trial data at a future medical meeting. Intellia also plans to discuss the design of a potential pivotal trial with regulatory agencies, including the U.S. Food and Drug Administration, that would potentially support a future filing for approval.

This data update “reinforces Intellia’s progress in opening a new era of medicine,” as it suggests that “treatment with a one-time, systemically delivered CRISPR-based investigational therapy has the potential to substantially reduce levels of a disease-causing protein,” Leonard said.

“Our Intellia collaboration continues to move the tremendous promise of genetics-based medicines closer to reality,” said George D. Yancopoulos, MD, PhD, Regeneron’s president and chief scientific officer.

According to Yancopoulos, these results “provide further insights from the first pioneering clinical trial in which CRISPR-based technology has been used to precisely edit a disease-causing gene in humans, and the durability results support the notion that this approach could one day be deployed for long-lasting benefit.”

Intellia, alone or in collaboration with Regeneron, is also advancing the development of potential CRISPR/Cas9-based therapies for inflammatory, bleeding, lung, and liver conditions associated with genetic defects.