Intellia Seeks to Advance Its Gene-editing Therapy to Human Trials

Marta Figueiredo PhD avatar

by Marta Figueiredo PhD |

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NTLA-2002 gene-editing therapy

Intellia Therapeutics is advancing clinical manufacturing activities to support its plans to file regulatory applications for first-in-human clinical trials of NTLA-2002, its experimental gene-editing therapy for hereditary angioedema (HAE).

The submissions are anticipated in the second half of the year, and the first trial is expected to evaluate the therapy’s safety, tolerability, and activity in people with HAE.

Besides NTLA-2002, Intellia is also advancing the development of two other gene-editing therapies: NTLA-2001 for transthyretin amyloidosis, a severe progressive disease, and NTLA-5001 for acute myeloid leukemia (AML), a type of blood cancer.

All three therapies are based on the CRISPR-Cas9 gene-editing tool, which allows researchers to edit parts of the genome by adding, removing, or changing specific sections of its DNA sequence. Of note, the genome is the complete set of DNA, including all of a person’s genes.

“Dosing our first patient with NTLA-2001, the first-ever systemically delivered CRISPR-based therapy, was a major milestone for our team, as we completed our transition to a clinical-stage company,” John Leonard, MD, Intellia’s president and CEO, said in a press release.

“Additionally, we are on track to submit first-in-human regulatory applications to begin clinical studies of NTLA-5001 for AML and NTLA-2002 for HAE, and we plan to nominate at least one new development candidate from our research portfolio,” Leonard added.

Administered directly into the bloodstream, NTLA-2002 was designed to completely remove the KLKB1 gene, which provides instructions for making the prekallikrein protein, from the genome of liver cells.

Prekallikrein is produced in the liver and converted in the blood into plasma kallikrein — a precursor of bradykinin, the inflammatory molecule produced in excess in HAE patients that leads to sudden swelling and pain attacks.

By eliminating the KLKB1 gene from liver cells, NTLA-2002 is designed to sustainably lower bradykinin levels down enough to prevent or reduce the frequency of HAE attacks. According to Intellia, the therapy also aims to eliminate the significant treatment burden associated with currently available HAE therapies.

The one-time investigational therapy is delivered specifically to liver cells through Intellia’s proprietary non-viral lipid nanoparticle platform, which involves microscopic spheres of fatty molecules that are stable in the bloodstream and can easily enter cells to deliver certain cargo.

The planned regulatory filings seeking permission to initiate first-in-human NTLA-2002 trials are supported by promising preclinical results showing that a single dose effectively reduced kallikrein levels in animal models.

Particularly, previous data highlighted that the therapy led to a 90% reduction in kallikrein activity in the blood — a therapeutically meaningful reduction expected to lessen HAE attacks — in non-human primates for at least 11 months.

Moreover, findings suggested that the gene editing is not lost as the liver undergoes normal cell-division processes.

The company recently shared new preclinical data about NTLA-2002 in a presentation, titled “NTLA-2002: CRISPR/Cas9-mediated gene knockout of KLKB1 to treat hereditary angioedema,” at the American Academy of Allergy, Asthma & Immunology 2021 Annual Meeting, held virtually Feb. 26–March 1.

Newly presented data showed that a single administration of NTLA-2002 resulted in robust KLKB1 elimination (in about 70% of cells) in a mouse model genetically modified to harbor the human KLKB1 gene and in non-human primates.

Treated mice also showed a greater-than-90% drop in plasma kallikrein levels and a reduction in vascular permeability, which is increased by bradykinin and plays a direct role in HAE attacks.

In monkeys, NTLA-2002 also led to reductions in both kallikrein levels and activity by more than 95%, which were sustained for at least 15 months.

“A single administration of NTLA-2002 resulted in robust, durable reduction of kallikrein protein and activity, supporting further development as a potential one-time treatment option for patients with HAE,” the researchers wrote in the abstract.

Intellia also noted that it is applying insights gained from the Phase 1 trial (NCT04601051) testing NTLA-2001 in people with the hereditary form of transthyretin amyloidosis to accelerate NTLA-2002’s clinical development for HAE.

“Intellia’s achievements in 2020 reflect important progress on both our full-spectrum strategy and our mission to deliver curative genome editing treatments for people with severe diseases,” Leonard said.