After Promising Early Data on Gene Editing, Intellia Will Launch ATTR Trial This Year

A single dose of NTLA-2001, Intellia Therapeutics’ investigational gene editing therapy for transthyretin amyloidosis (ATTR), results in a sustained reduction in the levels of the damaging transthyretin (TTR) protein for at least one year, according to preclinical data.

Based on these promising data in non-human primates, Intellia plans to launch a Phase 1 clinical trial testing the therapy in human ATTR patients, including those with familial amyloid polyneuropathy (FAP), by the end of 2020.

“As we prepare to enter the clinic with NTLA-2001, our first systemic treatment, we are extremely encouraged by the durability” of the therapy’s effects, Laura Sepp-Lorenzino, PhD, Intellia’s chief scientific officer, said in a press release.

The findings “further support our technology’s ability to develop potentially curative single-course therapies, and provide clear differentiation from chronic treatments and traditional [viral-based] gene therapy,” Sepp-Lorenzino added.

The results of the company’s research were presented recently by Anthony Forget, PhD, Intellia’s senior director of genome editing, at the 16^th Annual Meeting of the Oligonucleotide Therapeutics Society, which was held virtually. The presentation was titled “A Modular CRISPR/Cas9 Genome Editing Platform for Durable Therapeutic Knockout and Targeted Gene Insertion Applications.”

FAP, the hereditary form of ATTR, is caused by mutations in the TTR gene, which contains the instructions to produce the TTR protein. In turn, the aging-related form of the disease, which is also known as wild-type ATTR and accounts for most cases of the disorder, is not associated with any known mutations.

In ATTR patients, the TTR protein is or becomes unstable, leading to the formation and build-up of toxic protein clumps in several tissues that impairs their normal function.

Since the liver is the main source of TTR, a liver transplant — using a complete or partial healthy liver from a donor — was the mainstay treatment for FAP. Such transplants prevent the production of a defective TTR protein, ultimately slowing disease progression.

More recently, two disease-modifying therapies — Onpattro (patisiran) and Tegsedi (inotersen) — were approved as a treatment for FAP. Both work by binding to and blocking an intermediate molecule generated from the TTR gene and used to guide TTR protein production; these therapies lower the levels of toxic TTR.

However, they require frequent administration throughout life.

Now, Intellia presented preclinical data from its lead experimental candidate: the one-time, gene-editing therapy NTLA-2001, which uses CRISPR/Cas9 technology. Originally identified in bacteria as a defense mechanism, the CRISPR/Cas9 system allows researchers to edit parts of the genome by adding, removing, or changing specific sections of DNA.

The therapy is part of a co-development/co-promotion agreement between Intellia, the lead development and commercialization party, and Regeneron Pharmaceuticals.

It was designed to permanently inactivate the TTR gene in the liver by targeting and removing it from the genome of liver cells — a strategy known as knockout editing.

Based on Intellia’s proprietary CRISPR/Cas9 modular approach, the therapy delivers the CRISPR/Cas9 system to target cells through a non-viral, lipid nanoparticle delivery system.

By preventing the production of the TTR protein, the therapy is expected to halt or delay nerve cell and heart damage in hereditary and wild-type ATTR, with a single administration.

Newly presented, one-year data from non-human primates showed that a single intravenous (into-the vein) administration of NTLA-2001 resulted in a sustained, greater than 95% drop in TTR blood levels, which was considered therapeutically relevant.

These findings highlighted the therapy’s sustained knockout editing and TTR-level reduction through regular liver cell turnover (division into two identical cells) for one year.

Further studies in mice revealed that NTLA-2001’s effects were maintained even at a higher cell turnover rate, when the liver is regenerated following partial liver removal, supporting the therapy’s potential lifelong benefits.

In August, Intellia submitted its first clinical trial application (CTA) to the U.K.’s Medicines and Healthcare products Regulatory Agency to initiate a Phase 1 study of NTLA-2001 for the treatment of ATTR. The company is submitting additional regulatory applications to enable patient enrollment in other countries as part of its global clinical development plans.

Pending CTA authorization and subject to the impact of COVID-19, Intellia expects to dose the first ATTR patient by year-end with NTLA-2001, which will likely be the first into-the-vein CRISPR/Cas9-based therapy to enter clinical trials.

The trial will evaluate the safety and tolerability of ascending doses of NTLA-2001 in people with ATTR. The treatment’s pharmacokinetics — the movement of the drug into, through, and out of the body — and its pharmacodynamics, or its effects on the body, also will be assessed.

The first group of participants will receive a predefined therapy dose, after which researchers will decide if a higher dose should be tested in the next group of patients.

Intellia’s CRISPR/Cas9 modular platform also allows rapid development of other liver-targeted gene-editing therapies.

“Our modular delivery platform is enabling us to rapidly advance multiple product candidates in parallel — and to ensure that the therapeutic impact will be long-lasting for patients in need,” Sepp-Lorenzino said.

The company also is currently applying it to develop a knockout therapy for hereditary angioedema and a gene insertion therapy for hemophilia type A and B.