Early Data Favorable for NTLA-2001 Gene-editing Therapy

A single dose of Intellia Therapeutics’ investigational CRISPR/Cas9-based gene-editing therapy NTLA-2001 safely results in a rapid and strong reduction in the levels of the damaging transthyretin (TTR) protein, according to interim data from the first six familial amyloid polyneuropathy (FAP) patients given the therapy in a Phase 1 clinical trial.

The clinical data provide the first evidence that CRISPR-Cas9 — a gene-editing system used by bacteria as a defense mechanism — can safely and effectively be used in humans to add, remove, or change specific sections of DNA.

These early findings, concerning the first two doses tested, were shared in an oral presentation at the 2021 Peripheral Nerve Society Annual Meeting, held virtually, June 12–13 and 25–27, and published in The New England Journal of Medicine. The study is titled “CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis.”

Based on these promising data, Intellia will evaluate whether a higher dose of NTLA-2001 can promote an even deeper TTR drop. The trial (NCT04601051) is currently recruiting patients for such analysis in London, U.K., and in Auckland, New Zealand.

Following the identification of a recommended dose of NTLA-2001 in this dose-escalation part, the study will move to its second part, which will test the optimal dose in a larger number of patients. Intellia is filing additional regulatory applications to support a planned global study expansion.

This second part of the study is anticipated to start later this year, a time when additional trial data are expected to be presented at a medical or scientific meeting.

After completion of the Phase 1 study, and should its data continue to be promising, the company plans to move to approval-enabling trials in people with both nerve and heart damage associated with transthyretin (ATTR) amyloidosis, a group of disorders that also includes FAP.

“As the first-ever systemically administered CRISPR therapy candidate, NTLA-2001 shows strong potential to stop the production and accumulation of the misfolded TTR protein by inactivating the TTR gene at the root of the disease,” Julian Gillmore, MD, PhD, the trial’s coordinating investigator in the U.K., said in a press release.

“This approach could deliver life-changing, lifelong benefits to patients with all forms of ATTR amyloidosis, who continue to experience debilitating symptoms and complications of disease while on the standard of care,” added Gillmore, who also is a professor of medicine at the Royal Free Hospital’s National Amyloidosis Centre, in London.

“While further investigation is needed, these results are highly encouraging,” supporting NTLA-2001 “as the only one-time treatment either on the market or in development” for ATTR, Gillmore said.

John Leonard, MD, Intellia’s president and CEO, also said these findings are “truly opening a new era of medicine,” as they are “the first ever clinical data suggesting that we can precisely edit target cells within the body to treat genetic disease with a single intravenous [into-the-vein] infusion of CRISPR.”

ATTR amyloidosis comprises a group of conditions in which the TTR protein forms toxic deposits that build up in different tissues and organs, causing nerve cell damage, and in many cases, heart failure.

FAP, the hereditary form of ATTR amyloidosis, is caused by mutations in the TTR gene, which provides instructions for making the TTR protein. Wild-type ATTR, an acquired age-related form of the disease, is more common and is not associated with any known genetic mutations.

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.

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

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

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

These findings prompted the launch of the two-part Phase 1 trial, which is evaluating NTLA-2001’s safety, tolerability, pharmacokinetics (movement into, through, and out of the body), and pharmacodynamics (effects on the body) in up to 38 adults, ages 18–80, with FAP.

Eligible participants either have no access to approved treatments, or their disease has continued to worsen despite standard treatment.

In the study’s first part, patients receive a single into-the-vein injection of one of four doses of NTLA-2001 to determine its optimal dose, which will be evaluated in a greater number of participants in its second, expansion part. All participants will be followed for up to two years.

Newly presented results concerned 28-day data from the first six FAP patients (four men and two women) given the therapy at the first two tested doses (0.1 and 0.3 mg/kg). Their ages ranged from 46 to 64 years.

Data showed that the gene-editing therapy was generally well-tolerated at both doses, with the few reported adverse events being mild in severity, and none being serious. No significant changes in liver function or blood-clotting problems were observed.

In addition, the therapy led to dose-dependent reductions in blood TTR levels, with a mean drop of 52% in the 0.1 mg/kg dose group (range, 47–56%) and of 87% in the 0.3 mg/kg dose group (range, 80–96%).

Given that FAP’s standard of care, which requires life-long treatment, typically yields TTR reductions of about 80%, these early findings suggest the 0.3 mg/kg dose may lead to clinically meaningful benefits and that even greater TTR drops may be achieved with higher doses.

Additional participants are already being recruited to receive a single injection of the next escalating dose of NTLA-2001 (1 mg/kg).

“The interim results support our belief that NTLA-2001 has the potential to halt and reverse the devastating complications of ATTR amyloidosis with a single dose,” Leonard said.

NTLA-2001 has received orphan drug designation from the European Commission for the treatment of ATTR, a status meant to accelerate the therapy’s development and regulatory review.

“Solving the challenge of targeted delivery of CRISPR/Cas9 to the liver, as we have with NTLA-2001, also unlocks the door to treating a wide array of other genetic diseases with our modular platform, and we intend to move quickly to advance and expand our pipeline,” Leonard said.