Intellia prepping for pivotal trials of gene-editing therapy NTLA-2001

Studies will be supported by its first in-human study on FAP, ATTR-CM patients

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Intellia Therapeutics is planning to launch pivotal clinical trials of its gene-editing therapy NTLA-2001 in people with familial amyloid polyneuropathy (FAP) and ATTR amyloidosis with cardiomyopathy (ATTR-CM).

A pivotal trial is one where the data are expected to support an application for a therapy’s regulatory approval.

Intellia is actively preparing for a global Phase 3 trial in FAP patients through discussions with regulatory agencies. It also plans to submit an investigational new drug (IND) application with the U.S. Food and Drug Administration in the coming months to ask that U.S. trial sites be included in the global pivotal trial with ATTR-CM patients. Such a study would launch by the end of the year, pending discussions with regulatory bodies.

The pivotal trials will be supported by data from the first in-human study of the therapy, an ongoing Phase 1 trial (NCT04601051) that contains both FAP and ATTR-CM patient groups. Additional data from both groups are expected this year.

“We are working toward submitting our second [in-human] IND application and initiating a global pivotal trial for NTLA-2001,” John Leonard, MD, president and CEO of Intellia, said in a company press release. Leonard said the company is looking forward to sharing its findings from the interim data.

ATTR amyloidosis is an umbrella term that refers to diseases caused by the toxic buildup of clumps of an abnormal form of the transthyretin (TTR) protein in tissues.

FAP, also called hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN), is a form of ATTR amyloidosis marked mostly by nerve damage, whereas in ATTR-CM, damage from TTR mainly occurs in the heart.

NTLA-2001 works to disrupt the activity of the TTR gene responsible for producing TTR, thereby stopping the protein’s production and preventing its toxic accumulation. The one-time therapy specifically targets liver cells, where TTR is mainly produced.

NTLA-2001, which is being codeveloped by Intellia and Regeneron Pharmaceuticals, earned orphan drug status — which is aimed at accelerating a treatment’s development toward regulatory approval — in the U.S. and Europe in 2021.

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Results of  NTLA-2001 in Phase 1 trial

The two-part Phase 1 trial is exploring the therapy’s safety, pharmacological properties, and preliminary efficacy in up to 38 adults with FAP and 36 adults with ATTR-CM. All will be followed for up to two years.

In its first part, 15 FAP patients were given a single infusion of the therapy at one of four doses — 0.1, 0.3, 0.7, and 1 mg/kg. Interim efficacy data showed a single dose led to dose-dependent reductions in blood TTR levels after about a month.

Those reductions were sustained for at least six months and up to a year for some patients. In the highest dose group, the average reduction after six months was 93%.

The therapy was generally well tolerated. Common side effects included headache, back pain, rash, nausea, and infusion-related reactions.

In May 2022, dosing began in the second, dose-expansion part, wherein more FAP patients received a single infusion at the dose deemed best based on data from the first part. Enrollment in that phase was completed earlier this year.

The three patients who received the lowest dose of NTLA-2001 (0.1 mg/kg) in the first part are currently being given it at 55 mg — which was selected for the dose-expansion portion.

Additional findings are due to be presented this year.

A parallel study arm to evaluate NTLA-2001 in ATTR-CM patients was added to the Phase 1 trial in 2021. Interim data from the first part of that arm were presented at a scientific conference last year. Among 12 men with ATTR-CM, nine were given a dose of 0.7 mg/kg and three received the 1 mg/kg dose.

Similarly to findings in FAP patients, the therapy was generally well tolerated and resulted in significant reductions in blood TTR levels after a month that were sustained for at least four months and up to six months for some patients with available data.

Enrollment of ATTR-CM patients for the trial’s second, dose-expansion part was completed in December.

Additional results from these patients are expected this year, including longer-term safety data and exploratory efficacy outcomes.