Second NTLA-2001 dose safely lowers TTR levels in FAP patients

Re-dosing was associated with a median 95% decline in 3 participants

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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A second, therapeutic dose of Intellia Therapeutics‘ experimental gene-editing therapy NTLA-2001 safely and effectively reduced levels of the harmful transthyretin (TTR) protein in people with familial amyloid polyneuropathy (FAP).

That’s according to data from the three FAP patients first treated with a suboptimal, low dose of NTLA-2001 who later received a therapeutic dose in an ongoing Phase 1 clinical trial (NCT04601051). While the low dose led to a median 52% reduction in circulating TTR, the second dose was associated with a median drop of 95%.

“We were committed to providing [FAP] patients who intentionally received a very low dose of NTLA-2001 in the dose-escalation portion of our Phase 1 study the opportunity to receive the selected therapeutic dose if they did not reach the target protein reduction level,” Intellia said in an email to FAP News Today.

The findings were shared by Jӧrg Tӓubel, MD, visiting professor at King’s College London, and CEO of Richmond Pharmacology in London, in an oral presentation at the Peripheral Nerve Society Annual Meeting last month in Montreal. The talk was titled “Activity of Follow-On Dosing for an Investigational In Vivo CRISPR-Based LNP Therapy in Transthyretin Amyloidosis.”

The data “showcase an exciting new platform advancement for Intellia and the field of gene editing. For the first time ever, we demonstrated that re-dosing with CRISPR, utilizing our proprietary, nonviral … delivery platform, enabled an additive pharmacodynamic effect on the target protein,” Intellia President and CEO John Leonard, MD, said in a company press release. Pharmacodynamics refers to a therapy’s effects on the body.

“While NTLA-2001 is designed to be a single-dose treatment for ATTR amyloidosis, the ability to re-dose using our LNP [lipid nanoparticle] delivery system is an exciting platform advancement for CRISPR gene editing as we pursue treatment of diseases that develop outside the liver, where incremental editing may be useful,” the company said in the email.

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Testing NTLA-2001

ATTR amyloidosis is an umbrella term for diseases that are caused by an abnormal form of the TTR protein building up to form toxic clumps in tissue.

FAP, also called hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN), is a form of ATTR amyloidosis marked mostly by nerve damage that’s caused by mutations in the TTR gene, which codes for the TTR protein. ATTR amyloidosis with cardiomyopathy (ATTR-CM) is a form of the disease where damage from toxic TTR mainly occurs in the heart. It may be caused by TTR mutations or occur spontaneously.

NTLA-2001 is a gene-editing therapy being co-developed by Intellia and Regeneron Pharmaceuticals for FAP and ATTR-CM. It uses lipid nanoparticles, or tiny fatty molecules, to deliver the gene-editing technology CRISPR-Cas9 to liver cells, the main producers of TTR, and stop the protein’s production. This should reduce the buildup of the toxic aggregates, ease disease symptoms, and slow disease progression.

The two-part Phase 1 trial is assessing the safety, pharmacological properties, and early signs of efficacy of NTLA-2001 in 36 adults with FAP and 36 adults with ATTR–CM, who were added to the study’s protocol in late 2021.

In the first part, the patients received a single infusion of NTLA-2001 at escalating doses — 0.1, 0.3, 0.7, and 1 mg/kg — and were followed for up to two years.

Previous data showed TTR levels were reduced after about one month in a dose-dependent manner and sustained until the end follow-up’s end. Clinically-meaningful TTR level reductions (by more than 80%) were observed with doses greater than 0.1 mg/kg and the highest dose tested led to a 93% decline.

Both the 0.7 mg/kg dose, which corresponds to a total dose of 55 mg, and the 1 mg/kg dose, which corresponds to an 80 mg dose, were selected as the optimal doses to test in the dose-expansion part, where new participants would receive them.

“Based on our Phase 1 study, the therapeutic dose led to consistent, deep and durable reductions of [blood] TTR protein levels after a single infusion,” Intellia told FAP News Today.

Given that the three patients (median age, 54) who received the lowest dose failed to reach target TTR levels, they were offered a second treatment infusion with the 0.7 mg/kg dose.

Data after eight to 12 months of follow-up after re-dosing showed the additional dose was well tolerated, without any new safety concerns. Fatigue, headache, nausea, and infusion-related reactions were reported as adverse effects.

While the first, suboptimal dose led to a median reduction of 52% in blood TTR levels relative to levels before treatment, the second, therapeutic dose led to a median drop of 95% after about a month.

“Safety and pharmacodynamics of the NTLA-2001 re-dosing were consistent with those observed after a single 55 mg dose,” the company stated in the release.

NTLA-2001, at a dose of 55 mg, is now being evaluated in ATTR-CM patients within a global Phase 3 clinical trial (NCT06128629). A similar Phase 3 study in FAP patients is being discussed for the end of the year.