Clinical Update: CRISPR Therapy for Transthyretin Amyloidosis Results in Rapid and Prolonged Responses

Last summer (June 2021), Intellia Therapeutics and Regeneron shared clinical data from a Phase 1 trial that supported the safety and efficacy of NTLA-2001, a single-dose in vivo CRISPR-Cas9 therapy candidate for hereditary transthyretin (TTR) amyloidosis with polyneuropathy (ATTRv-PN).

Earlier this week, the companies announced updated data from this trial, which revealed rapid, deep and sustained responses in 15 patients.

NTLA-2001 is designed to reduce disease-causing protein TTR

NTLA-2001 is jointly developed by Intellia Therapeutics and Regeneron and was the first in vivo CRISPR therapy to be administered to humans via the bloodstream. It is designed to treat ATTR by selectively reducing the levels of mutated TTR protein in the blood, through CRISPR-based inactivation of the TTR gene in liver cells.

Previously released clinical data for the first six patients treated from cohorts in New Zealand and the UK revealed reductions TTR serum protein levels in the range of 52 % - 87 %, and no major safety concerns had presented as of Day 28 post-treatment. The companies disclosed in a press release at that time that enrolment was ongoing for a third cohort, who would receive a higher dose.

Updated data: a single dose of NTLA-2001 resulted in rapid and sustained reductions in serum TTR

The interim data released this week pertains to 15 patients with (ATTRv-PN) that were treated across four single-ascending dose cohorts. Three groups of three patients each received a single dose of NTLA-2001 at 0.1 mg/kg, 0.3 mg/kg, and 0.7 mg/kg, while the remaining six patients received a single dose of 1.0 mg/kg.

NTLA-2001 was adminstered intravenously and changes from baseline values of serum TTR were determined for each patient. Dose-dependant reductions in serum TTR were observed for all 15 patients with maximum reductions seen by Day 28 following treatment.

Mean reductions in serum TRR of 52%, 87%, and 86% were observed among the three patients in the 0.1 mg/kg, 0.3 mg/kg, and 0.7 mg/kg dose groups, respectively. A mean reduction of 93% was observed for the six patients in the 1.0 mg/kg cohort. Patient follow-up ranged from two to 12 months, and the reduction in TTR levels remained stable throughout the observation period. The companies report in their press release that NTLA-2001 was generally well-tolerated at all four dosing levels.

On track to initate polyneuropathy dose-expansion cohort

The U.S. FDA granted Orphan Drug Designation for NTLA-2001 for ATTR in October 2021, and Intellia Therapeutics since announced expansion of the Phase 1 trial to include adults with inherited transthyretin amyloidosis with cardiomyopathy (ATTRv-CM). In the latest press release, Intellia and Regeneron report that they are on track to initate the polyneuropathy dose-expansion cohrt in Q1 2022.

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