CRISPR Gene Therapy Durably Reduces TTR in Patients With ATTR Amyloidosis


Altogether, there was a 91% reduction in median serum TTR at day 28.

A single dose of NTLA-2001 CRISPR/Cas9 gene therapy yielded consistent, deep and durable total serum TTR reductions in patients with transthyretin amyloidosis (ATTR amyloidosis) with follow-up up to 12 months.1

“With 65 patients reported from the Phase 1 study, this update represents the largest clinical dataset for an in vivo CRISPR-based investigational therapy. These positive interim results add to the growing body of data that demonstrates deep and durable reductions of serum TTR after a single dose of NTLA-2001,” John Leonard, MD, president and chief executive officer, Intellia, said in a statement.2

The NTLA-2001 phase 1 study in ATTR amyloidosis has completed enrollment (N=72). The trial has enrolled 36 patients with ATTR with cardiomyopathy (ATR-CM) and 36 with ATTR with polyneuropathy (ATTR-PN). The patients with PN had a median age of 61 years (range, 19-75) and the patients with CM had a median age of 78 years (range, 46-86). Overall, most were male (83%).

“In other systemic amyloidoses, the residual, absolute concentration of the amyloid precursor protein is closely associated with clinical outcomes,” Julian D. Gillmore, MBBS, MD, PhD, FRCP, professor, University College London, said, during his presentation at the 4th Annual ATTR Amyloidosis International Meeting, held November 2-3, 2023, in Madrid, Spain.1 “For treatments that reduce TTR, with nonfluctuating steady state measures, the residual absolute serum could be a robust biomarker of ATTR amyloidosis therapy outcomes. With collaboration, this approach to biomarker development has facilitated progress in care and better outcomes in AA and AL amyloidosis.”

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The dose escalation portion treated 15 patients with ATTR-PN with doses of 0.1 mg/kg (n = 3), 0.3/kg (n = 3), 0.7 mg/kg (n = 3), 1.0 mg/kg (n = 6); and 36 with ATTR-CM with doses of 0.7 mg/kg (n = 3 NYHA class I/II, 6 NYHA class III) and 1.0 mg/kg (n = 3). The dose expansion portion treated 21 patients with ATTR-PN with doses of 55 mg (n = 16) and 80 mg (n = 5); and 24 patients with ATTR-CM with a dose of 55 mg (12 patients with NYHA class I/II and 12 with NYHA class III).

Altogether, there was a 91% reduction (interquartile range [IQR], 88-94) in median serum TTR at day 28, for a residual absolute TTR concentration at day 28 of 17 µg/mL (range, 11-24). The maximum median change after day 28 was –1.4 µg/mL (IQR, -4.7 to 1.7).

“The consistent and profound levels of reduction in all patients bolster our confidence that NTLA-2001 could potentially reset the standard of care for ATTR amyloidosis — both for treating the disease and how response is evaluated,” Leonard said.“We have also observed early signals of clinical activity in the initial cohorts and look forward to presenting the first clinical data beyond serum TTR levels once we have longer follow-up across all cohorts."

NTLA-2001 was generally well-tolerated, with the most common adverse events (AEs) of infusion-related reactions, which were mostly mild and resolved without sequelae. AEs including atrial flutter and cardiac failure were found to be unrelated to the therapy and liver enzyme elevations resolved without steroid intervention or hospitalization.

“Interim data from 62 patients with ATTR amyloidosis treated with NTLA-2001 continue to show a favorable safety and tolerability profile, with rapid, consistent, and durable reductions of TTR to low levels in all patients,” Leonard said.1

1. Gillmore JD, Täubel J, Gane E, et al. Enabling the development of serum [TTR] as a biomarker for treatment of ATTR amyloidosis. Presented at: 4th Annual ATTR Amyloidosis International Meeting, November 2-3, 2023; Madrid, Spain.
2. Intellia presents new interim data from the ongoing phase 1 study of NTLA-2001 at the 4th International ATTR Amyloidosis Meeting. News release. Intellia Therapeutics. November 2, 2023.

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