Intellia Nets Positive Data Across In Vivo CRISPR Therapies for ATTR Amyloidosis Cardiomyopathy, Angioedema


Administration of NTLA-2001 led to rapid and deep reductions in serum TTR by day 28.

Intellia has reported positive interim data from 2 ongoing clinical trials examining their in vivo CRISPR/Cas9 gene editing therapies, one for the treatment of transthyretin (ATTR) amyloidosis with cardiomyopathy and the other for hereditary angioedema (HAE).

Interim results from the phase 1 clinical trial of NTLA-2001, Intellia Therapeutics' and Regeneron Pharmaceuticals' investigational CRISPR/Cas9 gene editing therapy for the treatment of ATTR amyloidosis with cardiomyopathy demonstrate deep reductions in serum TTR over a 28-day period after patient's received the single-dose therapy.

Patients in the low-dose cohort (0.7 mg/kg; n=9) who had either Class I/II or Class III New York Heart Association (NYHA) heart failure saw a mean TTR serum reduction by day 28 of 93%, with a mean reduction of 92.5% in the high-dose cohort (1.0 mg/kg; NYHA Class I/II; n=3). These reductions were sustained through follow-up, which ranged from 2 to 6 months as of the July 1, 2022 data cutoff.

“Together with the previously reported data from the polyneuropathy arm of this landmark study, these results strongly suggest that NTLA-2001 could serve as a single-dose treatment regardless of disease manifestation. At these deep and consistent levels of protein reduction, we believe NTLA-2001 has the potential to halt and even reverse the underlying cause of ATTR amyloidosis," said John Leonard, MD, president and chief executive officer, Intellia, in a statement. "Given the similarly robust TTR reductions observed at the two doses tested, we have selected a fixed dose comparable to the 0.7 mg/kg level for evaluation across both arms in the ongoing dose-expansion portion of the study. We look forward to completing the Phase 1 study as we advance closer to a potential pivotal trial, which we expect will include patients in the US.”

In terms of adverse events (AEs), 2 of 12 patients treated reported transient infusion reactions, one of which was grade 3 and resolved without consequence. Notably, no significant liver findings were observed in patients in either dose level.

In the ongoing phase 1/2 clinical trial of NTLA-2002, Intellia's systemically administered CRISPR gene editing candidate, data from the ongoing dose escalation study demonstrated a dose dependent reduction in plasma kallikrein, the protein responsible for the overproduction of bradykinin which leads to debilitating swelling. Among 6 adult patients, single doses of 25 mg and 75 mg NTLA-2002 administered via intravenous infusion resulted in 65% and 92%, mean reductions in plasma kallikrein, respectively, with max reductions reached by week 8. Reductions were sustained through at least 16 weeks in the 25 mg cohort (n=3) and 8 weeks in the 75 mg cohort (n=3).

In addition, treatment with NTLA-2002 resulted in a mean reduction of HAE attacks of 91% in the 25 mg cohort through 16 weeks of observation, with 2 of 3 patients not having any HAE attacks since treatment and all 3 being HAE attack-free since week 10. Data for the 75 mg cohort is not yet available. Notably, 2 patients who were on prophylactic therapy prior to treatment have since had that they withdrawn with no HAE attacks.

“We are strongly encouraged by the greater than 90% reduction in HAE attacks observed in the 25 mg dose cohort, as these interim results support our belief that a single dose of NTLA-2002 has the potential to permanently prevent the debilitating swelling attacks associated with HAE," Leonard added.

The most frequent AEs were infusion-related reactions, most of which were grade 1, and no dose-limiting toxicities, serious AEs or AEs grade 3 or higher have been recorded, including no significant elevations of liver enzymes.

Based on these findings, Intellia introduced a third, 50-mg dose to the phase 1/2 study and will plan to include up to 2 doses for evaluation in the phase 2, placebo-controlled, dose-expansion study that is set to begin in early 2023.

1. Intellia and Regeneron Announce Initial Data from the Cardiomyopathy Arm of Ongoing Phase 1 Study of NTLA-2001, an Investigational CRISPR Therapy for the Treatment of Transthyretin (ATTR) Amyloidosis. News release. Intellia Therapeutics. September 16, 2022.
2. Intellia Therapeutics Announces Positive Interim Clinical Data for its Second Systemically Delivered Investigational CRISPR Candidate, NTLA-2002 for the Treatment of Hereditary Angioedema (HAE). News release. Intellia Therapeutics. September 16, 2022.
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