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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. https://ir.intelliatx.com/news-releases/news-release-details/intellia-and-regeneron-announce-initial-data-cardiomyopathy-arm
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. https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-announces-positive-interim-clinical-data