Intellia Therapeutics, Inc. (NASDAQ: NTLA) and Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) today announced positive interim data from an ongoing Phase 1 clinical study of their lead in vivo genome editing candidate, NTLA-2001, which is being developed as a single-dose treatment for transthyretin (ATTR) amyloidosis. The interim data released today include 15 hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN) patients treated across four single-ascending dose cohorts. Single doses of 0.1 mg/kg, 0.3 mg/kg, 0.7 mg/kg, and 1.0 mg/kg of NTLA-2001 were administered via intravenous infusion and changes from baseline values of serum transthyretin (TTR) protein were measured for each patient. Treatment with NTLA-2001 led to dose-dependent reductions in serum TTR and achieved maximal reductions by day 28, with mean reductions of 52%, 87%, and 86% among the three patients each in the 0.1 mg/kg, 0.3 mg/kg, and 0.7 mg/kg dose groups, respectively, and 93% among the six patients in the 1.0 mg/kg dose group.

Mean serum TTR reduction remained durable through the observation period, with patient follow-up ranging from two to 12 months. Additionally, the serum TTR reduction observed was consistent across all patients receiving doses at or greater than 0.3 mg/kg. At the 1.0 mg/kg dose level, all six patients achieved greater than 80% reduction and four of six patients achieved greater than 90% reduction by day 28. Further, the reduction in serum TTR observed at day 28 was sustained through the last measured timepoint for each of the six patients, which ranged from two to six months.

"Today's update reinforces Intellia's progress in opening a new era of medicine. These data suggest that treatment with a one-time, systemically delivered CRISPR-based investigational therapy has the potential to substantially reduce levels of a disease-causing protein. Data from the ongoing, first-in-human study of NTLA-2001 demonstrated rapid, deep and durable reduction of serum TTR protein. At 1.0 mg/kg, the highest dose level studied, patients with polyneuropathy reached a 93% mean serum TTR reduction by day 28. We believe this deep and consistent reduction shows promise for halting and even reversing disease progression in people with ATTR amyloidosis," said Intellia President and Chief Executive Officer John Leonard, M.D. "The NTLA-2001 proof-of-concept further validates our CRISPR technology platform and also supports the continued development of our genome editing approaches for a variety of diseases. Based on the safety and activity data generated to date, we believe we have increased the probability of success for our broader pipeline. Intellia looks forward to advancing our second in vivo clinical candidate, NTLA-2002, for the treatment of hereditary angioedema and additional in vivo candidates in 2022 in our pursuit of harnessing the full potential of genomic medicines."

NTLA-2001 is the first CRISPR/Cas9-based therapy candidate to be administered systemically for precision editing of a gene in humans. It is designed to inactivate the TTR gene in liver cells to reduce the production of misfolded TTR protein, which accumulates in tissues throughout the body and causes the debilitating and often fatal complications of ATTR amyloidosis.

"Our Intellia collaboration continues to move the tremendous promise of genetics-based medicines closer to reality. Today's data provide further insights from the first pioneering clinical trial in which CRISPR-based technology has been used to precisely edit a disease-causing gene in humans, and the durability results support the notion that this approach could one day be deployed for long-lasting benefit," said George D. Yancopoulos, M.D., Ph.D., President and Chief Scientific Officer of Regeneron. "Regeneron has always thrived at the intersection of biology and technology. We continue to expand both our research efforts through the Regeneron Genetics Center and our toolkit of cutting-edge technologies for genetics-based therapeutics, many of which are being developed in collaboration with Intellia. Genetics medicine holds enormous potential to treat, and potentially even cure, many life-threatening diseases, and we look forward to advancing this next chapter of medicine."

At all four dose levels, NTLA-2001 was generally well tolerated. The majority of adverse events were mild in severity with 73% (n = 11) of patients reporting a maximal adverse event severity of Grade 1. The most frequent adverse events included headache, infusion-related reactions, back pain, rash, and nausea. There were no clinically significant liver findings observed. There was a single related serious adverse event of vomiting (Grade 3) reported in a patient with concomitant medical history of gastroparesis in the 1.0 mg/kg dose group. Per the study protocol, the 1.0 mg/kg dose group was subsequently expanded from three to six patients to further characterize safety at this dose level. No additional patients in the 1.0 mg/kg dose group reported a Grade 2 or higher related adverse event. In addition, there was a single unrelated serious adverse event of COVID-19 pneumonia reported in the 0.7 mg/kg dose group.

The Phase 1 study, run by Intellia as the program's development and commercialization lead, is evaluating NTLA-2001 in patients with ATTRv-PN and ATTR amyloidosis with cardiomyopathy (ATTR-CM). Part 2 of the Phase 1 study will be a single-dose ATTRv-PN expansion cohort expected to begin in the first quarter of 2022. A fixed dose of 80 mg, which is expected to deliver a similar exposure to the 1.0 mg/kg dose, was selected for evaluation in Part 2 pending regulatory feedback. The transition from weight-based dosing to fixed dosing is based on the safety, tolerability, pharmacokinetic and activity profile of NTLA-2001 observed in Part 1 of the polyneuropathy arm. Patients also continue to be dosed with NTLA-2001 in Part 1 of the cardiomyopathy arm at the 0.7 mg/kg dose level, with plans to dose escalate to 1.0 mg/kg.

Intellia expects to complete enrollment of the Phase 1 study for both ATTRv-PN and ATTR-CM subjects in 2022 and present additional data at a medical meeting later this year. Intellia and Regeneron plan to move towards pivotal studies for both forms of ATTR amyloidosis, with an initial focus on the cardiomyopathy manifestations of the disease.

"In this Phase 1 study, NTLA-2001 was generally well tolerated as a single-dose treatment for ATTR amyloidosis patients with polyneuropathy, resulting in deep and durable reductions of serum TTR. These observations are consistent with animal data indicating potential life-long serum TTR suppression," said Ed Gane, M.D., Professor of Medicine at the University of Auckland, New Zealand and Chief Hepatologist, Transplant Physician and Deputy Director of the New Zealand Liver Transplant Unit at Auckland City Hospital, and study investigator. "Importantly, these early results suggest NTLA-2001 has the potential to deliver profound benefits for patients around the world."

Reference

https://investor.regeneron.com/news-releases/news-release-details/intellia-and-regeneron-announce-updated-phase-1-data