Intellia and Regeneron Report Positive Updated Phase 1 Data from Study of In Vivo Gene Editing Therapy for ATTR Amyloidosis

Intellia Therapeutics and Regeneron Pharmaceuticals reported 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 amyloidosis, a rare and fatal liver disease.

Photo: Intellia president and CEO John Leonard

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 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 percent in the lowest dose cohort, 87 percent in the second lowest dose cohort, and 86 percent among the three patients in the third lowest dose cohort, and 93 percent among the six patients in the highest dose group.

Transthyretin (ATTR) amyloidosis is a progressive disease. Hereditary ATTR (ATTRv) amyloidosis occurs when a person is born with mutations in the TTR gene, which causes the liver to produce structurally abnormal transthyretin (TTR) protein with a propensity to misfold. These damaged proteins build up as amyloid in the body, causing serious complications in multiple tissues, including the heart, nerves, and digestive system. ATTRv amyloidosis predominantly manifests as polyneuropathy (ATTRv-PN), which can lead to nerve damage, or cardiomyopathy (ATTRv-CM), which can lead to heart failure. Some individuals without the genetic mutation produce non-mutated, or wild-type TTR proteins that become unstable over time, misfolding and aggregating in disease-causing amyloid deposits. This condition, called wild-type ATTR (ATTRwt) amyloidosis, primarily affects the heart. There are an estimated 50,000 people worldwide living with ATTRv amyloidosis and between 200,000 and 500,000 people with ATTRwt amyloidosis.

NTLA-2001 is the first CRISPR/Cas9-based therapy candidate to be administered systemically for precision editing of a gene in humans. Intellia’s proprietary non-viral platform deploys lipid nanoparticles to deliver to the liver a two-part genome editing system: guide RNA specific to the disease-causing gene and messenger RNA that encodes the Cas9 enzyme, which carries out the precision editing.

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.

Robust preclinical data, showing deep and long-lasting transthyretin (TTR) reduction following in vivo inactivation of the target gene, supports NTLA-2001’s potential as a single-administration therapeutic. Intellia leads development and commercialization of NTLA-2001 as part of a multi-target discovery, development, and commercialization collaboration with Regeneron. The global phase 1 trial is an open-label, multi-center, two-part study of NTLA-2001 in adults with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) or transthyretin amyloidosis with cardiomyopathy (ATTR-CM).

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 (the lowest dose). At the 1.0 mg/kg dose level (the highest dose), all six patients achieved greater than 80 percent reduction and four of six patients achieved greater than 90 percent 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,” said Intellia president and CEO John Leonard. “Data from the ongoing, first-in-human study of NTLA-2001 demonstrated rapid, deep and durable reduction of serum TTR protein.”

At all four dose levels, NTLA-2001 was generally well tolerated. The majority of adverse events were mild in severity with 73 percent 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 highest dose group.

The phase 1 study 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.

Author: Rare Daily Staff