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Intellia and Regeneron Report Updated Data of Experimental In Vivo Gene Editing Therapy for ATTR Amyloidosis Shows Durability

June 27, 2022

Rare Daily Staff

Intellia Therapeutics and Regeneron Pharmaceuticals said additional positive interim data from an ongoing phase 1 study of their lead investigational in vivo genome editing candidate, NTLA-2001, which is being developed as a single-dose treatment for transthyretin amyloidosis, showed sustained durability.

Transthyretin amyloidosis, or ATTR amyloidosis, is a rare, progressive, and fatal 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.

NTLA-2001 could potentially be the first single-dose treatment for ATTR amyloidosis. NTLA-2001 is the first investigational CRISPR therapy candidate to be administered systemically, or through a vein, to edit genes inside the human body. 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. 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).

In an oral presentation at the European Association for the Study of the Liver (EASL) International Liver Congress, researchers included extended follow-up data from 15 patients with hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN) treated across four single-ascending dose cohorts in Part 1 of the study. Results demonstrated sustained durability of serum transthyretin (TTR) reduction through the last measured time point in the ongoing observation.

The companies said these data support NTLA-2001’s continued development as a potential one-time treatment to permanently inactivate the TTR gene and reduce the disease-causing protein. At the highest dose evaluated, treatment with NTLA-2001 at 1.0 mg/kg resulted in a 93 percent mean and 98 percent maximum serum TTR reduction by day 28 across the six patients treated.

With longer-term follow-up data now available, these deep reductions continue to be sustained through six months, with an observed mean reduction of 93 percent. Additionally, three patients in the 1.0 mg/kg cohort have reached nine months in the follow-up period with no evidence of a loss in TTR reduction after a single dose. In the 0.7 mg/kg dose cohort, the 86 percent mean serum TTR reduction observed at day 28 also remained durable through six months. Further, in the 0.1 and 0.3 mg/kg cohorts, patients have now reached 12 months of follow-up, and a durable response to treatment continues to be observed. Notably, patients in the 0.3 mg/kg cohort sustained an 89 percent mean serum TTR reduction at 12 months.

At all four dose levels, NTLA-2001 was generally well tolerated through the follow-up period (median follow-up of 10 months). The majority of adverse events were mild in severity with 73 percent of patients reporting a maximal adverse event severity of Grade 1. There was a single possibly 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. The most frequent adverse events included headache, infusion-related reactions, back pain, rash, and nausea. All infusion-related reactions were considered mild, resolving without clinical sequelae.

The safety and activity profile of NTLA-2001 observed in Part 1 indicates that NTLA-2001 has a favorable therapeutic window. These data combined with pharmacokinetic modeling and simulation data support the utilization of a fixed dose of 80 mg in Part 2, which is anticipated to yield similar exposures to the 1.0 mg/kg dose. Dosing is ongoing in Part 2, the single-dose expansion cohort of the polyneuropathy arm.

“Based on the interim data shared today, we believe NTLA-2001’s potential to be a transformational treatment for patients with ATTR amyloidosis is becoming clearer. The safety, depth of serum TTR reduction and durability profile demonstrated thus far highlights its potential for halting and reversing the disease after a single dose,” said Intellia President and CEO John Leonard. “These data further underscore the power of genomic medicines and bolster the probability of success across our broader in vivo genome editing platform.”

Photo: Intellia President and CEO John Leonard

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