Intellia Reports Positive Clinical Proof-of-Concept for Redosing CRISPR-based Therapy

Rare Daily Staff

Intellia Therapeutics presented new data demonstrating, for the first time, the potential for redosing with an experimental in vivo CRISPR/Cas9 genome editing therapy.

The data from the ongoing phase 1 study of NTLA-2001, a single-dose treatment in development for transthyretin (ATTR) amyloidosis, were presented at the Peripheral Nerve Society Annual Meeting in Montreal, Canada.

“For the first time ever, we demonstrated that redosing with CRISPR, utilizing our proprietary, non-viral LNP-based delivery platform, enabled an additive pharmacodynamic effect on the target protein,” said John Leonard, president and CEO of Intellia. “While redosing is not planned for the NTLA-2001 program for the treatment of transthyretin amyloidosis, part of our commitment to patients enrolled in the dose-escalation portion of the phase 1 study was to provide them with the opportunity to receive the therapeutic dose selected if they did not reach the target protein reduction level. These data provide platform proof-of-concept that we can re-dose, if necessary, enabling us to pursue treatment of other diseases where patients might need more than one dose to reach the desired therapeutic effect.”

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. There are an estimated 50,000 people worldwide living with ATTRv amyloidosis and between 200,000 and 500,000 people with ATTRwt amyloidosis. There is no known cure for ATTR amyloidosis and currently available medications are limited to slowing accumulation of misfolded TTR protein.

NTLA-2001 is designed to inactivate the TTR gene that encodes for the transthyretin (TTR) protein. NTLA-2001 is the first investigational CRISPR therapy to be administered systemically to edit genes inside the human body. Interim Phase 1 clinical data showed the administration of NTLA-2001 led to consistent, deep and long-lasting TTR reduction. Intellia leads development and commercialization of NTLA-2001 as part of a multi-target discovery, development and commercialization collaboration with Regeneron.

NTLA-2001 is currently being evaluated in patients with either ATTR amyloidosis with cardiomyopathy (ATTR-CM) or hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN). Development and commercialization of NTLA-2001 is led by Intellia as part of a multi-target collaboration with Regeneron. Data from the phase 1 trial has demonstrated that a one-time 55 mg dose of NTLA-2001 led to consistent, deep and durable reduction of serum TTR protein levels. This 55 mg dose was selected for further evaluation in the actively enrolling phase 3 MAGNITUDE trial for ATTR-CM and the planned phase 3 trial for ATTRv-PN.

In the phase 1 trial, the three initial patients enrolled in the dose-escalation portion received a 0.1 mg/kg dose of NTLA-2001, which led to a 52 percent median reduction in serum TTR by day 28. As expected, the 0.1 mg/kg dose resulted in lower-than-targeted serum TTR reduction. These patients were offered the opportunity to receive a follow-on dose of NTLA-2001 at the completion of the protocol-specified two years of observation. All three patients subsequently received a 55 mg dose, which led to the target pharmacodynamic effect and a 90 percent median reduction in serum TTR by day 28. The corresponding reduction from original baseline levels was a 95 percent median reduction in serum TTR. NTLA-2001 was generally well tolerated across all patients after receiving the follow-on dose. One of the three patients experienced a mild infusion-related reaction with the 55 mg dose. Safety and pharmacodynamics of the NTLA-2001 redosing were consistent with those observed after a single 55 mg dose. Further, favorable safety and tolerability continues to be observed, with patient follow-up beyond three years for the earliest dosed patient.

The ability to re-dose is a key advantage of Intellia’s non-viral, lipid nanoparticle (LNP)-based delivery platform. These results are the first-ever clinical data demonstrating redosing with a CRISPR-based medicine, enabling the potential treatment of diseases where a target additive pharmacodynamic effect is desired.

Photo: John Leonard, president and CEO of Intellia