Intellia Reports Positive Data on Redosing CRISPR Therapy with LNP Platform

Intellia Therapeutics has unveiled new data showcasing the potential for redosing with an investigational CRISPR/Cas9 genome editing therapy, NTLA-2001. This advancement was presented at the Peripheral Nerve Society Annual Meeting in Montreal, Canada. The data from the ongoing Phase 1 study of NTLA-2001, a single-dose treatment for transthyretin (ATTR) amyloidosis, marks a significant milestone in the gene editing field.

The company’s President and CEO, John Leonard, M.D., highlighted that this is the first time redosing with CRISPR, using Intellia’s proprietary non-viral lipid nanoparticle (LNP)-based delivery platform, has demonstrated an additive pharmacodynamic effect on the target protein. Leonard emphasized that while redosing is not currently planned for the NTLA-2001 program for transthyretin amyloidosis, patients enrolled in the Phase 1 study had the opportunity to receive a therapeutic dose if they did not achieve the target protein reduction. This proof-of-concept data suggests that redosing could be a viable approach for treating other diseases that may require multiple doses to achieve the desired therapeutic outcome.

NTLA-2001 is being tested in patients with either ATTR amyloidosis with cardiomyopathy (ATTR-CM) or hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN). Intellia is leading the development and commercialization of NTLA-2001 in partnership with Regeneron. The Phase 1 trial data showed that a one-time 55 mg dose of NTLA-2001 resulted in a consistent, deep, and durable reduction of serum TTR protein levels. This 55 mg dose has been selected for further evaluation in the ongoing Phase 3 MAGNITUDE trial for ATTR-CM and the planned Phase 3 trial for ATTRv-PN.

During the Phase 1 trial, the initial patients received a 0.1 mg/kg dose of NTLA-2001, leading to a 52% median reduction in serum TTR by day 28. This dose was lower than the targeted reduction. These patients were later offered a follow-on dose of 55 mg after two years of observation. The follow-on dose resulted in a 90% median reduction in serum TTR by day 28, with a corresponding 95% median reduction from original baseline levels. The follow-on dose was well tolerated, with one patient experiencing a mild infusion-related reaction. Safety and pharmacodynamics of the redosing were consistent with observations from the single 55 mg dose. Continued favorable safety and tolerability has been observed, with patient follow-up extending beyond three years for the earliest dosed patient.

The ability to re-dose is a significant advantage of Intellia’s non-viral LNP-based delivery platform, marking the first clinical demonstration of redosing with a CRISPR-based therapy. This capability opens up the potential for treating diseases where an additive pharmacodynamic effect is needed.

NTLA-2001, leveraging Nobel Prize-winning CRISPR/Cas9 technology, has the potential to be the first one-time treatment for ATTR amyloidosis. The therapy is designed to inactivate the TTR gene responsible for producing the transthyretin (TTR) protein. Interim Phase 1 data indicated that NTLA-2001 led to substantial and enduring TTR reduction. Intellia, in collaboration with Regeneron, is spearheading the development and commercialization of NTLA-2001.

Transthyretin amyloidosis (ATTR amyloidosis) is a severe, progressive, and often fatal condition. Hereditary ATTR amyloidosis (ATTRv) occurs due to genetic mutations causing the liver to produce abnormal TTR proteins, leading to amyloid deposits in various tissues. This disease can manifest as polyneuropathy (ATTRv-PN) or cardiomyopathy (ATTRv-CM). Wild-type ATTR amyloidosis (ATTRwt) affects individuals without genetic mutations, primarily impacting the heart. ATTR amyloidosis has no known cure, and current treatments only slow the accumulation of misfolded TTR protein.

Intellia Therapeutics aims to revolutionize medicine with CRISPR-based therapies, focusing on editing disease-causing genes within the human body for various conditions, including cancer and autoimmune diseases. The company's extensive experience and innovative platform continue to set new standards in gene editing.