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Investigational CRISPR Therapy Shows Efficacy Against Transthyretin Amyloidosis in Phase I Study

NEW YORK – Researchers at University College London, the University of Auckland, Intellia Therapeutics, Regeneron Pharmaceuticals, and elsewhere reported positive interim data from an ongoing Phase I clinical study of Intellia and Regeneron's lead in vivo genome editing candidate, NTLA-2001, which is being developed as a single-dose treatment for transthyretin amyloidosis, or ATTR.

In a paper published on Friday in the New England Journal of Medicine, the researchers noted that ATTR amyloidosis is a life-threatening disease characterized by progressive accumulation of misfolded transthyretin, or TTR, protein, predominantly in the nerves and heart. NTLA-2001 — which comprises a lipid nanoparticle encapsulating messenger RNA for Cas9 and a single-guide RNA targeting TTR — is designed to reduce the concentration of TTR in serum.

Circulating TTR is produced almost entirely within the liver, for which established targeting systems such as lipid nanoparticles are available, the researchers said. NTLA-2001 is administered by intravenous infusion and is intended to edit TTR in hepatocytes, leading to a decrease in the production of both wild-type and mutant TTR after a single administration.

Preclinical studies had shown durable knockout of TTR after a single dose of the therapy. For the Phase I trial, the researchers evaluated the safety and pharmacodynamic effects of single escalating doses of NTLA-2001 in six patients with hereditary ATTR amyloidosis with polyneuropathy. The patients were split into two groups of three, with each group receiving a different dose of the therapy.

After 28 days, the mean reduction from baseline in serum TTR protein concentration was 52 percent in the patients who received a dose of 0.1 mg per kilogram, ranging from 47 percent to 56 percent. The mean reduction was 87 percent in the patients who received a dose of 0.3 mg per kilogram, ranging from 80 percent to 96 percent, the researchers reported. They also noted that the patients had few adverse events, and those that did occur were mild.

The researchers also conducted off-target editing assays to determine the possibility of detrimental off-target effects and found that all the potential off-target loci that were identified were located in noncoding regions. Further, they found no evidence of off-target editing for each of these sites when they treated primary human hepatocytes with concentrations of NTLA-2001 up to three times as high as concentrations of the therapy that achieved greater than 90 percent reduction in TTR protein.

They also noted that studies in transgenic mice revealed a dose-dependent and durable effect of NTLA-2001. Editing of TTR reduced circulating serum TTR protein levels, which reached a low point by four weeks after dosing and were still maximally suppressed at 12 months of observation. After the mice had two-thirds of their livers resected and subsequently regenerated, the gene-editing percentage and corresponding protein levels were unchanged, supporting the theory that the edits are permanent.

"These are the first ever clinical data suggesting that we can precisely edit target cells within the body to treat genetic disease with a single intravenous infusion of CRISPR. The interim results support our belief that NTLA-2001 has the potential to halt and reverse the devastating complications of ATTR amyloidosis with a single dose," John Leonard, Intellia's president and CEO, said in a statement. "Solving the challenge of targeted delivery of CRISPR-Cas9 to the liver, as we have with NTLA-2001, also unlocks the door to treating a wide array of other genetic diseases with our modular platform, and we intend to move quickly to advance and expand our pipeline."

NTLA-2001 is the first CRISPR-Cas9-based therapy candidate to be administered systemically, via intravenous infusion, the company noted. The company also said that a third cohort to evaluate the efficacy of NTLA-2001 at the 1 mg per kilogram dose level is actively being enrolled in the trial.

Following the identification of a recommended dose in the dose-escalation portion of the study, Intellia expects to begin a single-dose expansion cohort in the second part of the Phase I trial later this year. And after completion of the trial, the company said it plans to study polyneuropathy and cardiomyopathy manifestations of ATTR amyloidosis as well.

The researchers noted that the study involved a very small number of patients with limited follow-up to date, adding that continued serial measurements of serum TTR concentration in these patients is planned in order to confirm the durability of the therapy's effect.