CRISPR Therapy for ATTR Amyloidosis Granted Orphan Drug Designation


The phase 1 study of NTLA-2001 previously showed positive interim data, including serum TTR reductions, which were reported in June 2021.

The FDA has granted orphan drug designation to Intellia Therapeutics’ investigational CRISPR therapy NTLA-2001 for the potential treatment of transthyretin (ATTR) amyloidosis.1

NTLA-2001, which is administered intravenously and edits the mutated TTR gene in-vivo in patients with ATTR amyloidosis, is currently being evaluated in a phase 1 trial (NCT04601051) enrolling adult participants with hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN). Investigators previously reported positive interim data, with an 87% mean reduction in serum TTR in participants treated with a single 0.3 mg/kg dose of NTLA-2001.2

“Orphan drug designation underscores the FDA’s recognition of NTLA-2001’s potential promise as a single-dose, novel therapy for the treatment of ATTR amyloidosis,” John Leonard, MD, president and chief executive officer, Intellia, said in a statement.1 “At Intellia, we are committed to advancing our modular genome editing platform to develop potentially curative treatment options for life-threatening diseases, and we look forward to working with the ATTR amyloidosis community and the FDA to bring a much-needed treatment option to patients.”

The phase 1 trial plans to enroll up to 38 participants with ATTR amyloidosis. It is primarily assessing safety, as measured by adverse events (AEs) and efficacy as measured by serum biomarker levels. Secondary outcome measures include measures of efficacy such as change from baseline in Familial Amyloid Polyneuropathy Stage, Polyneuropathy Disability score, Modified Body Mass Index, Neuropathy Impairment score, 10-Meter Walk Test, Norfolk Quality of Life-Diabetic Neuropathy, and n EuroQOL-5D-5L.

READ MORE: CRISPR Therapy Shows Some Benefit in Leber Congenital Amaurosis

Six participants are currently enrolled across the UK and New Zealand and have received doses of either 0.1 or 0.3 mg/kg of NTLA-2001. Interim efficacy data demonstrated reductions in serum TTR, with a maximum 96% reduction in 1 patient by day 28 with dose-dependent response. Participants in the lower-dose group had a mean 52% reduction in serum TTR at day 28 and those in the higher-dose group had a mean 87% reduction at day 28. Comparatively, chronic, standard-of-care treatments for ATTR amyloidosis typically yield around 80% TTR reductions.2 

In terms of safety, no serious AEs or liver events were observed in the first 6 patients by day 28. Given these safety data, the trial is now also enrolling participants to receive a 1 mg/kg dose level of NTLA-2001.

“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,” Leonard said in a previous statement.3 “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. With these data, we believe we are truly opening a new era of medicine.”

Intellia developed the therapy using their proprietary non-viral platform that uses lipid nanoparticles to deliver the NTLA-2001. The CRISPR therapy consists of guide RNA and mRNA encoding the Cas9 enzyme. The therapy is being developed as part of a development and commercialization collaboration with Regeneron.

1. Intellia Therapeutics receives U.S. FDA orphan drug designation for NTLA-2001, an investigational CRISPR therapy for the treatment of Transthyretin (ATTR) Amyloidosis. News release. Intellia Therapeutics. October 21, 2021.
2. Gilmore JD, Gane E, Taubel J, et al. CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis. N Engl J Med. 2021; 385:493-502. doi: 10.1056/NEJMoa2107454
3. Intellia and Regeneron announce landmark clinical data showing deep reduction in disease-causing protein after single infusion of NTLA-2001, an investigational CRISPR therapy for Transthyretin (ATTR) Amyloidosis. News release. Intellia Therapeutics. June 26, 2021.
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