Clinical Trials
Gene Editing
Gene Therapy
Regulatory & Standards

‘First-Ever’ Clinical Data Supports in vivo CRISPR Genome Editing Clinical Efficacy and Safety

Georgi Makin
28 June 2021

Intellia Therapeutics and Regeneron have announced positive interim clinical data following the administration of an investigational CRISPR therapy, demonstrating a marked reduction in a disease-causing protein.

The companies announced the positive data from an ongoing Phase I clinical trial of their leading in vivo genome editing candidate, NTLA-2001, which is reportedly the first CRISPR/Cas9-based therapy candidate to be administered via intravenous infusion for precision editing of a gene in a target tissue in humans.

Currently under development as a single-dose treatment for transthyretin (ATTR) amyloidosis, the Phase I study is evaluating the use of NTLA-2001 in patients living with hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN).

By inactivating the TTR gene in liver cells, NTLA-2001 prevents the production of misfolded transthyretin protein. In cases of ATTR amyloidosis, this misfolded protein can go on to accumulate in tissues throughout the body, leading to debilitating and even fatal complications.

Intellia President and CEO, John Leonard, commented:

“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. 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.”

The interim data announced refer to the first six ATTRv-PN patients tested across two single-ascending dose cohorts of the Phase I study. According to results published with The New England Journal of Medicine, single doses of either 0.1 mg/kg or 0.3 mg/kg of NTLA-2001 led to reductions in serum transthyretin protein, with mean reductions of 52% in the 0.1 mg/kg dose group, and 87% in the 0.3 mg/kg dose group. The team further reported one patient in the 0.3 mg/kg dose group exhibited a reduction of 96%.

When compared with standard treatment opportunities for ATTRv-PN, the team explained that chronic treatments tend to yield a transthyretin protein reduction of around 80%.

 As George Yancopoulos, President and CSO of Regeneron, explained:

“This is exciting early data both for people living with this devastating disease and for the entire scientific community working to maximize the potential of genetics-based medicines through cutting-edge research and technologies. Thanks to large-scale human genetics research, there have been many new genetic targets identified and confirmed to have an impact on human health. Combining this knowledge with the precision and enhanced convenience of a single CRISPR infusion unlocks new possibilities in treating – and potentially even curing – life-threatening and historically difficult-to-address diseases.”

The team reported that NTLA-2001 was ‘well-tolerated’ across both dose levels with no serious adverse effects or liver findings after 28 days. Following success in this early stage, Intellia reports that NTLA-2001 is continuing to be evaluated in the dose-escalation portion of the study, as the team investigates whether higher doses may lead to increased reductions, and therefore a greater clinical benefit.

Once a recommended dose has been identified, Intellia reports that the next step will be to begin a single-dose expansion cohort in Part II of the Phase I clinical trial later this year. The company then hopes to move to pivotal studies for both polyneuropathy and cardiomyopathy manifestations of ATTR amyloidosis.

As the study’s national coordinating investigator in the UK, Julian Gillmore, Professor of Medicine at the National Amyloidosis Centre, concluded:

“ATTR amyloidosis is a progressive and fatal disease that usually requires chronic, lifelong treatment. These interim Phase 1 data support NTLA-2001 as the only one-time treatment either on the market or in development.”

“As the first-ever systemically administered CRISPR therapy candidate, NTLA-2001 shows strong potential to stop the production and accumulation of the misfolded TTR protein by inactivating the TTR gene at the root of the disease. This approach could deliver life-changing, lifelong benefits to patients with all forms of ATTR amyloidosis, who continue to experience debilitating symptoms and complications of disease while on the standard of care. While further investigation is needed, these results are highly encouraging.”

Source: Intellia Therapeutics press release