Interim Data From Phase 1 CRISPR/Cas9 Genome Editing Support Efficacy and Safety for Transthyretin Amyloidosis
Encouraging results are emerging from a clinical trial of in vivo genome editing with CRISPR/Cas 9 technology (NTLA-2001; Intellia Therapeutics, Cambridge, MA and Regeneron Pharmaceuticals, Tarrytown, NY) for potential treatment of inherited transthyretin amyloidosis-peripheral neuropathy (ATTRv-PN). In this phase 1 study (NCT04601051), participants treated to date (n=6) with 0.1 or 0.3 mg/kg of the genome editing therapy had mean reductions in serum transthyretin (TTR) of 52% and 87%, respectively, over a 28-day period. A single participant had a 96% reduction in serum TTR. For the sake of comparison, it is noted that currently available therapy typically reduces TTR by 80%.
“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,” said Intellia president and chief executive officer John Leonard, M.D. “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.”
No serious adverse events have occurred, including no signs of liver dysfunction nor elevated liver enzymes. As a result, the trial is continuing in adose-escalation phase to determine if a higher dose could safely result in a deeper reduction of TTR for greater clinical benefit. A third cohort, who will be treated with 1 mg/kg of genome editing therapy is actively enrolling in this trial.
Julian Gillmore, MD, PhD, professor of Medicine, National Amyloidosis Centre, UCL Division of Medicine, Royal Free Hospital, UK, and the phase 1 national coordinating investigator noted, “. . .(t)his 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.”
NTLA-2001 is intended as a 1-time dose administered via intravenous infusion, for precision editing of the TTR gene target tissue in humans. Although these are early results in a small cohort of 6 individuals treated to date, they are remarkable as the first-ever clinical data supporting safety and efficacy of this technology for the treatment of a genetic condition. These data have been published in the The New England Journal of Medicine and presented at the Peripheral Nerve Society (PNS) annual meeting.