Intellia Therapeutics and Regeneron Announce First-Ever Clinical Data Demonstrating Safety and Efficacy of In Vivo CRISPR Gene Editing Therapy NTLA-2001 for ATTR Amyloidosis

Intellia Therapeutics and Regeneron Pharmaceuticals jointly announced that NTLA-2001, an in vivo CRISPR-Cas9 genome editing therapy developed by the two companies, has yielded positive interim data from its Phase 1 clinical study for the treatment of transthyretin amyloidosis (ATTR). The interim results showed that on Day 28, serum TTR protein levels in the 0.1 mg/kg dose group decreased by an average of 52% from baseline, while serum TTR protein levels in the 0.3 mg/kg dose group decreased by 87%. This represents the first data supporting the safety and efficacy of in vivo CRISPR genome editing in humans.Clinical TrialData. The interim data from this study were presented at the 2021 annual meeting of the Peripheral Nerve Society (PNS) and published in the *New England Journal of Medicine*.

Transthyretin amyloidosis or ATTR amyloidosis is a rare, progressive, and fatal disease.HeredityHereditary ATTR (ATTRv) amyloidosis refers to a condition in which a TTR gene mutation present at birth causes the liver to produce structurally abnormal transthyretin (TTR) proteins that undergo misfolding. These misfolded proteins aggregate into amyloid deposits within the body, resulting in severe complications across multiple tissues and organs, including the heart, nerves, and digestive system. ATTRv amyloidosis primarily manifests as either polyneuropathy (ATTRv-PN), which can lead to nerve damage, or cardiomyopathy (ATTRv-CM), which can result in heart failure.

Current treatment strategies for ATTR amyloidosis include reducing amyloid formation by stabilizing the TTR tetramer (diflunisal or tafamidis) or inhibiting TTR protein synthesis through degradation of TTR messenger RNA (mRNA) (inotersen or patisiran). While these therapies can alleviate symptoms, improve functional status, and prolong survival, their use is limited by the requirement for long-term administration. For patisiran, long-term treatment necessitates the continued use of corticosteroids and antihistamines, and patients receiving TTR stabilizers may still experience disease progression. Inotersen is associated with severe adverse effects, including glomerulonephritis and thrombocytopenia; meanwhile, in vivo gene editing using the clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system has emerged as a potential novel alternative to mRNA-targeted gene silencing.

In 2012, a research team led by Jennifer Doudna, co-founder of Intellia Therapeutics, developed the CRISPR/Cas9 genome editing tool, for which she was awarded the 2020 Nobel Prize in Chemistry. CRISPR/Cas9 gene editing can make permanent, precise modifications to a patient's chromosomes and repair potential genetic mutations, whereas more traditional gene therapies typically involve the non-permanent introduction of a gene into a patient's cells. These features of CRISPR/Cas9, along with otherGene therapyCompared to costly early gene-editing technologies (such as zinc finger nucleases and transcription activator-like effector nucleases), it offers significant therapeutic advantages.

NTLA-2001 is a novel CRISPR-Cas9 therapy based on in vivo gene editing, delivered by a proprietary liver-targeting lipidNanometerComposed of a lipid nanoparticle (LNP) delivery system, it encapsulates a single guide RNA (sgRNA) targeting human TTR and a Streptococcus pyogenes Cas9 mRNA sequence. Designed for intravenous infusion, it aims to silence TTR in hepatocytes, reducing the production of both wild-type and mutant TTR following a single dose.

The interim data released include 6 patients with ATTRv-PN from two single-ascending-dose cohorts in a Phase I trial currently being conducted in the UK and New Zealand. Three patients received a single dose of NTLA-2001 at 0.1 mg/kg, and three received a single dose at 0.3 mg/kg. NTLA-2001 demonstrated a dose-dependent reduction in serum TTR levels. Day 28 measurements showed an average serum TTR reduction of 52% in the 0.1 mg/kg cohort (n=3) and 87% in the 0.3 mg/kg cohort (n=3), with one patient achieving a 96% reduction. In contrast, standard-of-care therapy for ATTRv-PN requires long-term treatment and typically yields an approximate 80% reduction in TTR levels.

The 6 patients from the two dose cohorts included in the interim analysis generally tolerated NTLA-2001 well, with no serious adverse events reported through Day 28 and no hepatic or coagulation abnormalities detected in laboratory assessments.

Given the safety and tolerability profile of NTLA-2001 to date, a dose-escalation study is ongoing to determine whether higher doses can further reduce pathogenic protein levels, potentially yielding more meaningful clinical benefits. The evaluation of the third cohort at an NTLA-2001 dose level of 1 mg/kg is actively progressing.

After determining the recommended dose for the dose-escalation portion of the study, Intellia expects to initiate Part 2 of the Phase I trial—a single-dose expansion cohort study—later this year. Following completion of the Phase I trial, the company plans to conduct pivotal studies for ATTR amyloidosis with polyneuropathy and cardiomyopathy.

“The first clinical data demonstrate that with just a single intravenous dose of CRISPR, we can treat genetic diseases by precisely editing target cells in vivo. The interim results of the trial support our belief that a single dose of NTLA-2001 has the potential to halt and reverse the devastating complications of ATTR,” said Dr. John Leonard, President and Chief Executive Officer of Intellia. “With NTLA-2001, we have overcome the challenge of targeted delivery of CRISPR/Cas9 to the liver, and also opened the door to using our modular platform to treat a range of otherGeneticsWith the gateway to treating disease open, we plan to rapidly advance and expand our pipeline. These data give us confidence that we are truly ushering in a new era of medicine.(`BioonBioon.com）