Researchers from Intellia Therapeutics, Regeneron Pharmaceuticals, and clinical partners have published the first-ever clinical data that support the safety and efficacy of in vivo CRISPR genome editing in humans.

The team of researchers based in the U.S., the U.K., and New Zealand showed in a study that the companies’ lead in vivo genome editing candidate NTLA-2001 generated a dose-dependent sustained reduction of protein linked to transthyretin (ATTR) amyloidosis following a single dose in six patients living with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN).

In “CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis,” published Saturday in The New England Journal of Medicine—and in a presentation that day at the 2021 Peripheral Nerve Society (PNS) Annual Meeting—the researchers reported that a single 0.3 mg/kg dose of NTLA-2001 led to an 87% mean reduction in serum transthyretin (TTR) protein concentration in three of the ATTRv-PN patients by day 28, with individual reductions of 80%, 84%, and 96%.  

Standard of care for ATTRv-PN, which requires chronic treatment, typically yields TTR reductions of approximately 80%, Intellia and Regeneron said.

A single 0.1 mg/kg dose of NTLA-2001 resulted in a 52% mean reduction in serum TTR protein in the other three ATTRv-PN patients, with individual reductions of 47%, 52%, and 56% by day 28.

With these data, we believe we are truly opening a new era of medicine,” Intellia President and chief executive officer John Leonard, MD, declared in a statement. “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,” Leonard added.

NTLA-2001 also generated positive safety data: “Administration of NTLA-2001 was associated with only mild adverse events and led to decreases in serum TTR protein concentrations through targeted knockout of TTR,” the researchers reported in the NEJM study.

“Milestone” yields “impressive results”

Leonard’s perspective was echoed on Twitter by notables in genome editing.

“These impressive results from Gilmore et al. show that gene editing technologies, mRNA engineering & manufacturing, and in vivo delivery can already come together into one-time treatments that offer new hope for patients suffering from genetic diseases,” tweeted David R. Liu, PhD, of Harvard University and the Broad Institute, where he is director, Merkin Institute of Transformative Technologies in Healthcare.

“A milestone in gene editing as a new era of programmable one-time medicines comes closer to reality,” tweeted John Evans, CEO of Beam Therapeutics, which applies CRISPR base editing to develop curative precision genetic treatments.

Mani Foroohar, MD, managing director, Genetic Medicines and a senior research analyst with SVB Leerink, observed in a research note that NTLA-2001 “demonstrated a clear dose response, clean safety profile, and effective serum TTR reduction at least in line with Onpattro®—hallmarks of an approvable one-time treatment for ATTR amyloidosis with blockbuster potential to displace existing ASO and RNAi therapies, which are burdened with onerous chronic delivery schedules and extremely high price points.”

Onpattro (patisiran), marketed by Alnylam Pharmaceuticals, is a first-in-class small interfering ribonucleic acid (siRNA) treatment that won FDA approval in 2018 as the first therapy indicated for polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR) in adults.

“Investors will likely assume a very high probability of success for approval for NTLA-2001 and other liver targeted in vivo development candidates, barring any unfavorable long-term safety finding,” Foroohar added. “Given the news, we expect NTLA shares to react positively on Monday morning as investor focus shifts to the long-term safety profile of NTLA-2001, potential efficacy of NTLA-2001 in this hereditary TTR population vs the much larger wild-type population.”

Investors flocked to Intellia stock, which surged 54% in trading as of 1 p.m., to $137.21, while shares of Regeneron dipped about 1% to $547.01. Foroohar on Monday nearly doubled his 12-month price target for Intellia stock from $81 to $159 a share.

A day before the announcement of the Phase I interim results, shares of Intellia closed at $88.83 on Friday, up 2% from Thursday’s close, while Regeneron shares inched up 1% to $550.55.

Foroohar noted that Pfizer’s Vyndamax® (tafamidis) is standard of care for TTR patients “at a meaningfully lower price point than silencer therapies.”

Maury Raycroft, PhD, equity analyst at Jefferies, wrote in a research note that the first in vivo CRISPR/Cas9 gene editing data generated by Intellia and Regeneron “turned out better than we expected and in-line w/ the high bar on safety + efficacy that [Intellia] set heading into this event.

“Though early w/ only 28 day assessment and small #s, we believe at base-case NTLA has a platform for a 1X tx [therapeutic] for precise monogenic gene disruption (using LNP, Cas9 mRNA, & sgRNA working in concern to edit TTR gene in the liver), which they can build upon, as demonstrated in their preclin insertion data,” Raycroft noted.

“Results help de-risk CRISPR/Cas9 editing and in vivo editing [companies] we cover,” Raycroft added, citing as examples CRISPR Therapeutics in the former category, and Precision BioSciences and LogicBio Therapeutics in the latter.

The study provided interim data on NTLA-2001 from a Phase I trial (NCT04601051) designed to evaluate the therapy candidate’s safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD). Intellia is overseeing the trial as the development and commercialization lead for the NTLA-2001 program.

The trial, which is expected to reach an estimated enrollment of 38 patients with ATTRv-PN, is being conducted in the U.K. and New Zealand. Institutions participating in the study include the National Amyloidosis Centre, Division of Medicine, University College London, Royal Free Hospital; Richmond Pharmacology, St. George’s University of London—as well as New Zealand Clinical Research, University of Auckland, and the Department of Neurology, Auckland City Hospital, all in Auckland, New Zealand.

Dose escalation continues

NTLA-2001 continues to be evaluated in the dose-escalation portion of the study, in order to determine if a higher dose could result in a deeper reduction in disease-causing protein levels leading to the potential for more meaningful clinical benefit.

Cohort 3, evaluating NTLA-2001 at the 1 mg/kg dose level, is actively enrolling.

Once researchers identify a recommended dose in the dose-escalation portion of the study, Intellia said, it expects to begin a single-dose expansion cohort in Part 2 of the Phase I trial later this year.

Upon completion of the Phase I trial, Intellia said, it plans to move to pivotal studies for both polyneuropathy and cardiomyopathy manifestations of ATTR amyloidosis.

“Overall, NTLA-2001’s safety profile was very favorable, though much more patient follow-up will be needed to understand the long-term implications for sustained TTR knockdown, durability of treatment, and editing of the TTR gene locus,” Foroohar wrote.

According to Regeneron and Intellia, NTLA-2001 is the first CRISPR/Cas9-based therapy candidate to be administered systemically, via intravenous infusion, for precision editing of a gene in a target tissue in humans,

NTLA-2001 is being specifically developed as a single-dose treatment for ATTR amyloidosis. NTLA-2001 is designed to inactivate the TTR gene in liver cells to prevent the production of misfolded TTR protein, which accumulates in tissues throughout the body and causes the debilitating and often fatal complications of ATTR amyloidosis.

“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,” added George D. Yancopoulos, MD, PhD, President and chief scientific officer of Regeneron.

Regeneron began partnering with Intellia in 2016 to advance CRISPR/Cas9 gene-editing technology for in vivo therapeutic development. The companies’ collaboration was initially valued as potentially generating more than $125 million for Intellia, consisting of $75 million paid upfront, and a $50 million Regeneron investment in Intellia common stock.

In May 2020, Intellia and Regeneron agreed to expand the collaboration to co-develop potential products for the treatment of hemophilia A and hemophilia B, as well as extend the partnership until April 2024, at which point Regeneron has an option to renew for an additional two years. Regeneron agreed to pay Intellia another $70 million upfront, and invest another $30 million in Intellia common stock at $32.42 a share.

Under the expanded collaboration, Intellia also granted Regeneron exclusive rights to develop products for five additional in vivo CRISPR/Cas-based therapeutic liver targets and nonexclusive rights to independently develop and commercialize up to 10 ex vivo gene edited products made using certain defined cell types.

Intellia said it intends to present additional data from the study at a medical or scientific meeting later this year.

“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,” stated Julian Gillmore, MD, PhD, professor of medicine, National Amyloidosis Centre, UCL Division of Medicine, Royal Free Hospital, U.K., and the Phase I study’s national coordinating investigator and corresponding author.

“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,” Gilmore added. “While further investigation is needed, these results are highly encouraging.”