Intellia Gets FDA Clearance to Start First Ever Phase III Trial for an In Vivo CRISPR Drug

Clinical-stage genome editing company Intellia Therapeutics has received clearance from the US Food and Drug Administration (FDA) for its Investigational New Drug (IND) application to start a pivotal phase III trial of NTLA-2001 for the treatment of transthyretin (ATTR) amyloidosis with cardiomyopathy.

Intellia said NTLA-2001 is the first investigational in vivo CRISPR-based gene editing therapy cleared to enter late-stage clinical development. As an in vivo therapy, it can edit genes inside the body rather than in cells extracted from patients.

Intellia, which focuses on developing potentially curative therapies leveraging CRISPR-based technologies, plans to begin the Phase III trial for NTLA-2001 by the end of this year.

ATTR amyloidosis is a rare, progressive and fatal disease. Hereditary ATTR (ATTRv) amyloidosis occurs due to mutations in the TTR gene, which causes the liver to produce structurally abnormal transthyretin (TTR) protein with a tendency to misfold. Accumulation of the aberrant proteins as amyloid in the body causes serious complications in several tissues and organs, including the heart, nerves and digestive system.

There are two main types of ATTRv — polyneuropathy (ATTRv-PN), which can lead to nerve damage, or cardiomyopathy (ATTRv-CM), which can lead to heart failure. There is also a non-mutated form of ATTR amyloidosis where wild-type TTR proteins misfold and aggregate over time resulting in disease-causing amyloid deposits. This form of the condition, called wild-type ATTR (ATTRwt) amyloidosis, primarily affects the heart.

It is estimated that 50,000 people worldwide live with ATTRv amyloidosis and between 200,000 and 500,000 people with ATTRwt amyloidosis.

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Intellia will be trialing NTLA-2001 in the cardiomyopathy form of the disease. It’s also planning another study in the polyneuropathy disease type.

There are only a few treatments approved in the US to treat nerve damage caused by ATTR amyloidosis. This includes one from Pfizer, which is cleared for the cardiomyopathy disease form.

NTLA-2001 is being jointly developed by Intellia and Regeneron, with the two working in partnership since 2016. The companies recently expanded their collaboration to develop in vivo medicines for neurological and muscular diseases.

Intellia’s therapy is designed to be a one-time treatment for ATTR amyloidosis. Using CRISPR/Cas9, it knocks out the faulty TTR gene that leads to the production of abnormal TTR protein.

“The FDA clearance of the NTLA-2001 IND application allows us to initiate a pivotal Phase III trial in the United States, marking the first in vivo CRISPR-based candidate to begin late-stage clinical development. This is another important step forward for Intellia and our collaborator, Regeneron, as we aim to establish a new standard of care for the treatment of ATTR amyloidosis,” said Intellia president and chief executive officer John Leonard, MD.

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According to Kostas Biliouris, an analyst at BMO Capital Markets, the FDA’s confidence in CRISPR gene editing treatments appears to be growing. The IND clearance “signals that [the] FDA is comfortable with the potential risks of off-target editing related to in vivo gene editing therapies and provides further regulatory derisking for [Intellia’s] platform,” said Biliouris.

Emerging clinical data may have also bolstered Intellia’s case, Biliouris said.

“Today’s [IND application] clearance signals that [the] FDA is comfortable with the potential risks of off-target editing related to in vivo gene editing therapies and provides further regulatory derisking for [Intellia’s] platform,” wrote Kostas Biliouris, an analyst at BMO Capital Markets.

Other in vivo gene editing treatments cleared for US trials include ones from Sangamo Biosciences, Excision BioTherapeutics and another one being developed by Intellia. NTLA-2001 is the furthest along in testing for Intellia.

Vertex Pharmaceuticals and CRISPR Therapeutics are currently waiting for an FDA decision on an ex vivo treatment for sickle cell disease. With a December 8 target decision date, it would be the first CRISPR-based drug to enter the market in the US.