Intellia Trials CRISPR Drug as Permanent Cure to Fatal Hereditary Disease

by Eduardo Longoria
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By Eduardo Longoria

On October 19th, Intellia Therapeutics, Inc. announced the authorization of its Clinical Trial Application (CTA) by the United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA) to initiate its Phase 1 study, which will evaluate NTLA-2001 for the treatment of hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN).

If approved, Intellia’s lead candidate, NTLA-2001, could be the first permanent curative treatment for ATTR. The company’s in vivo liver knockout technology allows NTLA-2001 the possibility of life-long transthyretin (TTR) protein reduction after a single course of treatment. This investigational therapy uses Intellia’s proprietary non-viral lipid nanoparticle platform as a delivery mechanism.

“Our trial is the first step toward demonstrating that our therapeutic approach could have a permanent effect, potentially halting and reversing all forms of ATTR. Once we have established safety and the optimal dose, our goal is to expand this study and rapidly move to pivotal studies, in which we aim to enroll both polyneuropathy and cardiomyopathy patients,” said John Leonard, M.D., Intellia’s President, and Chief Executive Officer.


Transthyretin Amyloidosis (ATTR) – The Threat Within You

Transthyretin amyloidosis, or ATTR, is a rare, progressive, and fatal disease. Hereditary ATTR (hATTR) occurs when a person is born with a specific DNA mutation in the TTR gene, which causes the liver to produce a protein called transthyretin (TTR) in a misfolded form and build up in the body. The transthyretin (TTR) protein in healthy form is a tetramer (four chain unit) that in hATTR patients decomposes into its four constituent monomers and misfolds into the amyloids.

This disease is autosomal dominant, which requires only one copy of the defective gene for disease manifestation and is not gender-specific. It has a 50% chance of appearing in anyone with a parent who has the condition, rather than requiring both parents to be carriers. hATTR can manifest as polyneuropathy (hATTR-PN), which can lead to nerve damage, or cardiomyopathy (hATTR-CM), which involves heart muscle disease that can lead to heart failure. hATTR is diagnosed by a variety of tests ranging from genetic testing to biopsies to scintigraphy. The most prevalent treatment for hATTR is orthotopic liver transplant (donor organ in the same position as the removed organ).


Phase 1 Trial Goals

Intellia’s global first-in-human trial is intended to start by the end of 2020. It is an open-label, multi-center, two-part study that evaluates NTLA-2001 in adults with hATTR-PN (a hereditary form of amyloidosis with peripheral nerve damage). The 38 patient study consists of a single ascending dose phase in Part 1 and, following the identification of an optimal dose, a single-cohort expansion in Part 2.

The primary objectives are to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of NTLA-2001, including the measurement of serum TTR levels following a single intravenous infusion. The secondary objectives are to evaluate drug efficacy on clinical measures of neurologic function in hATTR-PN patients.

“I am pleased to be leading the Phase 1 clinical trial in the UK for NTLA-2001, which I believe to be a breakthrough, single-course, genome editing therapy with the potential to transform the lives of ATTR patients around the world,” said Julian Gillmore, M.D, Ph.D., FRCP, Professor of Medicine, National Amyloidosis Centre, UCL Division of Medicine, Royal Free Hospital, UK, the trial’s national coordinating investigator and an expert in the treatment of ATTR.

Beyond its first application in the UK, Intellia is submitting additional regulatory applications in other countries as part of its ongoing global development strategy. NTLA-2001 is part of a co-development/co-promotion agreement between Intellia, the lead development and commercialization party, and Regeneron Pharmaceuticals, Inc.


Getting Ahead in Competition

Besides liver transplants, a few cutting edge treatments are being worked on by Intellia’s competitors. In addition to gene therapy in the form of CRISPR-Cas9, there are anti-sense oligonucleotides and RNA interference (RNAi) and tetramer stabilizers and immunotherapies. Although effective, these therapies require periodic administration throughout the life of patients.

Alnylam pharmaceuticals’ RNAi drug, Onpattro (patisiran) approved in 2018, is a double-stranded siRNA in the form of a lipid complex that binds to the TTR protein and prevents its deformation through RNA interference. Ionis’ Tegsedi (inotersen), which is commercialized by its affiliate Akcea Therapeutics, is an antisense oligonucleotide inhibitor of the TTR protein that was also FDA Approved in 2018 for the treatment of the polyneuropathy of hATTR in adults. The duo is currently evaluating AKCEA-TTR-LRx, an antisense drug that uses Ionis’ advanced LIgand Conjugated Antisense (LICA) technology. In 2019, Pfizer’s Vyndaqel (tafamidis meglumine) and Vyndamax (tafamidis) were FDA approved for cardiomyopathy caused by ATTR.

Intellia is one of the several high-profile gene editing biotechs formed in the years after the arrival of CRISPR/Cas9. While the company is far from having a proven medicine, the enthusiasm for CRISPR’s therapeutic potential has raised its market value. The clinical trial of a permanent solution to a chronic, genetic and fatal disease shows potential as a major milestone in medicine and can radically increase the quality of life for those unfortunate enough to be born with this disease.

Editor: Rajaneesh K. Gopinath, Ph.D.

Related Article: CRISPR Technology in Disease Modelling and Drug Discovery



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