UK Approves Phase 1 Trial of Potential Gene Editing Therapy, NTLA-2001

A Phase 1 trial of NTLA-2001, a potential gene editing therapy for  familial amyloid polyneuropathy (FAP), was approved to open by the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA).

Intellia Therapeutics is planning to launch the open-label and two-part trial in people with hereditary transthyretin amyloidosis (ATTR) with polyneuropathy before the end of this year. It also plans to file similar regulatory requests with other countries.

“Starting our global NTLA-2001 Phase 1 trial for ATTR patients is a major milestone in Intellia’s mission to develop medicines to cure severe and life-threatening diseases,” John Leonard, MD, president and CEO of Intellia, said in a press release.

Preclinical data showed that a single administration of NTLA-2001 given non-human primates lowered transthyretin (TTR) protein levels to those that were therapeutically relevant, sustained for at least one year.

FAP, the hereditary form of ATTR, is caused by a mutation to the gene that codes for transthyretin (TTR), a protein produced in the liver and normally responsible for transporting vitamin A and thyroid hormone throughout the body.

If TTR is produced improperly, the protein can become unstable and form toxic protein clumps (called amyloids) that can accumulate in organs. Over time, these deposits become toxic and lead to disease symptoms.

Depending on the specific TTR mutation and other factors, ATTR can manifest as a polyneuropathy and cause nerve damage, or as a cardiomyopathy and cause heart damage.

To address problems with TTR protein production, researchers at Intellia, along with their partners at Regeneron Pharmaceuticals, developed NTLA-2001, a gene editing therapy that targets the TTR gene.

The treatment uses CRISPR/Cas9 editing technology, a technique derived from bacteria that allows researchers to edit the genome of a cell by specifying regions of DNA to be added, removed, or edited.

NTLA-2001 is designed to eliminate the TTR gene from the DNA of liver cells, which would reduce TTR production significantly and prevent the symptoms of ATTR from occurring.

The NTLA-2001 treatment is delivered to liver cells using a lipid nanoparticle system, or fat-based molecules that can be used to carry specific CRISPR/Cas9 components to target cells.

The Phase 1 trial will recruit up to 38 FAP patients for its first part, investigating the safety, tolerability, pharmacokinetics (how a treatment moves through the body) and pharmacodynamics (how the body responds to a treatment) of NTLA-2001 as primary trial goals.

Researchers will also assess the efficacy of NTLA-2001 based on clinical measurements of neurological function.

This first part is designed as a single ascending dose trial, meaning that subsequently enrolled patients will receive increasing doses of NTLA-2001 until an optimal dose is determined. That optimal dose’s safety and efficacy will then be tested for an extended period in the study’s second part.

Unlike other forms of ATTR treatment, which either require major surgery (liver transplant) or lifetime use of medications (Onpattro and Tegsedi) to reduce TTR levels, the gene edit performed by NTLA-2001 could potentially be effective with a single use.

In the preclinical studies of NTLA-2001 in non-human primates, researchers found that TTR levels in the blood were reduced by 95% for at least one year after the treatment was administered, suggesting potential long-lasting effects.

“I am pleased to be leading the Phase 1 clinical trial in the U.K. 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, MD, PhD, a professor of medicine at the National Amyloidosis Centre of the Royal Free Hospital in the U.K.

This trial is thought to be the first in which the gene editing CRISPR/Cas9 approach is administered directly into a patient’s vein.

In addition to filing applications with regulatory agencies worldwide, Intellia hopes to extend the treatment to FAP patients with cardiomyopathy in the future.

“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,” Leonard said. “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.”