The first patient has been dosed in a Phase 1 clinical trial evaluating NTLA-2001, Intellia Therapeutics’ investigational gene-editing therapy for the treatment of hereditary transthyretin amyloidosis with polyneuropathy (ATTR-PN), also known as familial amyloid polyneuropathy (FAP).
The trial (NCT04601051) is recruiting at a site in London, in the U.K., and seeks to enroll approximately 38 adult patients, ages 18–80, who have no access to approved treatments, or whose disease continued to progress despite the use of approved treatments.
“With today’s news, we’re entering a new era of potential genome editing cures for patients,” John Leonard, MD, Intellia’s president and CEO, said in a press release.
NTLA-2001 is a one-time gene-editing therapy based on the CRISPR/Cas9 technology. The technology was discovered first as a bacterial defense mechanism, but scientists learned to co-opt it as a highly targeted means of making changes, or edits, in the genome.
The new therapy is designed to remove the TTR gene from from patients’ liver cells. A mutation in this gene causes FAP, an inherited form of ATTR associated with polyneuropathy. Another type, known as wild-type ATTR, and accounting for the majority of the disorder’s cases, is not associated with any known mutations.
In both cases, unstable forms of the TTR protein accumulate in toxic levels throughout various organs, disrupting their normal function and causing problems with nerves (neuropathy) and, in many cases, heart failure.
Removing TTR, an approach called knockout editing, is expected to delay or even prevent the nerve and heart damage that accompanies both FAP and wild-type ATTR.
Intellia uses a non-viral, lipid nanoparticle delivery system to deliver NTLA-2001 directly to liver cells, where TTR is made. The therapy is expected to provide a lasting effect with a single treatment.
An earlier preclinical study done in non-human primates found that a single dose of NTLA-2001 resulted in a clinically relevant (more than 95%) and sustained drop in TTR blood levels for at least one year.
Further studies in mice showed this effect persisted even after the liver regenerated following partial liver removal, supporting the therapy’s potential lifelong benefits.
“Only a few short years ago, there were no treatments available for this devastating disease,” said Carlos Heras-Palou, MD, founder and president of the United Kingdom ATTR Amyloidosis Patients Association, who also has hATTR. “Now, a cure for ATTR utilizing the groundbreaking CRISPR/Cas9 gene editing technology may be within reach.”
The ongoing Phase 1 trial is testing the safety, tolerability, pharmacokinetics (how a drug moves through the body), and pharmacodynamics (what effects a compound has on the body) of a single intravenous (into-the-vein) administration of NTLA-2001 in people with FAP.
It will be conducted in two parts. In the first part, participants will receive ascending doses of NTLA-2001 to determine the medication’s optimal biologically active dose (OBD), which essentially is the safest and most effective dose.
The second part will consist of an open-label expansion part investigating the established dose in a broader patient population, including those with both polyneuropathy and cardiomyopathy (disease affecting the heart). This part is designed to further characterize the compound’s activity, establish an initial assessment of its effects on neurological function, and obtain additional safety information.
“Once we’ve assessed safety and established an optimal dose, we intend to rapidly initiate trials for the clinical manifestations of ATTR. NTLA-2001 may halt and reverse ATTR progression by producing a deeper, permanent TTR protein reduction for all patients – regardless of disease type – than the chronically administered treatments currently available,” said Leonard.
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