Gene-editing therapy leads to sustained drop in toxic TTR protein
NTLA-2001 also showing safety in Phase 1 FAP, ATTR-CM clinical trial
A single infusion of NTLA-2001, an experimental gene-editing therapy, generally is safe and leads to a marked reduction in blood levels of the harmful transthyretin (TTR) protein in people with familial amyloid polyneuropathy (FAP) and ATTR amyloidosis with cardiomyopathy (ATTR-CM).
These updated, interim data cover 65 of 72 patients in a Phase 1 clinical trial (NCT04601051), and they also show consistently low blood levels of TTR — the protein that forms toxic clumps in these diseases — for up to more than a year.
Findings were presented in the talk “Enabling the development of serum [TTR] as a biomarker for treatment of ATTR amyloidosis,” given at the 4th International ATTR Amyloidosis Meeting, held Nov. 2-3 in Madrid.
“These positive interim results add to the growing body of data that demonstrates deep and durable reductions of serum [blood] TTR after a single dose of NTLA-2001,” John Leonard, MD, president and CEO of Intellia Therapeutics, which is co-developing NTLA-2001 with Regeneron Pharmaceuticals, said in a company press release.
Gene-editing therapy that aims to prevent toxic TTR protein damaging tissues
“We have also observed early signals of clinical activity in the initial [patient groups] and look forward to presenting the first clinical data beyond serum TTR levels once we have longer follow-up across all [groups],” Leonard added.
Plans are underway for the launch of two pivotal Phase 3 trials of the gene-editing therapy, one in FAP patients and another in those with ATTR-CM expected to start this year. If positive, their data will be used to support regulatory applications seeking the therapy’s approval.
Both FAP and ATTR-CM are forms of ATTR amyloidosis, a group of diseases characterized by the accumulation of toxic clumps of TTR, called amyloid fibrils, in tissues. An hereditary form, FAP is caused mutations in the TTR gene and fibril buildup that particularly damages nerves. ATTR-CM, marked by toxic TTR buildup in the heart, may or may not be caused by TTR mutations.
NTLA-2001 uses the CRISPR-Cas9 gene-editing system — adapted from a bacterial immune defense mechanism — to inactivate the TTR gene in patients’ liver cells, the main producers of TTR, thereby stopping the protein’s production there.
Its goal is to prevent toxic aggregates from forming, in turn easing the symptoms of FAP and ATTR-CM with a single intravenous (into-the-vein) infusion.
The therapy has been designated an orphan drug in the U.S. and Europe, which is intended to speed its development toward regulatory review.
The fully enrolled two-part Phase 1 trial is testing the therapy in 36 adults with FAP and 36 with ATTR-CM.
In its initial dose-escalation part, 15 participants with FAP and 12 with ATTR-CM received a single infusion of NTLA-2001 at various weight-based doses (0.1 to 1 mg/kg), with the goal of assessing the best dose for the trial’s second, dose-expansion part.
Previously reported data concerning the FAP group indicated that the therapy led to dose-dependent reductions in blood TTR levels after about a month, with lower levels sustained for up to six months. Similar findings were observed in ATTR-CM patients.
Its dose-expansion part enrolled 21 FAP patients, 16 treated with NTLA-2001 at a fixed dose of 55 mg (corresponding to an 0.7 mg/kg dose) and five at an 80 mg dose (corresponding to the 1 mg/kg dose). In addition, 24 ATTR-CM patients were given the 55 mg dose.
Deep drop in TTR blood levels seen with 55 mg or 80 mg treatment doses
Newly presented data, collected through May 11, concerned the first 65 treated participants. Patients’ median age was 61 in the FAP group and 78 in the ATTR-CM group, and most in both groups were men.
NTLA-2001’s use at 55 mg or 80 mg led to deep TTR reductions regardless of patients’ starting levels, consistent with earlier findings from the trial’s dose-escalation phase.
Across the 62 patients who received a dose of 0.3 mg/kg or higher, TTR concentrations reached a median of 17 micrograms per milliliter after a month — a 91% reduction relative to levels at study’s start.
These reductions were sustained through the latest follow-up for all doses, including in 29 patients followed for at least a year.
These low TTR blood levels are expected to be sufficient for preventing TTR clumping and easing disease symptoms, Intellia stated.
“The consistent and profound levels of reduction in all patients bolster our confidence that NTLA-2001 could potentially reset the standard of care for ATTR amyloidosis — both for treating the disease and how response is evaluated,” Leonard said.
Phase 3 trials of NTLA-2001 scheduled or being planned for ATTR-CM, FAP
Findings also suggest that absolute TTR concentrations in the bloodstream “could be a robust biomarker of ATTR amyloidosis therapy outcomes,” the researchers wrote in the presentation.
Three FAP patients treated at NTLA-2001’s lowest dose (0.1 mg/kg) in the trial’s first part were retreated at 55 mg in its second part. Findings in these patients and others enrolled after May 11 will be shared at a future date, along with secondary trial efficacy goals related to symptoms of nerve and heart damage.
The therapy was reported to be generally well tolerated at all dose levels, with most adverse events being mild to moderate in severity, temporary, and resolving on their own. The most common were infusion-related reactions (38%), followed by headache (18%), diarrhea (17%), and back pain (11%).
NTLA-2001 at the 55 mg dose has been selected for the upcoming Phase 3 trials, Intellia announced.
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