Gene-editing therapy aiding FAP patients year or more later: Trial
Phase 3 studies opening into NTLA-2001 as one-time therapy for FAP, ATTR-CM
One year after a single dose of Intellia Therapeutics’ experimental gene-editing therapy NTLA-2001, blood levels of the disease-driving transthyretin (TTR) protein dropped by a mean of 91% in people with familial amyloid polyneuropathy (FAP).
Available data at two years showed sustained TTR level reductions, which were accompanied by evidence of disease stabilization or better on several clinical measures at the one- and two-year marks.
That’s according to results in up to 36 FAP patients given NTLA-2001, also known as nexiguran ziclumeran or nex-z, as part of a Phase 1 clinical trial (NCT04601051).
The ongoing study includes adults with ATTR amyloidosis with cardiomyopathy (ATTR-CM), another type of ATTR amyloidosis, with results in this group also showing therapeutic benefits.
Gene-editing therapy aiming to lower production of damaging TTR protein
“The Phase 1 data presented today offer compelling evidence that deep and persistently low levels of TTR reduction achieved with nex-z … may favorably impact disease progression for people living with ATTR amyloidosis,” John Leonard, MD, Intellia’s president and CEO, said in a company press release.
NTLA-2001’s benefits in FAP patients now are being confirmed in a Phase 3 trial called MAGNITUDE-2 (NCT06672237) that is enrolling up to 50 participants at sites outside the U.S. The first open site is in New Zealand.
Treatment safety and efficacy also are being evaluated in up to 765 adults with ATTR-CM in another Phase 3 trial, dubbed MAGNITUDE (NCT06128629).
“These results from the ongoing Phase 1 study increase our belief in the likelihood of success of our active Phase 3 studies based on our hypothesis that greater TTR reduction may lead to greater clinical benefit,” Leonard said.
ATTR amyloidosis is an umbrella term for diseases caused by the buildup of toxic clumps of the TTR protein. FAP, also known as hereditary ATTR amyloidosis with polyneuropathy, is characterized by the accumulation of toxic TTR aggregates mostly on nerves outside the brain and spinal cord, leading to nerve damage, or polyneuropathy.
When toxic TTR clumps build in the heart, it leads to a form of ATTR amyloidosis known as ATTR-CM. While FAP is caused by mutations in TTR, the gene that codes for the TTR protein, ATTR-CM may or may note be associated with TTR mutations.
91% drop in blood TTR levels seen year after single treatment in 33 patients
Being co-developed by Intellia and Regeneron Pharmaceuticals for FAP and ATTR-CM, NTLA-2001 uses the gene-editing technology CRISPR-Cas9 to disrupt the TTR gene in liver cells, the body’s main producers of the TTR protein.
This is expected to stop the protein’s production, preventing its toxic accumulation and ultimately easing disease symptoms and slowing its progression.
The ongoing two-part Phase 1 trial is testing several doses of NTLA-2001, given via an infusion directly into the bloodstream, in 36 adults with FAP and 36 adult ATTR-CM patients.
Interim data from its initial dose-escalation part showed that blood TTR levels were reduced after about one month in a dose-dependent manner. The two highest doses, 55 mg and 80 mg, were selected for testing in the trial’s dose-expansion part.
Newly announced results showed that the 33 FAP patients who received a dose of NTLA-2001 of at least 0.3 mg/kg (about 24 mg) experienced a 91% reduction in blood TTR levels one year after treatment. The 16 patients with two-year follow-up data showed persistently low TTR levels, without signs of waning effectiveness over time.
Preliminary results from all 36 FAP patients in terms of changes in clinical measures, including Neuropathy Impairment Score, modified Neuropathy Impairment Score (mNIS+7), and modified BMI (modified ratio of height and weight), also suggested stabilization or a lessening in disease severity after one and two years.
“We observed … positive and consistent trends, indicative of a disease-modifying effect, in patients with hereditary ATTR amyloidosis with polyneuropathy,” Leonard said.
Trial participants with ATTR-CM experienced similar sustained reductions in blood TTR levels with NTLA-2001 treatment that also were accompanied by signs of disease stabilization or lesser severity across multiple measures after one year.
NTLA-2001 was well tolerated across all patients and all dose levels tested. The most common treatment-related adverse events were infusion-related reactions, reported to be mild or moderate in severity.
Phrase 3 trial to assess treatment safety and efficacy over 18 months
The Phase 3 MAGNITUDE-2 study is assessing the safety and efficacy of NTLA-2001 (55 mg) relative to a placebo in up to 50 adult FAP patients who have not received previous treatment with TTR silencers, and who stop using TTR stabilizers.
TTR silencers like Onpattro (patisiran) or Tegsedi (inotersen) interfere with TTR protein production, while TTR stabilizers such as tafamidis meglumine prevent transthyretin from aggregating. Tafamidis meglumine is approved to treat FAP in the European Union, under the brand name Vyndaqel, but it is not an approved FAP treatment in the U.S.
The trial’s main goal is to assess changes in blood TTR levels at day 29 and in mNIS+7 scores after 1.5 years. After completing the main study period, patients assigned a placebo may choose to receive NTLA-2001.
“Looking ahead, we are focused on rapidly enrolling both MAGNITUDE and MAGNITUDE-2, where we will be testing a hypothesis that greater TTR knockdown [reduction] has a potential to modify this debilitating disease [ATTR amyloidosis] and change the treatment landscape in meaningful ways,” David Lebwohl, MD, Intellia’s chief medical officer, said in the company webcast.
“Assuming success, we anticipate that nex-z will be a welcome addition to the treatment choices for patients and physicians — one that has the potential to reset the standard of care as the best-in-class TTR-lowering drug,” Lebwohl added.
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