Experimental treatment reduces toxic heart protein in ATTR-CM trial
Long-term Cliramitug also safely eases heart damage markers
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Long-term treatment with the experimental therapy candidate cliramitug safely and effectively reduces toxic clumps of the transthyretin (TTR) protein and heart damage markers in adults with transthyretin amyloid cardiomyopathy (ATTR-CM).
That’s according to nearly three years of data from the Phase 1 NI006-101 clinical trial (NCT04360434), which confirmed the therapy’s favorable safety and efficacy profiles seen in the study’s first year. Cliramitug works by binding to toxic TTR aggregates — the underlying cause of ATTR-CM — and marking them for destruction.
Overall, NI006-101’s extension portion “provided additional data supporting the development of cliramitug as a treatment option for patients with ATTR-CM that is conceptually different and potentially complementary to existing treatment approaches,” researchers wrote.
The study, “Cliramitug for depletion of cardiac amyloid transthyretin: long-term follow-up of the NI006-101 trial,” was published in Nature Medicine. The trial was sponsored by Neurimmune, which is co-developing the treatment with Alexion, AstraZeneca Rare Disease. Most of the study authors are employees of either company.
Cliramitug aimed at slowing, reversing ATTR-CM progression
Cliramitug is currently being tested against a placebo for up to four years in more than 1,000 adults with ATTR-CM in a global Phase 3 trial called DepleTTR-CM (NCT06183931). The study, which will assess group differences in terms of death and cardiovascular clinical events, is expected to end in October 2027.
ATTR-CM is marked by the production of an unstable TTR protein that is prone to forming toxic clumps, called amyloid deposits, that accumulate in the heart, causing heart damage, or cardiomyopathy. It can be caused by mutations in the TTR gene (hereditary ATTR-CM) or aging-related processes (wild-type ATTR-CM).
Cliramitug (also known as ALXN2220 or NI006) is an antibody-based therapy designed to bind to abnormal TTR clumps, marking them for clearance by the immune system, without affecting the healthy TTR protein. This is expected to ease symptoms and potentially slow or reverse ATTR-CM progression.
The Europe-based NI006-101 trial involved 40 ATTR-CM patients, ages 18 and older, who were randomly assigned to receive either one of six cliramitug doses (0.3 to 60 mg/kg) or a placebo, initially as a single infusion, and then once every month for four months.
Those completing this placebo-controlled portion could enter the study’s open-label extension (OLE) portion, in which all received the therapy for eight months, followed by a second OLE portion (OLE2), in which all were treated with a 30 mg/kg monthly dose for up to one year.
Results from the trial’s first part indicated that cliramitug was generally safe and well tolerated and appeared to be associated with reductions in blood levels of heart damage markers (NT-proBNP, troponin T) and imaging measures of heart amyloid deposits relative to the placebo. These effects, as well as improvements in heart structure and function, were sustained in the first OLE portion.
Therapy continued to be generally safe and well tolerated
Now, the researchers reported the long-term data from the 23 patients who completed the trial’s OLE2 portion. In the whole NI006-101 trial, these participants received as many as 24 cliramitug monthly infusions over a median follow-up of 29.3 months (about 2.5 years) and a maximum of 35.4 months (nearly three years).
All OLE2 participants were men, with a median age of 70 years, and more than three-quarters (78.3%) had wild-type ATTR-CM. Most (87%) were receiving Vyndamax (tafamidis), an ATTR-CM-approved therapy that works by stabilizing the TTR protein, at the trial’s start (baseline). Participants were allowed to continue this treatment.
Data showed cliramitug continued to be generally safe and well tolerated in OLE2. Seven patients (30%) experienced serious adverse events, but these were deemed unrelated to cliramitug. One person discontinued the treatment due to serious adverse events associated with underlying heart disease.
At the end of the OLE2 portion, participants with available data showed a median relative reduction in signs of heart amyloid deposits, by 19.5% in heart MRI scans and 36.1% in scintigraphy scans, which use a radioactive tracer that specifically binds TTR amyloid deposits.
Patients previously treated with lower doses of cliramitug experienced further reductions in heart amyloid deposits with continued treatment and after escalating to higher doses. Those who had originally received the placebo also achieved similar benefits after switching to cliramitug.
Our findings demonstrate that long-term administration of cliramitug at high doses is well tolerated and may be associated with clinically meaningful reductions in [heart] ATTR burden and subsequent improvements in blood biomarkers, [heart] structure and function, and quality of life.
These imaging findings were accompanied by relative reductions in NT-proBNP (47.3%) and troponin T (19.7%). Echocardiography results showed that the treatment continued to preserve heart structure and function for most participants.
Quality of life, as assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ), also showed improvements over the course of the trial. By OLE2’s end, 17 of 22 participants (77.3%) had better KCCQ scores, and these changes were considered clinically meaningful for 70.6% of them.
Changes in exercise capacity were more variable. In the six-minute walk test, which measures how far a person can walk in six minutes, about half of the participants could walk farther at the end of the study.
“Our findings demonstrate that long-term administration of cliramitug at high doses is well tolerated and may be associated with clinically meaningful reductions in [heart] ATTR burden and subsequent improvements in blood biomarkers, [heart] structure and function, and quality of life,” the researchers wrote.
An ongoing Phase 2 NI006-102 trial (NCT07213583) is now evaluating the safety and efficacy of cliramitug retreatment in NI006-101 participants after a treatment pause since the end of the Phase 1 trial.
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