Amyloidosis results from the extracellular deposition of insoluble protein arrangements, formed from structural changes in different precursor proteins.
TTR is a protein synthesized by the liver that is involved in the transport of retinol (vitamin A) and thyroid hormone (thyroxine).
The clinical manifestations of ATTR are divided into neurological, cardiological and other systemic manifestations, such as orthopedic, renal, ocular, and central nervous system.
Cardiac involvement in ATTR refers to the infiltration of amyloid material into the walls of the heart, both atria and ventricles, causing thickening and the development of an infiltrative ATTR cardiomyopathy (ATTR-CM) with a restrictive pattern, with reduced relaxation and increased ventricular filling pressures.
The most frequent clinical manifestation of this form of cardiomyopathy is heart failure syndrome,
The presence of cardiac involvement by amyloidosis is the most powerful marker of a worse prognosis in the disease, both in the cases of AL amyloidosis and in the ATTRv form.
Patients with ATTRv have a variable prognosis depending on the existing mutation, with the V122I mutation worsening and a median survival of two years.
In the ATTRwt form, the prognosis is slightly better, with a median survival of 3.6 to 6 years, which varies depending on the age at diagnosis and the degree of cardiac involvement. To assist in prognostic assessment, a score composed of elevated biomarkers was developed: troponin T >0.05 ng/ml, and N-terminal pro–B-type natriuretic peptide (NT-proBNP) >3000 pg/ml, with the patient being classified according to the cutoffs into three stages. (I, II, and III).
The prominent clinical and epidemiological relevance of ATTR-CM, whose increased incidence is associated with the aging of the global population, given its high prevalence in the elderly population, has motivated the intensification of the search for specific therapeutic targets capable of altering the natural course of the disease.
Tafamidis was the first drug tested in a multicenter randomized controlled trial for the treatment of ATTR-CM. This drug binds to TTR with high affinity, at the thyroxine binding sites, increasing the stability of the tetramer and preventing its disaggregation and the consequent formation of monomers and the subsequent formation of insoluble amyloid fibrils (Central Illustration).
The effects of tafamidis were evaluated in a multicenter phase III, randomized, placebo-controlled clinical study (ATTR-ACT study),
Analysis of the results of the ATTR-ACT study indicate that tafamidis has a greater positive impact when started in less-advanced stages of the disease, as the benefits appear to be attenuated in patients with NYHA functional class III. As an exclusion criterion, the study did not consider patients with NYHA FC IV. Therefore, the role of tafamidis in advanced heart disease is uncertain.
Acoramidis is a TTR stabilizer whose mechanism of action simulates the effects of a mutation that increases the binding strength between TTR tetramers and reduces their dissociation rate. This medication was tested in a recently published randomized, placebo-controlled, multicenter study (ATTRibute-CM study).
Patisiran is a TTR hepatic synthesis silencer based on small-interference ribonucleic acid (RNA) technology. The results of a phase III, double-blind, randomized, and controlled trial testing patisiran in 360 ATTR-CM patients, both ATTRv and ATTRwt, were recently published. Patients were randomized in a 1:1 ratio, to receive patisiran (0.3 mg per kilogram of body weight) or placebo once every three weeks for 12 months. The main results showed at month 12 the decline in the 6-minute walk distance was lower in the patisiran group than in the placebo group (Hodges–Lehmann estimate of median difference, 14.69 m; 95%CI 0.69–28.69; p = 0.020); the Kansas City Cardiomyopathy Questionnaire – overall summary (KCCQ-OS) score increased in the patisiran group and declined in the placebo group (least-squares mean difference, 3.7 points; 95%CI 0.2–7.2; p = 0.040).
Eplontersen is another class of TTR hepatic synthesis silencer that is based on anti-sensing oligonucleotide technology, that has demonstrated beneficial effects on the ATTR polyneuropathy, and is currently been tested in a phase III, double-blind, randomized, and controlled trial in patients with ATTR-CM, with the final results been expected to be published in a near future.
As we briefly reviewed above, the past few years were especially prolific with the emergence of significant new therapies for ATTR-CM, with three important trials demonstrating positive results and changing the natural history of an inexorable and deadly disease.
But it is important to remark that, up to now, the available drugs mainly promote stabilization of disease progression in patients with no advanced heart disease but grant no reversal of structural cardiac disease in most cases. Therefore, the next step in this clinical scenario is the development of drugs able to promote the depletion of TTR deposits in myocardial tissue that could more deeply impact disease progression. The TTR-depleters based on monoclonal antibodies directed against the deposited amyloid fibers hold promise to fulfill these expectations. A recently launched multicenter randomized phase III clinical trial, the DepleTTR-CM, was the first trial, so far, designed to test this hypothesis.
The objective of the DepleTTR-CM study is to evaluate the safety and efficacy of a depleter of amyloid fibrils deposited in the myocardial interstitium, a monoclonal antibody anti-ATTR, currently called ALXN2220, but previously called NI006.
The reason for using this type of medication is based on the notion that reducing myocardial TTR load can translate into restoration of cardiac function and improved patient survival. Myocardial deposits of ATTR accumulate in the cardiac interstitium, impacting the mechanical and functional properties of the myocardium such as changes in diastolic relaxation, and with the progression of the disease, there is also impairment of systolic function. In peripheral sensorimotor neurons, ATTR deposits also cause polyneuropathy, which together with cardiomyopathy, are the main clinical manifestations of TTR amyloidosis.
In preclinical studies, NI006, a recombinant human anti-ATTR monoclonal IgG1 antibody that selectively binds to the amyloid conformations of ATTRv and ATTRwt, but not physiologically folded TTR, eliminated the protein by inducing phagocytosis of TTR fibrils with consequent removal of TTR deposits from tissues.
A recently published randomized phase I (Ia-Ib), double-blind, placebo-controlled, multicenter (in four European countries), combined single-dose progressive clinical trial was the first investigational study in humans and aimed to evaluate the safety profile and side effects of intravenous infusions (ranging from 0.3 to 60 mg per kilogram of body weight) in patients with ATTR-CM. Patients with ATTR-CM and chronic heart failure were randomized (in a 2:1 ratio) to receive intravenous infusions of NI006 or placebo every four weeks for four months.
In this study, the use of NI006, particularly at doses of at least 10 mg per kilogram administered every four weeks, was associated with changes in extracellular volume on cardiac magnetic resonance imaging and radiotracer uptake on scintigraphy, two image-based surrogate markers of cardiac amyloid burden. These observations were supported by changes in cardiac biomarker levels and functional measures. The safety profile of NI006 and the absence of anti-drug antibodies may be related to the amino acid sequence of the medicine of human origin and its selectivity for misfolded TTR, without binding to physiological TTR.
According to information available on
The study will enroll adult patients with ATTR-CM, ATTRv or ATTRwt, with symptomatic heart failure and increased NT-proBNP levels.
The specific criteria for participant eligibility are summarized in
| Inclusion criteria |
|---|
| Centrally confirmed diagnosis of ATTR-CM with either wild-type or variant TTR genotype. |
| End-diastolic interventricular septal wall thickness ≥ 11 mm for women or ≥ 12 mm for men on echocardiography measured at screening. |
| NT-proBNP > 2,000 pg/mL at screening. |
| Treatment with a loop diuretic for at least 30 days prior to screening. |
| History of heart failure NYHA class II–IV at screening. |
| Life expectancy of ≥ 6 months as per the investigator's judgment. |
| Males and females of childbearing ability must use contraception. |
ATR-CM: Transthyretin amyloid cardiomyopathy; NYHA: New York Heart Association; TTR: transthyretin; NT-proBNP: N-terminal pro–B-type natriuretic peptide.
The study exclusion criteria for participant eligibility are depicted in
| Exclusion criteria |
|---|
| Known leptomeningeal amyloidosis. |
| Known AL, or secondary AA, or any other form of systemic amyloidosis. |
| Acute coronary syndrome, unstable angina, stroke, transient ischemic attack, coronary revascularization, cardiac device implantation, cardiac valve repair, or major surgery within three months of screening. |
| Uncontrolled clinically significant cardiac arrhythmia, per investigator's assessment. |
| LVEF < 30% on echocardiography. |
| Renal failure requiring dialysis or an eGFR < 20 mL/min/1.73 m2 at screening. |
| Polyneuropathy disability score IV. |
AL: light-chain; AA: amyloidosis; LVEF: left ventricular ejection fraction; eGFR: estimated glomerular filtration rate.
The allocation method is randomized, ensuring an unbiased distribution of participants into different treatment arms. The interventional model is characterized by parallel assignment, where participants are distributed to either the experimental group receiving ALXN2220 or the control group receiving placebo. To maintain blinding and minimize bias, quadruple masking is employed, involving masking of participants, care providers, investigators, and outcomes assessors. In the experimental arm, participants receive ALXN2220 via intravenous infusion every four weeks for a duration of at least 24 months, with the possibility of extension up to 48 months, while those in the control arm receive placebo following the same administration schedule. Both ALXN2220 and placebo are administered via intravenous infusion, with dosing based on weight for the experimental group. These design elements are implemented to rigorously evaluate the efficacy and safety of ALXN2220 compared to placebo in the treatment of ATTR-CM, with the goal of informing clinical practice and improving patient outcomes.
The primary outcome measure of the study focuses on a composite of events comprising all-cause mortality and total cardiovascular clinical events. This measure will be evaluated from baseline throughout the duration of the study, extending up to month 48.
Secondary outcome measures include: (1) another composite measure of all-cause mortality and total heart failure events, assessed from baseline to the end of the study; (2) changes from baseline in the KCCQ-OS score, measured at month 24, offering insights into participants' perceived quality of life; (3) time to cardiovascular-related mortality, monitored from baseline to the end of the study; (4) changes from baseline in the 6-minute walk test (6MWT) at month 24, providing objective measures of functional capacity; (5) number of participants experiencing cardiovascular clinical events; and (6) time to all-cause mortality, recorded throughout the study period up to month 48. These outcome measures collectively aim to comprehensively evaluate the efficacy and impact of the intervention on clinical events, quality of life, functional capacity, and mortality rates among participants with ATTR-CM.
The study officially started on January 11, 2024, the date of the first patient randomization, and is estimated to complete the enrollment with 1,000 patients, on August 29, 2025.