Emerging Pharmacological Strategies for Cardiac Amyloidosis: A Qualitative Analysis of Interventional Clinical Trials Registered on ClinicalTrials.gov

1. Introduction

In the past, cardiac amyloidosis was regarded as a rare and atypical diagnosis. It is now recognized as an important contributor to the global burden of restrictive cardiomyopathy and heart failure.[1] Reported prevalence and mortality have increased substantially over the past two decades; as a result of improved detection and the widespread adoption of noninvasive diagnostic modalities, including bone scintigraphy and cardiac magnetic resonance imaging, rather than a true rise in disease incidence.[2,3] Earlier and more accurate diagnosis has consequently altered the clinical spectrum of cardiac amyloidosis, enabling identification of patients at less advanced stages of disease compared with historical cohorts.[3,4]

Transthyretin amyloid cardiomyopathy (ATTR-CM) and light-chain amyloidosis with cardiac involvement (AL-cardiac) are the two main types of cardiac amyloidosis. They have different pathophysiological causes and clinical courses. ATTR-CM is caused by misfolding of transthyretin, a transport protein produced by the liver, into insoluble fibrils that accumulate within the myocardium, producing a slowly progressive infiltrative cardiomyopathy that predominantly affects older adults.[5] In contrast, AL-cardiac amyloidosis arises from a plasma cell dyscrasia characterized by overproduction of monoclonal immunoglobulin light chains, which exert direct cardiotoxic effects in addition to forming myocardial deposits.[6]

In the past, the only management of cardiac amyloidosis available was supportive heart failure therapy and symptom control.[5] There were limited disease-modifying pharmacological options were at that time. Progress in understanding the molecular and cellular mechanisms underlying amyloid formation lead to the development of pharmacological strategies that target multiple stages of the amyloid cascade.[7] Contemporary approaches include transthyretin stabilizers that inhibit tetramer dissociation, gene-silencing therapies that reduce hepatic production of amyloidogenic precursor proteins, and amyloid-clearing monoclonal antibodies designed to promote removal of established myocardial deposits.[8] The emergence of these mechanism-based therapies has resulted in a rapidly expanding and increasingly heterogeneous clinical trial landscape, underscoring the need for structured synthesis of ongoing pharmacological development efforts.

In rare and evolving disease areas such as cardiac amyloidosis, registry-based analyses play a critical role in contextualizing therapeutic innovation and identifying research trends that may not yet be reflected in the published literature.[9,10,11] The ClinicalTrials.gov registry provides a comprehensive and standardized platform for capturing global interventional activity, facilitating evaluation of trial design, therapeutic mechanisms, and outcome priorities as new pharmacological strategies emerge.

Accordingly, the aim of this review is to perform a qualitative, registry-based analysis of interventional clinical trials registered on ClinicalTrials.gov to characterize current pharmacological strategies for cardiac amyloidosis, with particular emphasis on therapeutic drug classes, primary outcome domains, and the frequency of investigational agents.

2. Materials and Methods

This review was conducted as a qualitative, registry-based analysis of interventional clinical trials evaluating pharmacological treatment strategies for cardiac amyloidosis. The methodology followed the principles of the PRISMA statement to ensure transparent reporting of study identification, screening, eligibility assessment, and inclusion. The objective was to synthesize trial-level evidence describing emerging and established pharmacological approaches relevant to cardiac amyloidosis without performing quantitative meta-analysis.

Clinical trial data were obtained exclusively from the ClinicalTrials.gov registry, a publicly accessible database maintained by the U.S. National Library of Medicine. This registry was selected as the sole data source due to its comprehensive coverage of global interventional trials, standardized reporting structure, and suitability for systematic identification and qualitative synthesis of ongoing and completed pharmacological studies.

A structured search of ClinicalTrials.gov was performed using predefined condition-related terms relevant to cardiac amyloidosis. The initial search combined the terms “cardiac amyloidosis,” “ATTR cardiomyopathy,” “transthyretin cardiomyopathy,” and “AL amyloidosis.” The search was restricted to interventional studies involving adult participants, including both adults aged 18–64 years and older adults aged 65 years or above. Eligible study phases included Early Phase 1, Phase 1, Phase 2, Phase 3, Phase 4, and studies categorized as not applicable. Trials with recruitment statuses of not yet recruiting, recruiting, active but not recruiting, completed, enrolling by invitation, or unknown status were included. The search was limited to trials first posted between January 1, 2015 and November 30, 2025. This initial search yielded 187 records.

To improve specificity for cardiac amyloidosis and to exclude neuropathy-dominant forms of transthyretin amyloidosis, a refined search was subsequently conducted using Boolean exclusion terms. Records containing the terms neuropathy, polyneuropathy, FAP, or familial amyloid polyneuropathy were excluded. Application of these exclusion criteria reduced the dataset to 102 records, which were subjected to manual screening.

The remaining records were screened by reviewing study titles, condition descriptions, intervention types, and brief summaries to assess relevance to pharmacological treatment of cardiac amyloidosis. Studies were excluded at this stage if they were observational, diagnostic, imaging-only, device-based, procedural, or focused solely on supportive or symptomatic management. Additional exclusions included pediatric studies, trials targeting localized or non-systemic amyloidosis, systemic light-chain amyloidosis trials without explicit cardiac relevance, and studies lacking sufficient methodological information for qualitative assessment. Full registry entries of potentially eligible trials were then reviewed in detail to confirm cardiac disease relevance, pharmacological intent, and eligibility. Following this screening and eligibility assessment process, 18 interventional clinical trials were included in the final qualitative synthesis (Figure 1).

For each included study, relevant trial-level data were extracted from ClinicalTrials.gov and recorded in a structured spreadsheet. Extracted information included the trial registration number, study title, amyloidosis subtype, investigational drug or biological agent, therapeutic mechanism of action, study phase, recruitment status, planned or actual enrolment, primary outcome domain, and study design with comparator characteristics. Therapeutic class assignment was based on the dominant mechanism of action of the investigational intervention, allowing classification into transthyretin stabilizers, transthyretin silencers, amyloid-clearing monoclonal antibodies, amyloid disruptors or fibril-modifying agents, and cardiac phenotype–directed therapies relevant to transthyretin amyloid cardiomyopathy.

A descriptive qualitative synthesis was performed to summarize the characteristics of the included trials according to therapeutic class, outcome domains, and study design features. Given the heterogeneity of pharmacological interventions, trial designs, and outcome measures, no quantitative synthesis or meta-analysis was undertaken. As this study involved analysis of publicly available registry data without individual patient-level information, ethical approval and informed consent were not required. Gemini AI was used to generate graphical figure of amyloid cascade and relevant therapeutic targets (Figure 2).

3. Results

Study Selection

After initial registry filtering, systematic screening of the ClinicalTrials.gov dataset yielded 102 records for review. Following application of predefined inclusion and exclusion criteria focused on interventional pharmacological trials with explicit cardiac targeting or disease-modifying intent, 18 trials were selected for inclusion in this review.

General Characteristics of Included Trials

The 18 included trials primarily targeted two disease subtypes: transthyretin amyloid cardiomyopathy (ATTR-CM) and light-chain amyloidosis with cardiac involvement (AL-cardiac). As detailed in Table 1, fourteen trials focused on ATTR-CM, while four trials enrolled patients with AL-cardiac disease. The studies spanned clinical phases 1 through 4, with phase 3 trials representing the most common design. Planned or actual enrolment varied widely, ranging from small exploratory studies enrolling approximately 15 participants to large phase 3 trials enrolling up to 1,400 participants (Table 1). Enrolment was not reported for one included trial.

Pharmacological Strategies Evaluated

Five distinct therapeutic classes were identified among the pharmacological strategies evaluated. These included transthyretin (TTR) stabilizers, TTR silencers (small interfering RNA or antisense oligonucleotides), amyloid-clearing monoclonal antibodies, amyloid disruptors or fibril-modifying agents, and cardiac phenotype–directed therapies in ATTR-CM that did not directly target amyloid deposition. Classification was based on the dominant mechanism of action of each investigational intervention, as summarized in Table 1.

Frequency of Investigational Agents

The distribution of individual investigational agents across the included trials is presented in Table 2. CAEL-101 and eplontersen were the most frequently evaluated agents, each studied in three trials. ALXN2220, AG10/ALXN2060, and doxycycline were each evaluated in two trials. Other agents including NI006, coramitug, AT-02, tafamidis, trimetazidine, and empagliflozin were each assessed in a single interventional study.

Distribution of Therapeutic Drug Classes

As shown in Table 3, amyloid-clearing monoclonal antibodies constituted the largest therapeutic class, accounting for 8 of the 18 trials (44.4%) and the highest total reported enrolment (3,075 participants). This class included four ATTR-CM trials and four AL-cardiac trials. TTR silencers (n=3) and TTR stabilizers (n=3) followed, with total reported enrolments of 1,481 and 127 participants, respectively. Amyloid disruptors or fibril-modifying agents were evaluated in two trials enrolling 202 participants, while cardiac phenotype–directed therapies were assessed in two trials with a combined enrolment of 39 participants.

Primary Outcome Domains

Primary endpoints across the included trials were categorized into six outcome domains, as summarized in Table 4. Clinical events including all-cause mortality and hospitalization were the most frequently reported primary outcome domain, used in seven trials. Safety and tolerability were the primary endpoints in five trials, including the safety-focused CAEL-101 study. Biomarker or pharmacodynamic endpoints, such as transthyretin levels or stabilization, were primary outcomes in three trials. Cardiac structural or functional assessment using imaging modalities (e.g., echocardiography, cardiac magnetic resonance) served as the primary outcome in two trials, while functional or health-status measures (six-minute walk distance) were the primary endpoint in one trial. None of the included trials used hematologic or organ response as the sole primary outcome domain.

Trial Design and Comparator Characteristics

Trial design and comparator characteristics are detailed in Table 5. Parallel-group placebo-controlled designs were the most common, utilized in ten trials. Six trials employed a single-arm, open-label design without a reported comparator. Parallel-group active-controlled designs were used in two trials, both comparing investigational therapy with standard of care. One trial utilized a crossover design with a placebo comparator.

Summary of Results

In summary, 18 interventional clinical trials met the eligibility criteria for this review, representing a total reported enrolment of 4,924 participants across 11 unique pharmacological agents. Amyloid-clearing monoclonal antibodies were the most prevalent therapeutic class by both trial count and enrolment volume. Clinical events and safety were the most common primary outcome domains, and parallel-group placebo-controlled designs predominated. The distribution of included trials was weighted toward ATTR-CM, which accounted for 77.7% of the study population.

4. Discussion

The systematic search across the clinical trials registry identified therapeutic strategies targeting different stages of the amyloid cascade. Transthyretin (TTR) silencers act by degrading messenger RNA (mRNA) and thereby reducing hepatic synthesis of the amyloid precursor protein.[1] TTR stabilizers act by slowing the formation of new amyloid deposits through binding to the natural tetramer preventing its breakdown to monomers.[12] In contrast, amyloid-clearing monoclonal antibodies are designed to recognize epitopes on deposited fibrils, promoting immune-mediated clearance of established myocardial amyloid.[13] Fibril-modifying agents act by interfering with fibril assembly or altering fibril structure to enhance their clearance.[14] Cardiac phenotype-directed therapies represent a distinct category, since they do not directly target amyloid pathology but focus on myocardial function and the alleviation of heart failure symptoms within the framework of infiltrative cardiomyopathy.[15]

Clinical trial representation between the two types of cardiac amyloidosis, ATTR-CM and AL-cardiac shows an imbalance, reflecting significant differences pathophysiology and reflects fundamental differences in disease biology and clinical progression.[16] ATTR-CM typically follows a slowly progressive course over many years, creating a relatively stable platform for long-duration cardiovascular trials centered on clinical outcomes.[12] AL-cardiac amyloidosis, on the other hand, is often an aggressive disease with a high early death mortality.In contrast, AL-cardiac amyloidosis often presents as an aggressive disease with high early mortality. Consequently, AL-cardiac frequently necessitates urgent hematologic intervention and limits the feasibility of placebo-controlled designs or delayed treatment initiation.[17] Furthermore, the therapeutic development for each type has taken different courses. For AL, research has been driven by hematology-led plasma cell dyscrasia trials, whereas ATTR-CM studies have followed a cardiology-focused model targeting a single, organ-specific amyloidogenic protein.[18]

The diversity of primary outcomes in cardiac amyloidosis clinical trials adds some difficulty in interpreting current trials. In cases of clinical trials of rare diseases, it is challenging to follow clinical event endpoints as they require large sample sizes and prolonged follow-up.[19] Functional assessments, including six-minute walk distance and health-status questionnaires, offer sensitivity to change but may be influenced by non-cardiac factors such as age, frailty, or coexisting neuropathy.[20] Moreover, earlier diagnosis and improved disease awareness have shifted trial populations toward milder baseline disease, resulting in slower progression within placebo groups compared with historical cohorts. Consequently, detectable differences between active treatment and control arms may be less relative to earlier landmark studies.[16,21]

Clinical positioning of available and emerging therapies appears closely linked to disease stage along both biological and clinical progression.[1,22] In early or pre-symptomatic stages, limiting amyloid formation by upstream precursor suppression (TTR silencers) is most relevant to prevent irreversible myocardial injury.[23] Meanwhile, TTR stabilizers and amyloid-clearing antibodies serve as foundational mid-cascade intervention in symptomatic patients or positioned as adjunctive therapies in individuals with substantial residual amyloid burden, respectively.[24] In AL-cardiac amyloidosis, rapid suppression of the plasma cell clone remains the primary therapeutic priority, with fibril-targeting agents considered potential adjuncts only after adequate hematologic control has been achieved.[25,26] Although conceptual sequencing strategies including early combination approaches have been proposed, registry data indicate that robust comparative evidence to guide such strategies remains limited.[8,27]

The key unmet needs in pharmacological treatment of cardiac amyloidosis direct us to the future research focus. Although contemporary therapies attenuate disease progression, they do not provide consistent reversal of myocardial damage.[28,29] To improve care, researchers are focusing on several key areas; there is a need for highly sensitive biomarkers to define therapeutic response [30]. Multiple blood-based candidates are under evaluation in ATTR, including circulating TTR concentration, retinol-binding protein 4, and TTR aggregate–specific probes such as TAD1.[31,32] It is critical to set standards for disease progression and for functional and quality of life measures, as consensus-driven, prospectively validated standards are needed.[33,34,35] Many of these new life-changing drugs are extremely expensive, which prevents many patients around the world from getting fair and equal access to treatment. Because this disease affects many parts of the body, heart specialists (cardiologists) and blood specialists (hematologists) must work together more closely. This teamwork will help design clinical trials that focus on what matters most to the patient: feeling better, staying independent, and enjoying a higher quality of life.

Reviews that are based on registry-based data have a few inherent limitations, which must be considered when interpreting these findings.[11] This review relied exclusively on the ClinicalTrials.gov registry, there is a chance we missed some early-phase or locally sponsored international studies. Public registries also suffer from variable data quality, inconsistent coding and missing entries, as we found in one of the included studies did not report enrollment numbers. There is also a real risk that these public records make the research landscape look more advanced than it actually is, as registries aren’t always updated to show when a trial is terminated or ends in a negative result. Significant trial heterogeneity further complicates the synthesis, particularly regarding the evolving baseline characteristics of the study populations. Newer trials like HELIOS-B and ATTRibute-CM are enrolling “healthier” participants who were diagnosed at much earlier stages than the people in older landmark studies like ATTR-ACT. This makes finding measurable differences between drug and placebo arms harder and smaller to detect. Finally, the diversity of primary outcome domains that exists between studies (Table 4), limits the ability to perform direct comparisions across different pharmacological classes.

5. Conclusions

The shift in the pharmacological management of cardiac amyloidosis transitioning from purely palliative symptomatic care toward stage-specific, disease-modifying strategies represents a fundamental change in clinical practice. Recent advances in transthyretin silencers and the development of amyloid-clearing monoclonal antibodies suggest a broader capacity to intercept the amyloid cascade at distinct molecular checkpoints. While refined diagnostic protocols now facilitate detection in earlier, more milder phases of the disease, this improved prognostic outlook complicates the selection of clinical trial endpoints and the interpretation of long-term therapeutic efficacy. This situation highlights why we need solid, data-driven guidelines on which drugs to use first, how to combine them safely, and how to set clear standards for tracking a patient’s health over time.