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

<b>Introduction:</b> Cardiac amyloidosis, primarily comprising transthyretin amyloid cardiomyopathy (ATTR-CM) and light-chain amyloidosis with cardiac involvement (AL-cardiac), is an increasingly recognized contributor to the global heart failure burden. Management has shifted from supportive care to disease-modifying agents targeting specific stages of the amyloid cascade. This registry-based review qualitatively characterizes the current pharmacological clinical trial landscape through a registry-based analysis. <b>Methods:</b> A structured qualitative analysis of ClinicalTrials.gov was conducted for interventional trials registered between January 2015 and November 2025. Following PRISMA principles, studies were screened to include pharmacological interventions with explicit cardiac targeting while excluding neuropathy-dominant amyloidosis. Trial-level data regarding therapeutic classes, study phases, enrollment, and primary outcome domains were extracted and synthesized. <b>Results:</b> A total of 18 trials met the inclusion criteria (14 ATTR-CM; 4 AL-cardiac), representing a total enrollment of 4924 participants across 11 unique agents. Five therapeutic classes were identified: amyloid-clearing monoclonal antibodies (44.4% of trials), TTR silencers, TTR stabilizers, fibril-modifying agents, and cardiac phenotype-directed therapies. Monoclonal antibodies represented the largest class by both trial count and enrollment (3075 participants). Clinical events (n = 7) and safety/tolerability (n = 5) were the most frequent primary outcome domains. ATTR-CM trials dominated the landscape, accounting for 77.7% of the total study population, while parallel-group placebo-controlled designs were the most common study architecture (n = 10). <b>Conclusions:</b> The therapeutic landscape for cardiac amyloidosis is transitioning toward stage-specific, mechanism-based interventions. While ATTR-CM currently dominates research efforts, the expansion of silencers and monoclonal antibodies reflects an increasing capacity to intercept the amyloid cascade at distinct molecular checkpoints. However, significant heterogeneity in outcome measures and the shift toward diagnosing milder disease pose challenges for demonstrating clinical efficacy. Future priorities include standardized progression markers and addressing barriers to global access for these high-cost therapies.