Antibody ALXN2220 (Formerly NI006) for the Treatment of Transthyretin Cardiac Amyloidosis

Transthyretin cardiac amyloidosis is an increasingly recognized infiltrative cardiomyopathy that is implicated in a growing number of cases of heart failure. Although it was once considered a disease without a cure, there have been rapid advances in pharmacotherapy over recent decades. The agents currently approved by the United States Food and Drug Administration—tafamidis and acoramidis—are transthyretin stabilizers that prevent the breakdown of the physiologic transthyretin tetramer into fibril-forming monomers. While these agents help prevent disease progression, they do not reverse existing disease. ALXN2220 (previously called NI006) addresses this unmet need. A recombinant human IgG1 monoclonal antibody with high specificity for transthyretin monomers and amyloid fibrils, ALXN2220 stimulates macrophage-mediated phagocytosis of deposited amyloid fibrils. Phase 1 studies have demonstrated the tolerability of doses ranging from 0.3 to 60 mg/kg/month. At doses higher than 10 mg/kg/month, ALXN2220 has demonstrated the ability to decrease cardiac tracer uptake on scintigraphy and decrease the extracellular volume on cardiac magnetic resonance imaging at 4 and 12 months when compared with placebo. These imaging parameters are known surrogates for the burden of cardiac amyloid deposition. In addition, significant reductions in levels of n-terminal proBNP and troponin T, as well as improvements in Kansas City Cardiomyopathy Questionnaire scores were also noted. The adverse effect and immunogenicity profiles were encouraging as well. A multinational, placebo-controlled phase 3 trial (DepleTTR-CM) is ongoing to assess long-term efficacy, functional outcomes, and survival impact. These results are expected to provide critical real-world evidence on ALXN2220’s role in transthyretin cardiac amyloidosis management.