A Look Into the Future of ATTR-CM Clinical Trials

Summary for Physicians: Designing Future Trials in ATTR-CM

Future trials in ATTR-CM (transthyretin amyloid cardiomyopathy) should focus not only on evaluating the efficacy of novel therapies, including amyloid depleters, but also on enhancing our understanding of the mechanisms driving cardiac dysfunction, particularly in wild-type disease and nonresponders to current treatments. Key considerations for trial design include:

1. Mechanistic Research:
   1. Biomarker integration: Trials should incorporate biomarkers (eg, NT-proBNP, troponin, TTR, amyloid-related markers) to assess how therapies impact both amyloid burden and cardiac dysfunction. This will help define the relationship between amyloid deposition and heart failure progression.
   2. Molecular and genetic profiling: Including genetic testing (for TTR mutations) and advanced techniques such as RNA sequencing or proteomics could help identify specific molecular mechanisms underlying disease progression, particularly in wild-type ATTR-CM and in nonresponders.
   3. Tissue analysis: Endomyocardial biopsies or cardiac MRI with advanced imaging techniques could provide insights into amyloid infiltration, inflammation, and fibrosis, allowing for a deeper understanding of the pathological changes in the heart.
2. Patient Stratification:
   1. Stratified subgroups: Trials should stratify patients into distinct groups (eg, wild-type vs hereditary ATTR, responders vs nonresponders) to assess differential responses to therapies. This approach can identify factors that contribute to lack of response in certain patients and guide more personalized treatment strategies.
   2. Longitudinal data: Include long-term follow-up data to capture how treatments impact disease progression over time, particularly for patients with wild-type disease, who may have a slower progression.
3. Efficacy End Points:
   1. Surrogate end points: In addition to traditional clinical outcomes such as mortality or hospitalization, surrogate end points (eg, improvement in biomarkers, cardiac imaging findings, or exercise capacity) should be included to more quickly evaluate therapeutic effects.
   2. Functional end points: Measures such as the 6-minute walk test, quality-of-life assessments, and symptom questionnaires should be incorporated to assess the broader impact of therapy on daily functioning and patient well-being.
4. Inclusion of Nonresponders:
   1. Trials should explicitly include patients who have shown little to no benefit from current therapies (eg, tafamidis, diflunisal) to better understand the reasons behind therapy resistance. This can help identify potential new therapeutic targets or biomarkers associated with nonresponsiveness.
   2. Combination therapies: Investigating combination therapies, including amyloid depleters and other novel agents targeting different pathways involved in cardiac dysfunction (eg, inflammation, fibrosis), may provide insights into better treatment strategies for nonresponders.
5. Data Collection and Sharing:
   1. Emphasize real-world data collection and collaboration across centers to enhance the diversity of the patient population and improve generalizability. Multicenter collaborations, including registries and biobanks, could facilitate a deeper understanding of disease variability and therapeutic outcomes.

In conclusion, future clinical trials for ATTR-CM should integrate mechanistic studies, patient stratification, diverse end points, and a focus on nonresponders to better understand and address the underlying causes of cardiac dysfunction, leading to more effective, personalized treatment strategies.