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Review
. 2025 May;18(5):602-617.
doi: 10.1016/j.jcmg.2024.11.003. Epub 2025 Feb 21.

Development of Imaging Endpoints for Clinical Trials in AL and ATTR Amyloidosis: Proceedings of the Amyloidosis Forum

Sharmila Dorbala  1 , Rosalyn Adigun  2 , Kevin M Alexander  3 , Michela Brambatti  4 , Sarah A M Cuddy  1 , Angela Dispenzieri  5 , Preston Dunnmon  6 , Michele Emdin  7 , Omar F Abou Ezzeddine  5 , Rodney H Falk  8 , Mariana Fontana  9 , Justin L Grodin  10 , Spencer Guthrie  11 , Michael Jerosch-Herold  1 , A Alex Hofling  2 , Kristen Hsu  12 , Grace Lin  5 , Ahmad Masri  13 , Mathew S Maurer  14 , Clemens Mittmann  15 , Krishna Prasad  16 , Cristina C Quarta  17 , Jean-Michel Race  18 , Joseph G Rajendran  2 , Frederick L Ruberg  19 , Vandana Sachdev  20 , Vaishali Sanchorawala  19 , James Signorovitch  21 , Christophe Sirac  22 , Prem Soman  23 , Jens Sorensen  24 , Brett W Sperry  25 , Andrew W Stephens  26 , Norman L Stockbridge  2 , John Vest  27 , Jonathan S Wall  28 , Ashutosh Wechalekar  9 , Cynthia Welsh  2 , Isabelle Lousada  29
Affiliations
Review

Development of Imaging Endpoints for Clinical Trials in AL and ATTR Amyloidosis: Proceedings of the Amyloidosis Forum

Sharmila Dorbala et al. JACC Cardiovasc Imaging. 2025 May.

Abstract

Light chain amyloidosis and transthyretin amyloidosis are rare protein misfolding disorders characterized by amyloid deposition in organs, varied clinical manifestations, and poor outcomes. Amyloid fibrils trigger various signaling pathways that initiate cellular, metabolic, structural, and functional changes in the heart and other organs. Imaging modalities have advanced to enable detection of amyloid deposits in involved organs and to assess organ dysfunction, disease stage, prognosis, and treatment response. The Amyloidosis Forum hosted a hybrid meeting to focus on the use of imaging endpoints in clinical trials for systemic immunoglobulin light chain amyloidosis and transthyretin amyloidosis. Stakeholders from academia and industry, together with representatives from multiple regulatory agencies reviewed the use of imaging biomarkers with a focus on cardiac amyloidosis, described applications and limitations of imaging in clinical trials, and discussed qualification of imaging as a surrogate clinical outcome. Survey results provided important patient perspectives. This review summarizes the proceedings of the Amyloidosis Forum.

Keywords: amyloidosis; cardiac imaging; clinical trial endpoints.

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Conflict of interest statement

Funding Support and Author Disclosures The Amyloidosis Forum is funded by the Amyloidosis Research Consortium (ARC). ARC is funded through private/philanthropic donations and grants from for-profit pharmaceutical and biotechnology companies. ARC retains all influence, control, and autonomy over projects for which it has received external support. ARC has received grants from Alexion, Alnylam, Attralus, joint funding from AstraZeneca and Ionis, BridgeBio, GlaxoSmithKline, Intellia Therapeutics, Janssen, Life Molecular Imaging, Pfizer, Protego, and Prothena in support of the Amyloidosis Forum Pathways for the Development of Imaging Endpoints meeting. ARC was responsible for designing the meeting, co-developing the meeting agenda, recruitment of speakers, moderators, and panelists, production of meeting materials, hosting the hybrid meeting, and publications. U.S. Government Employee Disclaimer: This paper reflects the views of the authors and should not be construed to represent official views or policies of the U.S. Food and Drug Administration, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), or the U.S. Department of Health and Human Services. Medicines and Healthcare Products Regulatory Agency (MHRA) Disclosure: The positions expressed in this document are individual opinions and should not be interpreted as agreed positions or policy of MHRA or the UK government. European Medicines Agency (EMA) Disclosure: This paper reflects the views of the authors and should not be interpreted as official positions of EMA, or member agencies, specifically the Bundesinstitut fur Arzneimittel und Medizinprodukte (BfArM), or Agence Nationale de Securite du Medicament et des Produtis de Sante (ANSM). Dr Dorbala has received research grants from Pfizer, Attralus, GE Healthcare, Siemens, and Phillips; and consulting fees from Pfizer, BridgeBio, Novo Nordisk, and MedScape. Dr Alexander has received consulting fees from Alnylam, Arbor Biotechnologies, Bristol Myers Squibb, Intellia, and Novo Nordisk. Dr Brambatti is a shareholder at Ionis pharmaceuticals and employee and shareholder at Merck and Co. Dr Cuddy has received grant support from NIH 1K23HL166686-01 and American Heart Association 23CDA857664; and personal fees from Pfizer, Eidos/BridgeBio, Ionis, AstraZeneca, and Novo Nordisk. Dr Dispenzieri is on the advisory board and independent review committee of Janssen, Oncopeptides, and Sorrento; is on the data monitoring safety committee of Alnylam, Pfizer, and Takeda; and has received research dollars from BMS. Dr Ezzeddine has received research grants from Pfizer Inc; consulting fees from Alnylam Pharmaceuticals and Medscape from WebMD; and intellectual property on AI-enabled amyloid detection from ECG/Anumana, Inc. Dr Falk has received consulting fees from Alnylam and AstraZeneca. Dr Fontana is on the advisory board and/or a consultant for Alexion, Alnylam, Caelum, Intellia, Janssen, Novo Nordisk, Pfizer, Attralus, Lexeo, and Prothena. Dr Grodin has received sources of funding from Texas Health Resources Clinical Scholarship, Pfizer, Eidos/BridgeBio, and NHLBI (R01HL160892); and consultancy fees from Alnylam, AstraZeneca, Intellia Pfizer, Eidos/BridgeBio, and Sarepta. Dr Guthrie is an employee and shareholder of Attralus. Dr Hofling is a U.S. government employee. Dr Lin is an advisory board member for Ionis (Cardio TTransform Trial); and has received research funding for an investigator-initiated trial on TTR amyloid from Pfizer and Biotronik. Dr Masri has received research grants from Pfizer, Ionis, Attralus, and Cytokinetics; and fees from Cytokinetics, BMS, Eidos, Pfizer, Ionis, Lexicon, Alnylam, Attralus, Haya, BioMarin, and Tenaya. Dr Maurer has received grant support from NIH R01HL139671 and R01AG081582-01; grants and personal fees from Alnylam, Pfizer, Eidos, Prothena, and Ionis; and personal fees from AstraZeneca, Akcea, Intellia, and Novo Nordisk. Dr Mittmann is an employee of EMA/BrArM. Dr Quarta is an Alexion/AstraZeneca employee. Dr Race is an employee of EMA/ANSM. Dr Rajendran is a U.S. government employee. Dr Ruberg has received research grants from NIH/NHLBI (HL139671), Alnylam, Akcea/Ionis, and Pfizer; and consulting fees from AstraZeneca. Dr Sanchorawala has received research support from Celgene, Millennium-Takeda, Janssen, Prothena, Sorrento, Karyopharm, Oncopeptide, Caelum, and Alexion; consultant fees from Pfizer, Jansen, and Attralus; and is on the scientific advisory board for Proclara, Caelum, Abbvie, Janssen, Regeneron, Protego, Pharmatrace, Telix, Prothena, and AstraZeneca. Dr Signorovitch is an employee of Analysis Group, Inc, which has received consulting fees from ARC. Dr Sirac has received a research grant from Attralus, Inc. Dr Soman has received institutional grants from Pfizer; and consultancy fees from Pfizer, Anylam, BridgeBio, and Spectrum Dynamics. Dr Sperry has received personal fees from Pfizer, AstraZeneca, Alnylam, and BridgeBio. Dr Stephens is a full-time employee of Life Molecular Imaging, GmbH. Dr Stockbridge is a U.S. government employee. Dr Vest is an employee and shareholder of Alnylam Pharmaceuticals. Dr Wall is an inventor of IP related to iodine (124)I evuzamitide; and is co-founder, shareholder, and chief scientific officer of Attralus, Inc. Dr Wechalekar is on the advisory board/received honorarium from Janssen, GlaxoSmithKline, Prothena, Alexion/AstraZeneca, and Attralus. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

FIGURE 1
FIGURE 1. Prognostic Value of Baseline Longitudinal Strain in AL Amyloidosis and Changes With Therapy
Prospective observational study of newly diagnosed patients (N = 915) with AL amyloidosis chemotherapy (ALCHEMY) seen at the UK National Amyloidosis Centre (NAC) (February 2010–August 2017). (A) Overall survival by baseline longitudinal strain showing a highly significant worsening of overall survival with worsening longitudinal strain category: longitudinal strain ≤−16.2%: 80 months, −16.1% to −12.2%: 36 (95% CI: 20.9–51.1) months, −12.1% to −9.1%: 22 (95% CI: 9.1–34.9) months, and ≥−9.0%: 5 (95% CI: 3.2–6.8) months (P < 0.0001). (B) Overall survival by ≥2.0% longitudinal strain response at 12 months showing patients with a <2.0% longitudinal strain improvement, overall survival was not reached at 50 months, compared with a median survival of 72.0 (95% CI: 64.8–79.2) months. Reproduced with permission from Cohen et al. AL = systemic immunoglobulin light chain amyloidosis.
FIGURE 2
FIGURE 2. GLS and Myocardial Work by Echocardiography as Indicators of Disease Stability in ATTR-CM
In a study of 23 patients with ATTR-CM treated with tafamidis for at least 1 year compared with 22 control subjects with ATTR-CM who did not receive therapy, global longitudinal strain (GLS) and myocardial work index at 1 year worsened less in the tafamidis cohort, suggesting stabilization of amyloidosis. Reproduced with permission from Giblin et al. ATTR-CM = transthyretin amyloidosis–cardiomyopathy; CMR = cardiac magnetic resonance; ECV = extracellular volume fraction.
FIGURE 3
FIGURE 3. Changes in ECV on CMR Imaging as an Indicator of Disease Response in AL Amyloidosis
Kaplan-Meier survival curves, with shaded 95% confidence regions, displaying survival in all patients according to change in amyloid burden (measured by the change in extracellular volume on follow-up CMR) after 6 months. Reproduced with permission from Martinez-Naharro et al. Abbreviations as in Figures 1 and 2.
FIGURE 4
FIGURE 4. ECV on CMR Imaging as an Indicator of Disease Stabilization in ATTR-CM
Longitudinal changes in modified look-locker inversion recovery sequence-derived ECV. In a group of 35 patients treated with tafamidis (61 mg every day) for a median of 9 months (green bar), compared with 19 historical control treatment naive patients (red bar), the progression of interstitial ECV expansion worsened less in the tafamidis cohort. Reproduced with permission from Rettl et al. SAP = serum amyloid P; other abbreviations as in Figures 1 and 2.
FIGURE 5
FIGURE 5. Changes in Quantitative Cardiac Uptake of 99mTc-DPD Using SPECT/CT as an Indicator of Disease Stabilization in ATTR-CM
In 40 patients who received tafamidis for a median of 7 months, those with greater than median improvement in myocardial DPD SUV retention index (A) demonstrated a small but statistically significant improvement in LVEF on CMR (B). Reproduced with permission from Rettl et al.
FIGURE 6
FIGURE 6. PET to Quantify Amyloid in the Heart and Multiple Organs
Demonstration of the value of 124I-evuzamitide PET/CT to image amyloid in the heart and various organ systems. %ID = percent injected dose; CAA = cardiac amyloid activity; PET = positron emission tomography; other abbreviation as in Figure 5.
FIGURE 7
FIGURE 7. Prognostic Value of 18F-Florbetapir PET/CT to Quantify Amyloid in the Heart and Predict Outcomes
Eighty-one participants with newly diagnosed systemic AL amyloidosis were prospectively enrolled and underwent 18F-florbetapir PET/CT. This Kaplan-Meier analysis demonstrates a graded response to 18F-florbetapir PET/CT % ID and outcomes in patients with AL amyloidosis. Patients with the lowest tertile showed the best outcomes and in the highest tertile showed the worst outcomes. Reproduced with permission from Clerc et al. Abbreviations as in Figures 1, 5, and 6.
FIGURE 8
FIGURE 8. Patient Perspectives on the Value of Imaging: Survey Results
Results of informal online survey (N = 653 respondents) provide the patient perspective on the value of imaging in their management of amyloidosis. Mean score represents patient response on a 5-point progressive scale with 1 representing “not important” and 5 representing “very important.” AI = artificial intelligence; ATTR = transthyretin; ATTRv = variant; ATTRwt = wild type.
CENTRAL ILLUSTRATION
CENTRAL ILLUSTRATION. Imaging Targets and Potential Imaging-Based Surrogate Endpoints
Misfolded precursor proteins deposit as amyloid fibrils in various organs including the heart, disrupting organ structure (heart and other organs), causing organ dysfunction, and poor clinical outcomes. Bone-avid SPECT tracers provide a highly specific signal for amyloid, especially ATTR amyloid, in the heart. Amyloid-binding PET tracers image a molecular signal of amyloid, including AL, ATTR, and other types, in the heart and in systemic organs. Echocardiography visualizes structural and functional changes in the heart. MRI characterizes changes in the tissues from amyloid deposition in the heart as well as in the liver and spleen. Amyloid deposition impacts functional status and health-related quality of life, ultimately resulting in the need for cardiac transplantation or death. The survival curve is reproduced with permission from Grogan et al. 6MWD = 6-minute walk distance; AL = immunoglobulin light chains; ATTR = transthyretin; MRI = magnetic resonance imaging; PET = positron emission tomography; QoL = quality of life; SPECT = single-photon emission computed tomography.
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References

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