Moving Forward in Amyloidosis

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Transthyretin (TTR) and immunoglobulin light chain (AL) are the most common forms of amyloidosis  in North America. The outcome of patients with AL and ATTR amyloidosis has been negatively impacted by diagnostic delays and limited (AL) or absent (ATTR) therapeutic options. Our amyloidosis program is active in preclinical and clinical research in amyloidosis, with the goal of rapid bench-to-bedside 
translation of research findings to improve the lives of our patients.

Early Diagnosis of Amyloid Cardiomyopathy

Advanced cardiac involvement is the factor that most negatively affects outcome in AL amyloidosis. Diagnostic delays are frequent and novel biomarkers are needed to identify cardiac involvement in earlier phases of the disease. A recent breakthrough, 18F-florbetapir PET/CT, has provided, for the first time, specific and quantitative imaging of myocardial amyloid, including toxic amyloid protofibrils. Led by Sharmila Dorbala, MD, MPH, we are evaluating myocardial 18F-florbetapir retention as a biomarker for disease aggressiveness in AL. We have already shown that there is uptake in myocardium in patients with AL when ventricular wall thickness and serum cardiac biomarkers are normal, indicating it can detect early cardiac disease. This ongoing study will also assess the effects of light chain reduction due to chemotherapy on myocardial structure, function, and metabolism and define the time course of these changes through 18F-florbetapir, cardiac MRI parameters, and 11C-acetate PET.

Advancement in AL Amyloidosis Treatment

In January 2021, the FDA approved the first treatment for newly diagnosed AL amyloidosis based on the results of the randomized, phase 3 multicenter clinical trial comparing standard of care cyclophosphamide, bortezomib, and dexamethasone (CyBorD) to daratumumab-CyBorD (DaraCyBorD). Combinatorial chemo-immunotherapy incorporating CD38-targeting antibody daratumumab showed superior ORR (92% vs. 77%), depth of response, and time to hematologic complete response (CR) compared to CyBorD. Importantly, both cardiac and renal response at 6 months was doubled in DaraCyBorD.

In the newly diagnosed space, we are about to open two randomized phase 3 clinical trials, targeting IIIA and IIIB AL amyloidosis patients, evaluating the impact of adding the antifibrillary antibody, CAELUM001, to standard of care chemotherapy. (NCT04512235 and NCT04504825). In early-phase clinical studies, this compound has shown promise in accelerating renal and cardiac response in AL amyloidosis.

Finally, we anticipate opening several studies in the relapsed/refractory space including an eagerly awaited, all-oral ECTN trial incorporating venetoclax for t(11;14) patients.

FDA-approved Treatment for ATTR Amyloidosis

TTR is a normal serum protein, predominantly synthesized by hepatocytes. In the sporadic form of ATTR, circulating, conformationally unstable wild-type (WT) deposits as amyloid fibrils in the heart. Germline mutations in TTR can cause hereditary ATTR (hATTR) with involvement of the heart and/or peripheral or autonomic nervous system (hATTR-P). Tafamidis works by stabilizing the TTR protein, slowing the formation of amyloid fibrils and hence, disease progression, reducing heart failure hospitalizations and mortality. Tafamidis was FDA-approved in 2019 for the treatment of WT or mutant ATTR cardiomyopathy. Inotersen (an anti-sense oligonucleotide, ASO) and patisiran (a small interfering RNA, siRNA), are approved for hATTR-P based on results of phase 3 studies showing marked reduction in TTR serum levels and stabilization of neurological assessments. We are currently participating in clinical studies evaluating inotersen, patisiran, and next-generation ASO/siRNA in hereditary ATTR-cardiomyopathy. (NCT04136171) Excitingly, as a monogenic, dominant disease, with well described mutations, CRISPR-Cas9-based TTR gene editing was evaluated in a first-in-humans clinical trial in hATTR-P with promising results.

An Out-of–the-Box Approach to Treating AL Amyloidosis

The Bianchi Laboratory is eagerly working on a pipeline of several amyloidosis-based projects spanning from studies of fundamental mechanisms of disease pathogenesis to novel therapeutic approaches. Excitingly, the work of Maria Moscvin, MD, a postdoctoral fellow in the lab, on targeting immunoglobulin-free light chain secretion via botulinum neurotoxin, has been showcased at the most recent International Myeloma Workshop and FASEB Hematologic Neoplasia meetings. We are anticipating that this work will shed light on the molecular mechanisms supporting light chain secretion in AL amyloidosis and lay the foundation for novel, out-of-the box therapies to tackle the Achilles’ heel of this disease to improve patient outcome.


Images from each of the 3 study groups (Cardiac-AL-prior to chemotherapy [A], remission Cardiac-AL [B], Non-Cardiac AL by the consensus criteria prior to chemotherapy [C and D]) shows myocardial 18F-florbetapir uptake, most marked in A, but also seen in a cohort of patients in C, who had normal ventricular wall thickness and cardiac serum biomarkers; Cardiac MRI showed abnormal late gadolinium enhancement and mildly elevated extracellular volume in group C too. We found that the non-cardiac AL group could be divided into preclinical cardiac involvement or not based on [18F]florbetapir retention index of >0.06 min-1 (C) or <0.06 min-1 (D).

The subject in the last column (D) had no late gadolinium enhancement and a normal calculated extra-cellular volume, with minimal (if any) LV myocardial [18F]florbetapir uptake.