Dr. Ahmad Masri, Director of the Cardiac Amyloidosis Program at Oregon Health & Science University (OHSU), reminds us about the traditional approach to diagnosis of cardiac amyloidosis. Unfortunately, this has not been enough. Thankfully, over the past decade that has all changed. He talks about OSHU’s approach to diagnosis today and what other data is used to arrive at a diagnosis of cardiac amyloidosis, offering four sample patient cases for insights.
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Transthyretin Amyloidosis (ATTR) Treatments: Stabilizers, Silencers, Depleters, and More!
Transthyretin (TTR) is a protein, mainly produced by the liver. The name transthyretin is derived from the protein’s function of transporting the hormone thyroxin as well as retinol. (2) In the case of Transthyretin Amyloidosis, TTR proteins (in the form of a tetramer) separate into individual monomers and become misfolded. The misfolded proteins aggregate into amyloid fibrils which deposit throughout the body, eventually causing symptoms that may be cardiac, neuropathic, gastrointestinal, etc. in nature.
The two main types of ATTR are Wild Type and Hereditary. Wild Type Amyloidosis is a disorder predominately of older men in their 70s and beyond. Hereditary Amyloidosis is associated with an inherited genetic mutation.
The four main types of treatments for ATTR, either currently available or in development, consist of stabilizers, silencers, depleters, and gene editors. Note the treatments discussed below include those that are FDA-approved at the time of writing; new FDA-drugs will likely become available in the future.
Stabilizers
TTR stabilization therapy aims to prevent misfolding/destabilization of TTR as shown circled in blue on the illustration below.
There are several TTR stabilization therapies available, including acoramidis, tafamidis, and diflunisal.
Acoramidis (AG10) binds to TTR at thyroxine binding sites and slows dissociation of the TTR tetramer. (5) Acoramidis was approved by the FDA in 2024 for wild-type and hereditary ATTR patients with cardiomyopathy. The drug is administered orally, twice per day.
Tafamidis binds to the TTR and stabilizes the TTR tetramer, thus slowing misfolding and inhibiting the formation of amyloid fibrils. (4) Tafamidis was FDA approved in 2019 for wild-type and hereditary ATTR patients with cardiomyopathy. The drug is administered orally, once per day.
Diflunisal is a non-steroid anti-inflammatory (NSAID) drug, primarily used to treat pain associated with arthritis, but can be used “off-brand” as a TTR stabilizer. A study proved that diflunisal prevented amyloid fibril formation by tying TTR binding sites in a similar manner to tafamidis. Diflunisal has been shown to halt disease progression and improve quality of life. (3)
Silencers
In the case of hereditary amyloidosis, TTR silencer therapy aims to prevent destabilization of TTR by silencing errant “messenger RNA” signals. There are multiple silencing therapies available, including patisiran,vutrisiran, inotersen, and eplontersen.
An illustration of the silencing process associated with vutisiran is shown below. The process utilizes small interfering RNAs (siRNA) which results in a single stranded RNA which cleaves the messenger RNA, thus destroying it. (7)(8)
Vutisiran is a newer version of patisiran. It is given as an injection once every three months and must be administered at a healthcare facility. Vutisiran is currently FDA approved for ATTR with polyneuropathy, however, recent clinical trial results show promising data associated with treatment of cardiomyopathy.
Eplontersen is a newer version of inotersen and is FDA approved for polyneuropathy. It can be self-administered monthly via an auto-injector at home. A clinical trial for its use in the treatment of cardiomyopathy is ongoing.
Since TTR proteins serve to transport retinol, a vitamin A supplement must be prescribed to patients using silencer therapy.
Depleters
Also known as antibody therapies, there are a number of treatments currently under development that are designed to remove amyloid that has been deposited in bodily organs and tissue, including
ALXN-2220, AT02, NNC6019.
For example, ALXN-2220 is an investigational antibody that incorporates a fundamental mechanism of the human immune system. The ALXN-2220 antibody specifically targets insoluble ATTR fibrils, eliminating ATTR by activating immune cells which ingest and destroy cellular debris. (6)
Gene Editors
In the field of genome engineering, the term “CRISPR” is often used loosely to refer to the various systems that can be programmed to target specific stretches of genetic code and to edit DNA at precise locations. With this system, genes in living cells are permanently modified, allowing for the correction of mutations at precise locations in the human genome. (9)
CRISPR NTLA-2001 is a form of gene editing, currently in clinical trial, that is designed to edit mutated DNA associated with hereditary amyloidosis. This therapy would be a one-time treatment to remove the area of the DNA with the mutation in the liver cells producing the TTR.
… And More
Looking ahead, research of new treatments is active and exciting. The future looks brighter than ever for ATTR patients!
For further information on this paper’s subject matter, please view:
Bibliography
- Sperry, Brett, “Expert Insights Into Amyloidosis, ATTR Amyloidosis Treatments: Stabilizers and Silencers,” Amyloidosis Speakers Bureau, 2024. https://drive.google.com/file/d/1qoAETBYDjDj3zHzxqqxHvAfoq1sfiuEd/view
- “Protein Biosynthesis” https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/protein-biosynthesis
- Morfino, P., Aimo, A., Vergaro, G., Sanguinetti, C., Castiglione, V., Franzini, M., Perrone, M. A., & Emdin, M. (2023). Transthyretin stabilizers and seeding inhibitors as therapies for amyloid transthyretin cardiomyopathy. Pharmaceutics, 15(4), 1129. https://doi.org/10.3390/pharmaceutics15041129
- Coelho, T., Merlini, G., Bulawa, C. E., Fleming, J. A., Judge, D. P., Kelly, J. W., Maurer, M. S., Planté-Bordeneuve, V., Labaudinière, R., Mundayat, R., Riley, S., Lombardo, I., & Huertas, P. (2016, June). Mechanism of action and clinical application of Tafamidis in hereditary transthyretin amyloidosis. Neurology and therapy. https://pmc.ncbi.nlm.nih.gov/articles/PMC4919130/
- National Institutes of Health. (n.d.). DailyMed – ATTRUBY- acoramidis hydrochloride tablet, film coated. U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=913552ef-875d-4cb7-bf05-a7d20a394c38
- Michalon, A., Renaud, L., Machacek, M., Cortijo, C., Udata, C., Mercuri, M. F., Buller, F., Hock, C., Nitsch, R. M., Kahr, P. C., & Grimm, J. (2024). Prediction of Cardiac ATTR Depletion by NI006 (ALXN2220) Using Mechanistic PK/PD Modeling. Clinical Pharmacology and Therapeutics, 117(1), 261. https://doi.org/10.1002/cpt.3455
- “What Is RNAi – RNAi Biology.” UMass Chan Medical School, 7 Jan. 2022, umassmed.edu/rti/biology/rna/how-rnai-works/.
- “RNAi Therapeutics: How RNA Interference Works: Alnylam® Pharmaceuticals.” RNAi Therapeutics | How RNA Interference Works | Alnylam® Pharmaceuticals, alnylam.com/our-science/the-science-of-rnai
- Questions and answers about CRISPR. @broadinstitute. (2014, December 17). https://www.broadinstitute.org/what-broad/areas-focus/project-spotlight/questions-and-answers-about-crispr
Amyloidosis and the Gut
Dr. Melissa Hershman, assistant professor from the OHSU Division of Gastroenterology & Hepatology, provides an informative overview of how, and where, amyloidosis can present in the G.I. tract. She reviews patient symptoms, many of which are nonspecific and can be associated with other more common issues, delaying diagnosis. Dr. Hershman goes through how G.I. amyloidosis is tested for, where in the G.I. tract biopsies are most commonly performed, and how the tissue is stained for diagnosis by pathology. In closing, she reviews the array of treatments available to assist patients.
Patient Insights: West African Descent – BE AWARE!
Our patient speakers at the Amyloidosis Speakers Bureau are powerful educators and offer compelling insights. Have a listen to this brief clip from Greg with his call out to those of West African descent — BE AWARE there is a high prevalence believed to be carriers of hereditary amyloidosis.
For those that would like a more clinical explanation of this genetical variant, we invite you to view this video by Dr. Kevin Alexander, advanced heart failure and transplant cardiologist at the Stanford Amyloid Center. In it he discusses transthyretin cardiac amyloidosis (ATTR-CM) and how today this is a “common rare disease,” more prevalent than previously appreciated. He summarizes findings from a study to understand diagnosis across the U.S. and how ATTR-CM disproportionately affects black individuals. This statistic is driven by the belief that 3-4% of African descendants carry the V122I TTR variant – translating to over 1 million carriers. Kevin offers a screening algorithm for who to screen for ATTR-CM, and examines sub-groups of African Americans that are important not to overlook.
The Future for Patients with Transthyretin Cardiac Amyloidosis is Looking Brighter
The treatment for patients with Transthyretin Cardiac Amyloidosis has advanced significantly since 2018 when there were no FDA-approved therapies. In this presentation, Dr. Mat Maurer from Columbia University shares how diagnostic imaging techniques have significantly improved, thereby reducing the need for an invasive heart biopsy. In addition, he shares fascinating statistics on how the age and stage of diagnosis has been evolving. Based on today’s clinical trials, providers are optimistic that the expansion of options for patient care will continue.
The future is indeed looking brighter.
