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AMVUTTRA is now FDA-APPROVED for ATTR-CM in U.S.
AMVUTTRA® (vutrisiran) was approved by the FDA in March 2025 for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular mortality, cardiovascular hospitalizations and urgent heart failure visits.
The approval expands the indication for AMVUTTRA, which now becomes the first and only therapeutic approved by the FDA for the treatment of ATTR-CM and the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) in adults.
“AMVUTTRA is an RNAi therapeutic that works upstream to deliver rapid knockdown of TTR, addressing the disease at its source, with only four convenient subcutaneous doses per year. By rapidly knocking down TTR production, AMVUTTRA substantially decreases deposition of TTR fibrils, which form amyloid and cause irreversible cardiovascular damage and premature death in patients with ATTR-CM.” according to Alnylam’s press release.
Autologous Stem Cell Transplantation in AL Amyloidosis: what, why, when, and for whom?
Dr. Heather Landau is an oncologist and hematologist at the Memorial Sloan Kettering Cancer Center, bone marrow transplant specialist, and director of their Amyloid Program. In this video Dr. Landau reviews the history and goal of treatment for AL amyloidosis. Next she delves into detail and experiences of using high dose therapy and autologous stem cell transplant to treat light chain (AL) amyloidosis. In conclusion, she will discuss how the treatment landscape has changed based on recent advances.
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
Harnessing Your Immune System: CAR-T and Bispecific Antibodies
Dr. Morie Gertz, professor of medicine at the Mayo Clinic in Rochester and world renowned expert in amyloidosis, talks about how the immune system can be harnessed in the fight against amyloidosis and multiple myeloma. He discusses two immune-directed therapies: CAR-T and Bispecific Antibodies. Dr. Gertz eloquently, and in an easy-to-understand way, summarizes the goal of immune-directed therapies and the two approaches today, including the processes, outcomes, advantages, and risks to be considered. This is a must-watch video for physicians from a legendary expert.
The Use of RNA Interference Science in the Treatment of Hereditary Amyloidosis
Hereditary transthyretin amyloidosis (hATTR) is a severe, adult-onset inherited systemic disease which can affect the peripheral and autonomic nervous system, heart, kidney and the eyes. (1)
TTR (transthyretin) is a protein found in blood plasma and blood serum as well as in the cerebrospinal fluid (CSF). The protein is mainly synthesized (assembled) by the liver and the choroid plexus (CP). The name transthyretin is derived from the protein’s function of transporting the hormone thyroxin as well as retinol. The protein is created by a process called biosynthesis. Biosynthesis is carried out in accordance with genetic instructions encoded from ones DNA. The DNA instructions create messenger RNA (mRNA), which in turn biosynthesize transthyretin proteins in the form of a tetramer. (2)
In the case of hereditary amyloidosis, a DNA mutation causes an errant mRNA signal, which results in destabilization of the tetramer and misfolding of the protein. The misfolded TTR proteins aggregate into amyloid fibrils as shown in the figure below. (3) The Amyloid then deposits throughout the body, eventually causing symptoms that may be cardiac, neuropathic, gastro-intestinal, etc. in nature.
RNA interference (RNAi) is a natural process that controls gene “expression” to messenger RNAs (mRNA), thus blocking the RNA instruction for creating a protein.
The figure shown below illustrates this process. (4) In basic terms, the interfering process begins with a long double-stranded RNA (dsRNA) being “diced” into small fragments by an enzyme called a “Dicer”. These fragments, referred to as small interfering RNAs (siRNA), bind to proteins called argonaute proteins. After binding to an argonaute protein, one strand of the double-stranded RNA is removed. The remaining strand then binds to the targeted messenger RNA. The argonaute protein then cleaves the messenger RNA, destroying it.
RNA interfering therapeutic medicines mimic this natural process, utilizing designed small interfering RNAs (siRNA) that ultimately bind to and destroy disease-causing RNA. As a result, the cell is no longer able to produce the misfolded Amyloid protein. One such therapeutic is the drug Vutisiran, used to treat hereditary amyloidosis with polyneuropathy. The figure shown below shows how Vutisiran carries out the same silencing process. (5)
For additional information on ATTR Treatments such as stabilizers and silencers, please view the short Expert Insights video below by Dr. Brett W. Sperry from our Amyloidosis Lecture Series.
Sources —————————————–
- Carroll, A., Dyck, P. J., Carvalho, M. de, Kennerson, M., Reilly, M. M., Kiernan, M. C., & Vucic, S. (2022, June 1). Novel approaches to diagnosis and management of hereditary transthyretin amyloidosis. Journal of Neurology, Neurosurgery & Psychiatry. https://jnnp.bmj.com/content/93/6/668
- “Protein Biosynthesis” https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/protein-biosynthesis
- Diagnostic Algorithm for Transthyretin Amyloidosis with Lower… | Download Scientific Diagram, researchgate.net/figure/Diagnostic-algorithm-for-transthyretin-amyloidosis-with-lower-gastrointestinal_fig1_348081318. Accessed 28 Oct. 2024.
- “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
ATTR Amyloidosis Treatments: Stabilizers and Silencers
Dr. Brett Sperry, cardiologist and director of the Cardiac Amyloidosis Program at Saint Luke’s Mid America Heart Institute, provides an excellent overview of FDA-approved ATTR amyloidosis treatments. He goes into detail about the biology behind silencers and stabilizers and exactly how they impair amyloidosis progression. In addition, he previews the future, summarizing new categories of drugs on the horizon.
Update: In November, 2024 the FDA approved Attruby (Acoramidis) for ATTR-CM (wild-type and hereditary/variant).
The future is indeed exciting!
ATTRUBY (acoramidis) is now FDA-APPROVED for ATTR-CM in U.S.
Attruby (Acoramidis), was approved by the FDA on November 22, 2024 for ATTR-CM patients (both wild-type and hereditary) in the U.S.
Orally-administered, Attruby is a near complete TTR stabilizer (>= 90%), designed to reduce cardiovascular death and cardiovascular-related hospitalization. In addition, Attruby has been shown to preserve the native function of TTR as a transport protein of thyroxine and vitamin A.
To honor the courage of our U.S. clinical trial participants, BridgeBio will provide these patients Attruby free for life.
AL Amyloidosis: The Past, Present, and Future
Dr. Morie Gertz, professor of medicine at the Mayo Clinic in Rochester and world renowned expert in amyloidosis, shares his views on the past, present, and future treatments of AL (light chain) amyloidosis. Over his four decades of experience with this disease, he has diagnosed and treated thousands of patients, advanced research, and managed countless clinical trials. This makes him the perfect professor to orate on the dramatic evolution of treating this historically devastating disease to the optimism of today, and the breakthrough world of tomorrow. This is a must-watch video from a legendary expert.
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.
