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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:

ATTR Amyloidosis Treatments: Stabilizers and Silencers

CRISPR/Cas9 – Editing the Code of Life

 

 

Bibliography

  1. Sperry, Brett, “Expert Insights Into Amyloidosis, ATTR Amyloidosis Treatments: Stabilizers and Silencers,” Amyloidosis Speakers Bureau, 2024. https://drive.google.com/file/d/1qoAETBYDjDj3zHzxqqxHvAfoq1sfiuEd/view
  1. “Protein Biosynthesis” https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/protein-biosynthesis
  1. 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
  1. 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/
  1. 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
  1. 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
  1. “What Is RNAi – RNAi Biology.” UMass Chan Medical School, 7 Jan. 2022, umassmed.edu/rti/biology/rna/how-rnai-works/.
  1. “RNAi Therapeutics: How RNA Interference Works: Alnylam® Pharmaceuticals.” RNAi Therapeutics | How RNA Interference Works | Alnylam® Pharmaceuticals, alnylam.com/our-science/the-science-of-rnai
  1. 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.

Overview of Amyloidosis for Patients

In this video “Amyloidosis Awareness” from the Amyloidosis Support Groups, narrated by Michael York you’ll hear a brief yet comprehensive overview of amyloidosis designed specifically for patients. It discusses what amyloidosis is, the wide range of symptoms, and which organs are typically involved. It focuses on the most common types, AL (light chain) and TTR (transthyretin), and summarizes the kinds of treatments that are currently available.

 

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!

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.

Orthopedic Manifestations in Amyloidosis

Dr. Mazen Hanna, cardiologist at the Cleveland Clinic and co-director of the Amyloid Program, discusses orthopedic manifestations in amyloidosis. Increasingly, such manifestations are known to be associated with multiple orthopedic pathologies and recognized as a missed opportunity for earlier diagnosis of transthyretin (ATTR) amyloidosis. He recounts the development of a pioneering study connecting carpal tunnel release surgery and amyloidosis. Dr. Hanna concludes this presentation with patient cases and the importance of biopsying tenosynovial tissue from CTR surgery; it’s easy, quick, and inexpensive.

Humanizing Medical Education: Beyond Bullet Points

The content of medical education is appropriately clinically centered. The delivery of this content remains relatively unchanged over the decades – typically taught by medical professionals through lectures, PowerPoint presentations, and patient case studies. We posit that there is an essential missing component: the patient voice. During the didactic years, medical students rarely hear from patients about their symptoms, diagnostic journey, emotional management, support and resources, and relationship with the medical community. By humanizing medical didactic education, patient insights can offer an impactful and durable education that complements traditional didactics, developing what we believe will be better and more empathetic future medical practitioners.

Why is Amyloidosis so Often Misdiagnosed?

Dr. Angela Dispenzieri from the Mayo Clinic discusses why amyloidosis is often misdiagnosed. The complexity of the disease and commonality of symptoms are two of the reasons she examines. In addition, she offers guidance on appropriate diagnostic pathways.

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.

Transplant: Inpatient vs Outpatient

There is no cure for Amyloidosis.

There are, however, an increasing number of treatment alternatives that can significantly reduce, if not eliminate, the disease and put the patient into remission. The most aggressive treatment is a stem cell transplant (SCT); sometimes referred to as a bone marrow transplant.

Stem cells are cells in the bone marrow from which all blood cells develop. This treatment aims to eradicate, typically through high-dose chemotherapy (e.g., melphalan), the faulty plasma cells which make the amyloid light chains. Once eradicated, fresh cells, harvested from the patient themselves (autologous), a donor (allogeneic), or an identical twin (syngeneic), are infused into the patient. This will help to recreate a healthy bone marrow and hopefully stop further production of the amyloid protein.

This complex treatment typically takes four to six weeks and is performed on an inpatient, outpatient, or some combination, depending on the hospital. There are meaningful differences that are important to know and incorporate into each patient’s personal situation in order to make an informed decision.

From the Healthcare Perspective

Across the country, there are multiple hospitals that perform SCTs to treat amyloidosis. While hard data is elusive, the tally of transplants at each facility, we know, is not spread evenly. We do know that Mayo Clinic (Mayo) and Boston University (BU) dominate the list and perform the majority of transplants. It may not be a surprise, then, that these two hospitals are considered amyloidosis Centers of Excellence in the U.S. They see a high volume of cases, have extensive depth and breadth of expertise, and have sophisticated diagnostic equipment. They are also the two hospitals who have pioneered performing outpatient transplants. The good news is this is evolving, with more centers across the country expanding their transplant program to treat amyloidosis.

Everyone would agree that hospitals are germ and bacteria magnets, which can be dangerous for transplant patients with low to no immune systems. BU and Mayo, for example, found patients were better able to withstand the everyday germs outside of the hospital better than the more potent ones within hospitals. This provides a strong incentive for hospitals to consider outpatient, or if they choose the inpatient route, must be ever super mindful of this reality.

There are risks with SCT, and patient safety is key. Having a patient in-house during the treatment affords the hospital maximum control during the process, while being outpatient transfers some responsibility to the caregiver, such as monitoring the patient’s temperature, food, and fluid intake. Being inpatient also affords the quickest access to experts, equipment, and drugs in the event things go awry, which does happen. Mayo has found that a meaningful percentage (38% according to Dr. Morie Gertz) of patients never need hospitalization during the SCT process; however, on the occasions where it is necessary the duration averages a handful of days.

Treating patients on an outpatient basis requires hospitals to alter their process and training, and rely on the patient and caregiver to assume a more engaged role. Without question, hospitals benefit significantly from the experience of performing high volumes of outpatient transplants. Mayo, according to Dr. Morie Gertz, performed their first SCT in March 1996, and their first outpatient SCT in September 1998. In total, they have performed 744 SCTs and currently average about 33 transplants per year. According to Dr. Vaishali Sanchorawala, BU performed their first SCT in July 1994, and their first outpatient SCT in October 1996. In total, they have performed roughly 675 SCTs for AL Amyloidosis, with an annual run rate ranging between 25 and 50. Together, these institutions have over two decades of valuable experience. According to experts, small volume and the resultant lack of experience is likely the key driver behind why hospitals elect to perform SCTs on an inpatient basis.

From the Caregiver Perspective

Caregivers play a critical role in the SCT process, working closely with the healthcare team to ensure the patient is progressing appropriately. They are so critical, in fact, that regardless of inpatient or outpatient, hospitals will not proceed with a SCT unless they are confident the patient has capable and continuous caregiver support.

The role of a caregiver varies greatly between an inpatient and outpatient process. When inpatient, the caregiver provides important emotional support, as being confined to a hospital for weeks on end can be draining and discouraging. This can range from just being present, to chatting, to light activities. Caregivers also assist in the physical need for exercise, helping and encouraging the patient to walk whenever and however many steps possible. The caregiver role may be filled by one or more persons, often impacted by the distance the hospital is from home.

Outpatient SCT procedures are significantly more demanding of caregivers. For the duration of treatment, the hospital will require the patient and caregiver(s) to be proximal to the hospital. Mayo, for example, requires patients to be within ten minutes of the hospital. Fortunately, there are many hotels, motels, inns, and homes for rent (HomeAway, VRBO) that are transplant-friendly and reasonably priced. It is 24/7 support, monitoring the patient’s key indicators, administering and monitoring meds, transporting the patient to/from the hospital daily, securing meds, shopping and preparing food, maintaining the household (e.g., laundry, sanitizing, etc.), and on and on. The list is extensive and exhaustive. Arranging for such intensive support can be a challenge. Some patients assemble a series of caregivers who rotate in/out for periods of time, others are able to secure one dedicated caregiver for the entire time, and in rare instances, the patient is able to have a team of caregivers for the duration.

Whichever caregiver structure is chosen, it is important to also consider self-care for the caregiver. Mini breaks can go a long way to help sustain their ability to meet the needs of the patient and the requirements set forth by the hospital.

From the Patient Perspective

For patients, it is all about getting through this treatment and hopefully arriving at a successful outcome. Time distills down to weeks, then days, and then when things are their most difficult, just getting through the next hour is the focus.

Having a good and capable caregiver(s) in place can help the patient focus only on themselves, knowing the caregiver will take care of everything else.

Side effects of the SCT can be multiple and vary from patient to patient. The list of effects can include fatigue, fever, diarrhea, nausea/vomiting, loss of appetite, mucositis, and hair loss. Fortunately, the healthcare team can be very helpful in mitigating these effects.

Exercise is important to ward off muscular atrophy and does improve recovery. Every step matters. Both Mayo and BU find patients do better and are home quicker if they spend less time in bed and more time moving around. In addition, patients tend to benefit from the required additional movement needed when living away from the hospital.

Emotionally, a SCT is tough. No way around that. But having distractions, whether provided by the caregiver, getting out of bed to exercise or being out and about via outpatient does contribute to an improved psyche. Having any sense of normalcy is welcome.

Cost differs greatly between inpatient and outpatient treatment, with outpatient coming in meaningfully less expensive. Anecdotal information has outpatient transplants at roughly 50% off the cost of inpatient transplants. Yet regardless of the approach, SCTs are extraordinarily expensive, and most likely patients need their insurance to sign off before treatment can begin. One of the considerations by insurance companies is which hospital the patient is proposing for treatment. During our personal experience, where we dealt with two national insurance companies, both informed us that having treatment at a Center of Excellence made a difference.

Finally, what is it really like? While situations vary widely from patient to patient, as may treatments and outcomes, hearing about a SCT straight from a patient who has been there is helpful. Having had an outpatient stem cell transplant in July 2017, hear Mackenzie’s perspective while fresh post-Mayo. Additionally, preparing for an outpatient SCT is more involved for the patient and caregiver; we have provided SCT and Post-Chemo Tips on the Resources page of our website which others may find helpful.

Closing Thoughts

There is strong evidence over many years and many transplants that patient outcomes are better when performed on an outpatient basis. There are, however, notable implications for the healthcare providers, patients and caregivers, depending on which approach is chosen. Inpatient, outpatient and hybrid approaches can provide successful outcomes, but knowing these differences in advance is helpful to the decision-making process.

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Special Thanks

Morie A Gertz, M.D., M.A.C.P.

Consultant | Division of Hematology | Roland Seidler Jr. Professor Department of Medicine | College of Medicine | Mayo Distinguished Clinician

Mayo Clinic

Vaishali Sanchorawala, M.D.

Professor of Medicine | Director, Autologous Stem Cell Transplant Program | Director, Amyloidosis Center

Boston Medical Center and Boston University School of Medicine

 

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