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 Table of Contents  
Year : 2021  |  Volume : 2  |  Issue : 2  |  Page : 32-37

Transthyretin amyloid cardiomyopathy: Treatment pipeline, clinical trials, and challenges

1 Department of Pharmacology, Delhi Institute of Pharmaceutical Sciences and Research, Delhi, India
2 Department of Nursing, Rajkumari Amrit Kaur College of Nursing, Delhi, India

Date of Submission29-Apr-2021
Date of Decision15-May-2021
Date of Acceptance18-May-2021
Date of Web Publication26-Jul-2021

Correspondence Address:
Dr. Sweety Sharma
Department of Pharmacology, Delhi Institute of Pharmaceutical Sciences and Research, Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jphpc.jphpc_8_21

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Transthyretin amyloid cardiomyopathy (ATTR-CM) is potentially a fatal disease characterized by abnormal buildup of amyloid fibrils primarily in the heart causing progressive heart failure. It is categorized into two subtypes-hereditary ATTR and wild type ATTR. Previously, no treatment is available, due to which liver transplantation, multi-organ transplantation, and symptomatic treatment were the only therapies at that time. Approval of Vyndaqel (tafamidis meglumine) and Vyndamax (tafamidis) capsules in 2019, acts like a kick in the research fields due to which other therapeutics are now emerging. Several clinical trials are going on to evaluate the efficacy of different drugs in ATTR-CM. Most of the clinical trials demonstrated positive outcomes which leads to further evaluation for confirmation. In this review treatment pipeline, ongoing clinical trials and challenges related to ATTR-CM are described.

Keywords: Amyloid, amyloidosis, cardiomyopathy, transthyretin, transthyretin amyloid cardiomyopathy

How to cite this article:
Sharma S, Sharma B. Transthyretin amyloid cardiomyopathy: Treatment pipeline, clinical trials, and challenges. J Public Health Prim Care 2021;2:32-7

How to cite this URL:
Sharma S, Sharma B. Transthyretin amyloid cardiomyopathy: Treatment pipeline, clinical trials, and challenges. J Public Health Prim Care [serial online] 2021 [cited 2023 May 29];2:32-7. Available from: http://www.jphpc.org/text.asp?2021/2/2/32/322309

  Introduction Top

ATTR amyloidosis is a rare disease characterized by the abnormal build-up of amyloid deposits in the body's organs and tissues.[1] It is either misdiagnosed or underdiagnosed which making it difficult to characterize its worldwide prevalence.[2] However, in the United States, its estimated prevalence was found to be <200,000 persons. It has been reported in ∼10% of patients with heart failure (HF) and a preserved ejection fraction or those undergoing aortic valve replacement.[3] There are two forms of ATTR amyloidosis-transthyretin amyloid polyneuropathy (ATTR-PN) and ATTR cardiomyopathy (ATTR-CM).[4] ATTR-PN is a disease in which Amyloid fibrils deposit primarily in peripheral nerves resulting from a genetic mutation in the transthyretin (TTR) gene.[5] ATTR-CM is the abnormal build-up of amyloid fibrils primarily in the heart causing progressive HF.[6] ATTR-CM progresses with bi-ventricular thickening, diastolic dysfunction from loss of compliance, and congestive HF symptoms from elevation in cardiac filling pressures.[7] ATTR-CM is further categorized into two subtypes-hereditary ATTR (hATTR) and wild type ATTR (wtATTR).[8] Heredity ATTR is caused by a mutation in the TTR gene. It can occur in people in their 50s and 60s.[9] wtATTR is associated with aging. It is thought to be more common than hATTR. It usually affects men after the age of 60.[1] TTR is a 127-amino acid, 56 kDa transport protein which is primarily secreted by the liver. It is also produced in lesser amounts by the choroid plexus for CSF (cerebral spinal fluid) and retinal pigmented epithelial cells for the vitreous of the eye. Normally, it circulates as a homotetramer but due to genetic mutation (hATTR) or aging (wtATTR), tetramers can dissociate into monomers that mis-assemble into amyloid fibrils.[7] Suspected patients of ATTR-CM can be evaluated by echocardiography or cardiac magnetic resonance imaging.[10] When it is suspected then Nuclear Scintigraphy, Cardiac Biopsy, genetic testing can be performed to diagnose it.[11] As awareness of this condition increases, and disease diagnosis improves, better treatment plans can be implemented.

  Treatment Top

The goals of treatment are to stop disease progression and to minimize the effects of disease on the body.[12],[13] Treatment is focused on supportive care, reduction and ideally elimination of TTR from the plasma, stabilization of the tetrameric structure of TTR, and dissolution of the existing ATTR amyloid matrix.[14] Previously, the only available options for treatment were symptom management and liver or heart or both transplantations. Symptomatic management includes medicines such as diuretics, blood thinners, inotropic agents, etc.[12],[13] Treatment classes include TTR stabilizers, human monoclonal antibodies, gene silencers, and CRISPR/Cas9 gene editing.[15] Currently, three drugs are approved for the treatment of ATTR diseases. Treatment pipeline and class of different therapeutics in the research of ATTR diseases are shown in [Figure 1] and [Figure 2].
Figure 1: Treatment pipeline for transthyretin amyloid disease

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Figure 2: Potential therapeutics in research pipeline

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Following approved and emerging drugs are available for the treatment of ATTR: [16]

  • Inhibition of TTR gene expression-patisiran
  • Antisense oligonucleotides-inotersen
  • Tetramer Stabilization-tafamidis, AG-10, difusinal
  • Inhibition of Oligomer Aggregation and Oligomer Disruption-epigallocatechin gallate
  • Degradation and Reabsorption of Amyloid Fibers-doxycycline-taurosodeoxycholic acid
  • Supportive Treatment of Cardiac Involvement-drug therapies, cardiac pacing, cardiac transplantation.

Liver transplantation-TTR mainly has a hepatic origin because it is mostly synthesized by the liver. So, liver transplantation suppresses the production of circulating mutant TTR which further stops amyloid formation and ultimately disease progression. Orthotopic liver transplantation (OLT) for ATTR was first performed in 1990.

Previously it became an accepted treatment for TTR-FAP, because at that time the outcomes were encouraging but in non-TTR V30M cases is associated with lower survival rate and amyloidosis progression. There is another liver transplantation namely, domino liver transplantation which was first performed in 1995.[17],[18]

Patisiran-It is a hepatically targeted double standardized small interfering rna. It inhibits the synthesis of TTR by binding to a genetically conserved sequence in 3' untranslated region of mutant and wild-type TTR messenger RNA causing its degradation.[19] It was approved by FDA in 2018, indicated for polyneuropathy of hATTR in adults. A Phase 3 trial evaluating the efficacy of patisiran in patients of hereditary TTR amyloidosis with polyneuropathy showed that patisiran improves several clinical manifestations of the disease.[20] Patisiran is administered every 3 weeks through the intravenous route. Patients are premedicated with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers) to reduce the risk of infusion reactions. It results in decreased levels of both normal and mutant TTR proteins.[21] Another phase 3 APOLLO study conducted in patients with hATTR amyloidosis with polyneuropathy showed that patisiran improves outcomes of polyneuropathy as compared to the placebo group.[22]

Inotersen-Is is a 2-′-O-methoxyethyl–modified antisense oligonucleotide. It inhibits TTR synthesis in the liver.[23] It inhibits both TTR protein whether mutant or wild type.[24] It was approved by the FDA in 2018, indicated for polyneuropathy of hATTR in adults.

Tafamidis-It is a TTR stabilizer (tetramer stabilizer). It stabilizes both mutant and wild type TTR. It works by binding to protein (TTR) and preventing tetramer dissociation and further amyloidogenesis. It is the first approved treatment for ATTR-CM.[25] Tafamidis and tafamidis meglumine were approved by the FDA in 2019 indicated for the treatment of ATTR-CM. In a cohort study, tafamidis treatment was associated with longer median major cardiovascular outcome (MCO)-free survival time (n = 98): 1565 days as compared to 771 days without treatment, suggesting that tafamidis is associated with a lower occurrence of cardiovascular outcomes in a real-life population.[26] A multi-state, cohort, Markov model developed to simulate disease course throughout a lifetime demonstrated that tafamidis is expected to more than double the life expectancy and quality-adjusted life years of ATTR-CM patients as compared to standard of care.[27] Another analysis also showed that tafamidis reduced the cumulative mortality and hospitalization risk as compared to placebo in patients with ATTR-CM.[28]

AG-10 (Investigational drug)-It is a potent TTR stabilizer. It gets Orphan Drug Designation by US FDA.[29] AG10 exhibits remarkable selectivity for TTR binding in human serum in the presence of other serum proteins. In dose-dependent manner it selectively stabilized serum WT-TTR and it was found to be significantly more effective than tafamidis at all concentrations tested.[30] It has the potential to be a safe and effective treatment for patients with either mutant or wild-type ATTR.[29]

NI006: NeuraImmune Therapeutics (Investigational drug)-It is a human antibody which is directed against ATTR consisting of misfolded and aggregated forms of TTR.[31]

Tolcapone (Investigational drug)-It has a TTR stabilizing activity. It also gets Orphan Drug Designation by US FDA.[32]

Diflunisal (Investigational drug)-It is a nonsteroidal anti-inflammatory drug with TTR stabilizing activity. Limited data are available which showed its effects on cardiac structure and function.[33] It is a second-line drug for ATTR-CM.[34] A retrospective study evaluating the efficacy of diffusional in ATTR-CM patients showed that it leads to positive outcomes in some measurable parameters of Cardiac structure and function only after 1 year of administration.[33]

Epigallocatechin-3-gallate (investigational herbal drug)-It is an extracted component of green tea. It has been proved to have multiple effects on human pathological and physiological processes.[35] It is mentioned in some studies that it works by inhibiting TTR aggregation and Amyloid fibril formation.[36],[37] Some studies showed supporting evidence of epigallocatechin-3-gallate against ATTR-CM.[38]

Curcumin (investigational herbal product)-It is a chemical constituent derived from turmeric (Curcumin longa). It has been used for thousands of years in the treatment of various diseases.[39] It works by inhibiting TTR aggregation and fibril formation through the generation of small off-pathway oligomers. It is reported that TTR load is reduced in up to 70% and cytotoxicity associated with TTR aggregation is also reduced.[40],[41]

Polyglutamate-doxycycline (Investigational drug)-It is a tetracycline antibiotic. It is found to be effective in disruptions of Amyloid fibrils.[42] Its conjugated form with polyglutamate showed enhanced clearance of Amyloid fibrils.[43]

  Clinical Trials Top

Several clinical trials are going on to evaluating the activity of various therapeutics in ATTR-CM patients as shown in [Table 1]. A multicentre, placebo-controlled, phase 3 trial, evaluating the efficacy of tafamidis in patients with ATTR-CM showed that Tafamidis was associated with lower all-cause mortality as compared to placebo and lower rate of cardiovascular-related hospitalizations.[44] In a dose-specific assessment, patients were randomized to receive tafamidis 80 mg, 20 mg, or placebo for 30 months. It was observed that the combination of all-cause mortality and cardiovascular-related hospitalizations were significantly reduced in both doses group of tafamidis as compared to placebo.[45] A randomized, double-blind, placebo-controlled study evaluating the safety and tolerability of AG10 in ATTR-CM patients with symptomatic, chronic HF showed that its administration was well tolerated and without safety signals.[46] A phase II, open-label study evaluating the efficacy, tolerability, safety, and pharmacokinetics of Doxycycline plus tauroursodeoxycholic acid showed that this combination stabilizes the diseases for at least 1 year in most of the patients.[47]
Table 1: List of ongoing clinical trials conducted for treatment of transthyretin amyloid cardiomyopathy

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  Challenges Top

ATTR-CM is a rare disease and several challenges are associated with its diagnosis and treatment.

  • Its phenotypic and genetic heterogeneity makes it difficulty in the diagnosis of ATTR-CM, lack of specialist and specific diagnostic tests also pose a challenge, need for organ tissue for histologic analysis to obtain a definitive diagnosis, hypertrophic phenotype can lead to misdiagnosis, Patients with hATTR can also be difficult to diagnose[2]
  • There is limited sensitivity and specificity of ECHO for ATTR-CM which may contribute to missed or late diagnoses of amyloidosis[48]
  • Symptoms of amyloidosis are usually nonspecific which, often resulting in delayed or missed diagnosis.[49] According to one targeted literature review, it was found that mean and median diagnostic delays were 6.1 and 3.4 years for ATTRwt-CM and 5.7 and 2.6 years for ATTRv-CM while misdiagnosis occurred in 34%–57% of patients when reported. Evidence of unnecessary or inappropriate evaluations or treatments that patients had undergone due to misdiagnosis was also reported[50]
  • Awareness among cardiologists also poses a great challenge in its diagnosis. Some physicians are not aware or partly aware about this[51]
  • Another common diagnostic challenge is differentiating ATTR from primary amyloidosis and the high prevalence of MGUS in ATTRwt also poses a diagnostic challenge[52]
  • Symptoms of ATTR-CM can mimic other more common cardiac conditions; it can be challenging to diagnose[53]
  • Challenges in the liver transplantation-disproportionate supply of deceased organ donors, prolonged waiting time for OLT, unpredictable rate of symptomatic progression, risk of developing ATTR amyloidosis in DLT recipient.[17]

  Primary Care Top

Primary preventive measures for the disease are not there. Medical and surgical treatments serve as secondary prevention after diagnosis has been made while supportive care for complications serve as tertiary prevention.[54] There is knowledge Gaps of ATTR-CM Predominantly In Primary Care Providers. A cross-sectional observational design survey showed that all HCP (health care providers) stated some level of awareness to ATTR-CM, but the majority (84.79%) were not confident in differentiating hATTR with ATTR-wt, and 73.91% were not familiar about the various mutations in hereditary ATTR-CM.[55] For treatment of ATTR-CM, doctors focus on easing the symptoms of HF and slowing or stopping the formation and depositing of fibrils. Important new therapies are now available, so patients should talk to their physicians about treatment options. ATTR-CM may already be advanced by the time the patient receives a diagnosis because of the many different and subtle ways it may present. Starting the conversation with health care provider could be a lifesaver. It is important that you talk with your primary care provider if you have any questions or concerns.[56] Patients should share any symptoms they experiencing with the PHP, as early diagnosis is important to begin appropriate treatment. Counseling programs can help people to know more about the disease. Once the diagnosis has been made, PHP remains the main source of information, as experienced by a patient named Randy in 2018. It's helpful for hereditary ATTR-CM patients to discuss their diagnosis with their family members who may also be at risk. Understanding about symptoms and having knowledge of their family's health history can help empower them to have more proactive conversations with their doctor about the disease which may lead to earlier genetic testing and counseling to determine if they have the mutation.[57] Better awareness among the primary care providers of the clinical presentation and modern treatment landscape is essential to improve timely diagnosis and early treatment of this disease.[58]

  Recent Advances Top

Machine learning model in the identification of potential wtATTR-CM: A machine learning model in 1071 cases and 1071 nonamyloid HF controls was derived and validated in 3 nationally representative cohorts and a large, single-center electronic health record-based cohort. It was observed that this model performs well in identifying patients with cardiac amyloidosis in the derivation cohort and all four validation cohorts.[59]

99 mtechnetium (99 mTc) bone-avid compounds: This 99 mTc compound allows accurate noninvasive diagnosis of TTR cardiac amyloidosis (ATTR-CM) in the context of a negative monoclonal light chain screen.[60]

With the increasing use of cardiac MRI (magnetic resonance imaging) in investigating CM and repurposing of technetium-labeled bone scintigraphy, clinicians are now often able to diagnose ATTR-CM without the need of endomyocardial biopsy.[61]

  Conclusion Top

ATTR-CM is a progressive disease which is either misdiagnosed or underdiagnosed which making it difficult to characterize it. Several challenges associated with its diagnosis and treatment. This disease needs correct and timely diagnosis and intervention. Awareness is also required among cardiologists and other physicians so they can timely diagnose the problem and implement the treatment accordingly. Several approved and investigational therapeutic agents are now available. Still, future studies are needed to tackle the challenges associated with its treatment. This paper provides information about current and emerging treatments and diagnostic options for ATTR-CM that can help to spread knowledge among primary health care providers so that timely diagnosis and early treatment of this disease can be made.

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Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2]

  [Table 1]


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