Shopping Cart

Introduction

Amyloidosis is a group of disorders characterized by deposition of protein fibrils in tissues and organs.¹ The term “amyloid” is derived from the Latin word for “starch” (amylum) and was named by pathologist Rudolf Virchow in the 1850s. Amyloid diseases are classified based on the distribution of the deposits (systemic vs localized), genetic association (acquired or inherited), and their clinical pattern.

Amyloidosis

Amyloidosis is a systemic disorder characterized by deposition and accumulation of a protein-derived material (ie, amyloid) in bodily organs.^1-3 The proteins associated with amyloid build-up are typically misfolded and aggregate into fibrils or “clumps.” Local damage to the cells and tissues surrounding the plaque is common and ultimately manifests in a variety of clinical complications. Several forms of amyloidosis can occur, including primary, secondary, and hereditary.⁴ The most common form, primary amyloidosis, is caused by plasma cell abnormalities in the bone marrow. Secondary amyloidosis is caused by an inflammatory protein (serum amyloid A) and is associated with inflammatory disorders including inflammatory bowel disease and rheumatic diseases. Hereditary TTR amyloidosis (hATTR), also known as mutant transthyretin amyloidosis (mATTR), is caused by an abnormality in the gene that encodes for the TTR protein.⁵ All hereditary amyloidoses follow an autosomal dominant pattern of inheritance.⁴ Genetic disease, in general, is determined by the expression found on 2 copies of a gene, a copy each from one’s father and mother. Dominant expression requires only 1 mutated copy of the gene to result in potential manifestations of the disease. In a patient with the disease, the risk of passing to offspring is 50%. The risk is the same in males and females. Not all individuals with the mutation, however, manifest symptoms.

What is Transthyretin?

Transthyretin (TTR) is a protein found in the majority of vertebrate species.^1-3 The tetrameric protein, which is synthesized primarily in the liver, is mainly a carrier protein for thyroid hormones (thyroxine) as well as retinol (vitamin A). Some other areas of synthesis include the central nervous system (CNS), eye, pancreas, heart, skeletal muscle, and spleen. According to research, breakdown of the protein mainly occurs in the liver, muscle, kidney, and skin.⁶

Disease Distribution

Hereditary ATTR is rare, occurring in about 50,000 people worldwide; however, due to the insidious onset of symptoms, the true prevalence is likely underreported.^4,7 In the United States, the estimated incidence of disease is approximately 1 case/100,000 in Caucasians and about 4% in African Americans.^1,4 More than 100 mutations in the TTR gene have been discovered, with Val30Met (V30M) being the most common mutation globally, with clusters reported in Portugal, Sweden, and Japan.^4,8 The most common mutation in the United States is which is thought to have originated in West Africa as indicated by expression rates of the mutation in the Caribbean islands.^8,9

Diagnosis

Patient presentation varies depending on which areas of the body have amyloid buildup and how much buildup has occurred.^1,9 Unfortunately, this variation in presenting signs and symptoms may lead to a delay in diagnosis or lack of an accurate diagnosis.⁹ If undiagnosed and untreated, amyloid buildup can lead to tissue and organ damage and eventually death. The age of onset of hATTR varies, ranging from the second to the ninth decade of life.⁵ Diagnostic and genetic testing are recommended in patients with signs, symptoms, or manifestations of amyloidosis. Active disease is diagnosed in patients with a TTR gene mutation that exhibits 1 quantified or objective symptom or sign related to hATTR or at least 1 possibly related symptom plus 1 abnormal test result.¹⁰ In the absence of clinical symptoms, 2 abnormal test results must be present. Aspiration of abdominal fat and/or organ biopsy is usually collected prior to a diagnosis. The biopsy is stained with a histology dye called Congo red, which produces a green color under certain light conditions when amyloid is present.¹¹ Distinguishing the type of amyloidosis present is the next important step in diagnosis. For example, in the case of hATTR, molecular genetic testing for mutation in the TTR gene can help confirm the hereditary nature of the amyloidosis. In certain amyloid centers in Europe, a technique called radiolabeled serum amyloid P (SAP) scanning can evaluate the extent and distribution of amyloid accumulation in the body.⁴

Complications of Disease

Amyloid deposits can occur in many areas of the body including the heart, nerves, and gastrointestinal (GI) tract.^4,5 Cardiac effects are common, reported in about 50% of patients, and include ventricular wall thickening and/or hypertrophy, cardiomegaly, and heart failure. Arrhythmia can also occur. On average, death occurs 10 years after diagnosis, commonly due to cardiovascular complications.^5,12 When cardiomyopathy is the main symptom of hATTR, prognosis is poor, and death commonly occurs 5 to 6 years after symptom onset.¹² Neuropathy is also common in hATTR and may include autonomic symptoms such as diarrhea, decreased sweating, orthostatic hypotension, or erectile dysfunction.^3,8 Peripheral sensorimotor neuropathy often starts in the feet with loss of feelings of temperature and pain and eventually leads to difficulty walking due to gait changes and loss of balance.^5,8 GI manifestations can include dysmotility and/or obstruction, malabsorption, ulceration, bleeding, protein wasting, or diarrhea.^4,5 Weight loss can also occur if patients experience difficulty eating due to amyloid deposits in the tongue, loss of taste, or early satiety due to dysmotility. Some forms of amyloidosis are characterized by problems of the liver, spleen, kidney, skin, or joints, but these organs are less commonly affected in patients with hATTR. Involvement of the CNS is rare but has been reported.^4-5,8 Some examples of clinical manifestations and their associated features are presented in Table 1. Recently, the American Heart Association has provided expert consensus recommendations for the management of patients with suspected TTR amyloidosis-associated cardiomyopathy.¹³ It is estimated that up to 10% of heart failure cases in elderly African Americans are likely precipitated by undiagnosed amyloidosis.

Disease Monitoring

It is recommended that patients follow up with specialists routinely to monitor for disease progression, usually every 6 to 12 months.¹⁰ Regular laboratory tests should be ordered to evaluate the patient for worsening heart or renal function. Diagnostic tests such as an echocardiogram are recommended. Motor skill evaluations that test for changes in neurological status are also recommended. Staging systems have been proposed to evaluate symptom severity and disease progression and are presented in Table 2; however, no official scoring system has been adopted by clinicians as standard practice.⁵

Current Management Strategies

Until recently, there were no targeted treatment options for hATTR.⁴ Management has historically been limited to supportive care of end-organ complications and maximizing quality of life (QoL). Heart failure treatment and nonpharmacologic or pharmacologic therapies to manage GI, neuropathic, and other symptoms are also appropriate.

A 2013 guidance document for clinicians lists the following options for management of some common symptoms of hATTR: antiarrhythmics for cardiac arrhythmia; diuretics and angiotensin converting enzyme inhibitors for heart failure; midodrine, fludrocortisone, compression stockings, or elevating the head to minimize symptoms of orthostatic hypotension; loperamide for severe diarrhea; gabapentin, pregabalin, amitriptyline, or duloxetine for neuropathic pain; surgery for carpal tunnel syndrome; iron and erythropoietin for anemia; and levothyroxine for hypothyroidism.⁵ Clinicians should be aware that some medications often recognized as cornerstone therapy for certain disease states may exacerbate symptoms of amyloidosis. For example, amyloid fibrils may interact with calcium channel blockers and beta blockers, which are relatively contraindicated in amyloidosis to avoid potential heart block and worsening heart failure.¹ Similarly, digoxin binds to amyloid fibrils and can lead to accumulation of the drug in the body. Use is cautioned in patients with diagnosed hATTR.

Since the pathophysiology of hATTR is related to increased TTR protein, preventing TTR protein production, removing excess TTR protein, or preventing/reducing amyloid deposits are current approaches to minimizing the morbidity and mortality associated with this condition.^4,5 Liver transplantation has been used to prevent or decrease amyloid deposits since most TTR protein is produced in hepatocytes, but this intervention is not helpful in patients with more advanced disease.^4,5,8 Liver transplantation is not a cure for hATTR and some of the complications of this condition (such as arrhythmia) can manifest after transplant.^5,8 however recent disease-modifying agents have been approved by the United States Food and Drug Administration (FDA) and may delay or spare the need for a liver transplant in certain patients.

Newly Approved Medications

In August 2018, the first medication for hATTR received FDA approval.¹⁶ This medication, patisiran, is a small interfering ribonucleic acid (siRNA) medication that binds to and causes degradation of TTR messenger RNA. The result is a reduction in TTR protein levels in both serum and tissues. Data that supported approval of the drug were derived from the APOLLO trial.¹⁷ In this trial, patients from multiple centers in nearly 20 countries were assigned in a 2:1 ratio to receive patisiran or placebo. Both arms of the study received patisiran or placebo via intravenous (IV) infusion every 3 weeks for 18 months. Randomization was stratified per Neuropathy Impairment Score (NIS), age at onset of disease, and prior use of TTR stabilizers (in this case, agents that are available internationally, but not in the United States, or that do not have a labeled indication for hATTR-associated polyneuropathy). The primary endpoint of the APOLLO trial was change from baseline after 18 months in the modified Neuropathy Impairment Score+7 (mNIS+7), an objective scoring system in which higher scores indicate worsening neuropathy. A total of 154 patients were required to achieve 90% power to detect an 8.95-point difference between the treatment and control group.¹⁷

Two hundred twenty-five patients enrolled in the APOLLO trial with a median age of 62.¹⁷ One-hundred sixty-seven patients (74%) of the participants were male, and 163 patients (72%) identified as Caucasian. Approximately half of the patients could ambulate without assistance at baseline and the other half required assistance to ambulate. New York Heart Association (NYHA) class I and II heart failure were equally prevalent in both groups at baseline. Over half of the participants had previously tried a TTR stabilizer.¹⁷

Patients treated with patisiran 0.3 mg/kg intravenously every 3 weeks had a decreased score from baseline in the mNIS+7 score (indicating improvement), whereas patients receiving placebo had increased scores: a difference in score of -6.0 compared with 28.0 in patients receiving placebo (net difference of -34 points; 95% CI -39.9 to -28.1; P < 0.001).¹⁷ Patients who received patisiran also experienced significantly better improvements in QoL scores, gait speed, and body mass index (all P < 0.001) after 18 months compared with patients who received placebo. Furthermore, a subgroup analysis of the APOLLO study (in patients with thickened ventricular walls at baseline) found that patisiran significantly reduced left ventricular wall thickness and increased cardiac output compared with placebo.¹⁸

Prior to APOLLO, a phase 2 study for patisiran was conducted as a multicenter, open-label, multiple-dose escalation study.¹⁹ The study was designed to examine safety and tolerability of patisiran as well as assess pharmacokinetic and pharmacodynamic parameters.¹⁹ Patients were at least 18 years of age, had biopsy-proven ATTR, neuropathy, and a body mass index (BMI) between 17 and 33, with adequate hepatic and renal function. Patients were put into cohorts of 3 and administered 2 doses of patisiran via IV infusion.

A total of 29 patients were included in the intention-to-treat analysis.¹⁹ The mean age was 55.6 years and the majority of participants were male (69%). All study participants were Caucasian. Twenty-six patients were able to complete the study. Administration of patisiran at 0.3 mg/kg once every 3 weeks had the largest effect in reducing concentration of TTR, and the authors concluded that patisiran was safe and effective at this dosage. This is the labeled dosage reflected in the patisiran prescribing information for patients weighing less than 100 kg; for patients weighing 100 kg or more, the recommended dosage is 30 mg once every 3 weeks.¹⁶

The most common adverse event associated with patisiran in the phase 2 study was infusion-related reactions (10.3%).¹⁹ Additionally, reductions in serum TTR were strongly correlated with reductions in vitamin A. This is reflected by a warning in the patisiran prescribing information and recommendation for supplementing vitamin A intake with the recommended daily allowance.¹⁶ Patients with ocular symptoms of vitamin A deficiency should be referred to an ophthalmologist.

In clinical trials, patisiran was generally well tolerated, though the number of patients in each trial was relatively low (n = 29 and n = 225).^17,19 The most common adverse event reported was upper respiratory tract infections (eg, nasopharyngitis, pharyngitis, rhinitis), which was reported in 29% of patients in the APOLLO trial.¹⁶ Other adverse events included those associated with infusion reactions (19%) such as back pain, abdominal pain, flushing, nausea, and peripheral edema.¹⁷ It should be noted that research has been terminated on another first-generation siRNA medication, revusiran.²⁰ In Phase 3 studies, a higher number of patient deaths were reported when compared with placebo. An investigation into the deaths was unable to confidently conclude if revusiran administration was the causative agent; however, no evidence of drug-related cardiotoxicity was noted.

To reduce the risk of infusion-related reactions, premedication with acetaminophen (Tylenol®) 500 mg, IV dexamethasone (Decadron®) 10 mg or an equivalent corticosteroid, diphenhydramine (Benadryl®) 50 mg IV or an equivalent antihistamine, and ranitidine (Zantac®) 50 mg IV or an equivalent is required at least 60 minutes before the time of infusion.¹⁶ If IV formulations of the premedications are not available, oral equivalents may be used. Patisiran should be infused via a dedicated line with a 1.2-micron polyethersulfone (PES) in-line infusion filter. Patisiran should not be administered in bags or infused in lines that contain di(2-ethylhexyl)phthalate (DEHP). The recommended initial infusion rate is 1 mL/min for 15 minutes, followed by an increase to 3 mL/min until the end of the infusion.¹⁶

Inotersen is an antisense oligonucleotide medication that binds to TTR mRNA and prevents the formation of the TTR protein.²¹ Inotersen received FDA approval in October 2018 after beneficial results were demonstrated in the NEURO-TTR trial.²² In this trial, patients from multiple centers in 10 countries were assigned in a 2:1 ratio to receive subcutaneous injections of inotersen (300 mg) or placebo. Both arms of the study received inotersen or placebo via subcutaneous injection every week for 15 months. The primary endpoint of the NEURO-TTR trial was change from baseline score after 66 weeks in the mNIS+7 composite score. A total of 135 patients were required to achieve 90% power to detect a 9.6-point difference between the treatment and control groups.²²

A total of 172 patients were enrolled in the trial; 112 were randomized to the inotersen group and 60 were randomized to receive placebo.²² The median age was 59 years. Most of the patients were male (69%) and Caucasian (92%). The majority of patients in the trial could ambulate without assistance at baseline (67%) and 63% had cardiomyopathy.²² Cardiomyopathy was more common in the inotersen group vs the placebo group. Over half of the participants had previously tried a TTR stabilizer (eg, diflunisal, tafamidis).²²

Patients treated with inotersen had a significantly lower change from baseline in the mNIS+7 score compared with placebo; the difference in least-squares mean change from baseline to week 66 between the 2 groups was -19.7 points (95% CI -26.4 to -13.0; P < 0.001).²² These results were consistent when controlled for disease stage, mutation type, and the presence or absence of cardiomyopathy. Patients who received inotersen also experienced significantly better improvements in QoL scores compared with placebo.

Safety information with inotersen is derived from the NEURO-TTR trial, as well.²² In the trial, inotersen administration was associated with more frequent treatment-related adverse events (78% versus 38%) and serious adverse events (7% vs 2%) when compared with placebo. The most severe adverse events associated with the drug include thrombocytopenia and glomerulonephritis. Over 50% of patients experienced a platelet count < 140,000/mm³ during the first 3 months of treatment. About 3% of patients ultimately discontinued therapy due to a platelet count of < 25,000/mm³. Furthermore, 5 patients in the inotersen group died (vs none in the placebo group) with 1 death considered possibly related to the study drug (intracranial hemorrhage in the setting of Grade 4 thrombocytopenia).

These safety findings have resulted in a boxed warning about the possibility of unpredictable and potentially life-threatening thrombocytopenia with inotersen.²¹ Inotersen also has a boxed warning about the potential for glomerulonephritis. Due to the risk of severe bleeding from thrombocytopenia and glomerulonephritis, inotersen distribution is limited by a Risk Evaluation and Mitigation Strategy (REMS) program.²³ The aim of the program is to ensure prescribers are aware of the adverse effects and adhere to requirements such as counseling patients about the signs and symptoms of serious bleeding and glomerulonephritis. Periodic monitoring forms are also required and should be submitted to the REMS program administrator. Patients are also enrolled in a registry to monitor long-term safety and use of inotersen. For pharmacies and pharmacists that dispense inotersen, additional steps such as registration of the pharmacy and designated representative need to be in place before the medication can be ordered and dispensed. No more than a 30-day supply of medication may be dispensed to a patient at a time. Similar to patisiran, the inotersen prescribing information also carries a warning for reduced vitamin A levels and a recommendation to supplement intake and refer to an ophthalmologist if symptoms of vitamin A deficiency occur.²¹ Though inotersen is limited by a REMS program, an advantage of the medication is its subcutaneous delivery, allowing for self-administration.²¹ In clinical trials, patients were required to receive only 13 out of 67 doses at prespecified clinical visits. The other injections could be given at home by the patient, a caregiver, or other trained individual.²²

The most recent medication approved by the FDA for the treatment of hATTR-associated disease is tafamidis, a TTR stabilizer that prevents the deposition of TTR proteins (ie, amyloid) in tissues.²⁴ The medication had been previously approved as the first pharmacotherapeutic option for amyloidosis in several countries across Europe, Latin America, and Asia.²⁵ Data from a phase 3 clinical trial (ATTR-ACT) supported the drug’s approval in the United States.²⁶ In this trial, patients from multiple centers were assigned in a 2:1:2 ratio to receive 80 mg of tafamidis, 20 mg of tafamidis, or placebo for 30 months. The primary endpoint of the ATTR-ACT trial was all-cause mortality, followed by frequency of cardiovascular-associated hospitalizations. A total of 400 patients were required to achieve 90% power to detect a 30% reduction in mortality and 1-point reduction in the frequency of hospitalization due to cardiovascular-related events. Patients were stratified based on TTR status and baseline NYHA class.²⁶

A total of 441 patients were ultimately enrolled in the trial.²⁶ The median age was 75 years. Patients were predominantly male (90%). In these patients, all of whom had cardiomyopathy, researchers found that all-cause mortality was significantly lower in the tafamidis groups (20 or 80 mg orally daily) vs the placebo group, (29.5% vs 42.9%, hazard ratio 0.70; 95% CI 0.51-0.96). The number of cardiovascular-associated hospitalizations was also lower in the tafamidis-treated group vs placebo (0.48 vs 0.70 hospitalizations per year; relative risk 0.68; 95% CI 0.56-0.81). Tafamidis administration was also associated with a reduced rate of decline in functional capacity and QoL. Adverse effects were similar between groups. The efficacy of tafamidis for polyneuropathy in patients with hATTR has also been reported and the 20 mg dose is currently approved by the European Medicines Agency for stage 1 polyneuropathy.²⁷

The safety of tafamidis was comparable in relation to placebo based on a few clinical studies.^26,27 The most common serious treatment emergent adverse event was urinary tract infection (UTI).²⁸ It should be noted, however, that the study reporting an increased incidence of UTI was also composed of patients with higher incidences of polyneuropathy. In trials where cardiomyopathy was the prevalent disease manifestation, rates of UTI were lower for patients receiving tafamidis compared to placebo. Other adverse events reported in the literature include falls, pleural effusions, and slight renal impairment. A study by Merlini and colleagues (n = 21) reported a potential for increased risk of arrhythmia (specifically, premature atrial contractions).²⁹ After further analysis, the trial concluded that tafamidis had no adverse effects on cardiac conduction. This conclusion was confirmed by a second study from Klamerus and colleagues where supratherapeutic doses of tafamidis were administered to healthy volunteers resulting in no differences in cardiac function between the treatment group and placebo.³⁰ No treatment-related deaths have been reported in trials with tafamidis.^26-28

Currently, tafamidis is available in 2 forms, tafamidis (Vyndamax™) and tafamidis meglumine (Vyndaqel®).²⁴ The recommended dose is tafamidis 61 mg (1 capsule) or tafamidis meglumine 80 mg (4 capsules) once daily, by mouth. The two forms may not be substituted on a per milligram basis. Table 3 summarizes information on the FDA-approved medications for amyloidosis.

Other Pharmacologic Therapies and Medications in Development

Diflunisal, a nonsteroidal anti-inflammatory drug (NSAID) that is already on the market, has a similar mechanism of action as tafamidis and has been prospectively studied in the setting of hATTR.²⁸ Results from a randomized, placebo-controlled study of patients receiving 250 mg of diflunisal twice daily revealed that the difference in mean change of the NIS+7 (where greater scores indicate worsening neuropathy) was significantly better (P < 0.001) in the diflunisal group (+8.2 points) compared with placebo (+26.3 points).³¹ Overall, researchers concluded that while diflunisal cannot remove or inhibit TTR synthesis, administration has shown to significantly slow neurological disease progression. The efficacy of diflunisal in regard to hATTR-associated cardiomyopathy was only evaluated in a single-arm, open-label study with 13 patients.³² The results of the study indicate there were no appreciable changes in ejection fraction or left-ventricular mass index, indicating that diflunisal may slow cardiovascular decline in these patients. Larger, randomized trials are required before clinicians may confidently select diflunisal for the management and prevention of hATTR-associated cardiac complications. Currently, diflunisal is not FDA-approved for the treatment of hATTR; however, the medication is available as a generic drug and may therefore be a potentially cost-effective option for some patients.³³ Decisions regarding use of diflunisal should consider the risk for NSAID-induced adverse effects, such as reduced renal function, hypertension, and thrombocytopenia, which may exacerbate or precipitate symptoms of hATTR.²

Another therapy that has been tested for the management of hATTR-associated cardiomyopathy is the combination of doxycycline and ursodeoxycholic acid.²⁸ In a retrospective study by Karlstedt and colleagues, 38% of patients that received doxycycline 100 mg twice daily, and ursodeoxycholic acid 250 mg 3 times daily, showed significant improvement in left ventricular global longitudinal strain (-12% to -17%; P < 0.01).³⁴ Of note, a majority of patients that demonstrated improvement in their symptoms were younger and had better baseline cardiac function.

Vutrisiran is another RNA-interfering medication that is currently under evaluation in Phase 3 trials for the management of TTR amyloidosis.^35,36 The HELIOS series of trials aims to evaluate the efficacy and safety of vutrisiran in patients with hATTR. Patients will be randomly allocated in parallel fashion to receive either vutrisiran or patisiran (HELIOS-A) or placebo (HELIOS-B). Currently, vutrisiran is being studied as a 25 mg subcutaneous injection administered once every 3 months. HELIOS-A is open-label, whereas HELIOS-B is double-blinded. The primary endpoints in HELIOS-A will be the change from baseline in the modified NIS+7 (mNIS+7) and change from baseline in Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) total score at month 9.³⁵ The primary endpoint for HELIOS-B is composite all-cause mortality and frequency of recurrent cardiovascular hospitalizations at 36 months.³⁶

Patient Counseling Points

A diagnosis of hATTR results in a significant impact to patient and caregiver QoL.³ A recent report characterized the burden of disease on patients’ and caregivers’ mood, functional status, health-related quality of life (HRQoL), and caregiver burden.³⁷ This report collected information based on various QoL screening tools such as the Hospital Anxiety and Depression Scale (HADS), Short Form 12 (SF-12), and Norfolk QoL-DN. A total of 38 patients and 16 caregivers completed the survey. Overall, research indicated that patients with hATTR had lower scores on the SF-12 compared with age-matched population norms. Furthermore, caregivers of patients with hATTR reported moderate fatigue and higher rates of clinically significant depression and anxiety.³⁷

The societal costs and disease burden associated with hATTR were explored in a study by Inês and colleagues in Portugal.³⁸ Using public databases, previous studies, and prior literature, the calculated annual cost-of-illness in Portugal was over $58 million. Treatment for the disease accounted for 52% of total costs. Researchers concluded that the cost of disease was high but comparable to other rare disease states.

Early detection of hATTR is essential in improving patient outcomes.^1-5 Pharmacists can help ensure patients displaying symptoms are referred to an appropriate provider to begin testing for the disease. As stated previously, symptoms may manifest in a variety of ways. Some patient-reported symptoms may include dark floaters in the eye (ocular), increasing fatigue or shortness of breath (cardiac), decreased urinary output (renal), pain or tingling in the legs (neurological), loss of appetite or alternating episodes of severe diarrhea and constipation (GI), and sexual dysfunction or dizziness (autonomic neuropathy). Patients that frequently seek over-the-counter care of some of these combined symptoms may require consultation with a pharmacist who can refer the patient to a physician to facilitate timely diagnosis. Often, patients that present with a mixture of symptoms may seek medical attention from separate specialists. According to the Amyloidosis Foundation, patients often see 5 or more doctors across different specialties before a diagnosis of hATTR is made.³⁹ Because of fragmented care, it is estimated that the time between symptom onset and diagnosis may take 4 years for patients with hATTR presenting with peripheral neuropathy and up to 8 years for patients presenting with cardiomyopathy.⁴⁰

Genetic testing is also a critical component of ensuring an accurate diagnosis.^1-5 Proper referral to a genetic counselor may help patients and families understand the full spectrum of the disease.⁴¹ An expert in genetic counseling may be an effective collaborator with the medical and pharmacy teams and help relay the appropriate facts regarding the disease state to the patient. The genetic counselor may serve as a helpful resource in explaining how the disease could be passed down to offspring and promote safe family planning. Other potential benefits of consulting a genetic counselor include helping family members understand their risk for hATTR and helping patients and family members identify signs and symptoms of hATTR that can result in earlier screening for the disease.

Summary

Amyloidosis is a systemic disorder characterized by deposition and accumulation of a protein-derived material (ie, amyloid) in bodily organs. The hereditary form of the disease is a rare, autosomal dominant disorder that may manifest in a variety of complications such as ocular disease, cardiac disease, or general neurologic decline. Significant morbidity and mortality is associated with the disorder and proper diagnosis is usually delayed due to the insidious onset of symptoms. Until recently, orthotopic liver transplant was the only long-term treatment option for the disorder. Newly approved medications that inhibit TTR formation or stabilize the TTR tetramer have demonstrated beneficial disease outcomes in clinical trials. Current FDA-approved treatments for hATTR include patisiran, inotersen, and tafamidis. Additional medications including the combination of doxycycline and ursodeoxycholic acid and vutrisiran are also being researched across the globe. Multidisciplinary care consisting of physicians, pharmacists, and psychosocial support groups are essential to improving the QoL and disease outcomes associated with hATTR.

References

1. Berk JL, Sanchorawala V. Amyloidosis. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 20^th ed. New York, NY: McGraw-Hill; 2018. http://accesspharmacy.mhmedical.com. Accessed February 14, 2020.
2. Gertz MA, Mauermann ML, Grogan M, Coelho T. Advances in the treatment of hereditary transthyretin amyloidosis: A review. Brain Behav. 2019;9(9):e01371.
3. Sekijima Y. Hereditary transthyretin amyloidosis. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. Seattle, WA: University of Washington; 1993. http://www.ncbi.nlm.nih.gov/books/NBK1194/. Accessed February 14, 2020.
4. NORD: National Organization for Rare Disorders. Amyloidosis. https://rarediseases.org/rare-diseases/amyloidosis/. Accessed February 14, 2020.
5. Ando Y, Coelho T, Berk JL, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis. 2013;8:31.
6. Misumi Y, Ando Y, Goncalves NP, Saraiva MJ. Fibroblasts endocytose and degrade transthyretin aggregates in transthyretin-related amyloidosis. Lab Invest. 2013;93(8):911-920.
7. Gertz MA. Hereditary ATTR amyloidosis: burden of illness and diagnostic challenges. Am J Manag Care. 2017;23(7 Suppl):S107-S112.
8. Plante-Bourdeneuve V, Said G. Familial amyloid polyneuropathy. Lancet Neurol. 2011;10(12):1086-1097.
9. Gertz MA, Benson MD, Dyck PJ, et al. Diagnosis, prognosis, and therapy of transthyretin amyloidosis. J Am Coll Cardiol. 2015;66(21):2451-2466.
10. Conceição I, Coelho T, Rapezzi C, et al. Assessment of patients with hereditary transthyretin amyloidosis – understanding the impact of management and disease progression. Amyloid. 2019;26(3):103-111.
11. Adams D, Ando Y, Beirão JM, et al. Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy [published online ahead of print January 6, 2020]. J Neurol
12. Coelho T, Ericzon BG, Falk RJ, et al. A guide to transthyretin amyloidosis. Amyloidosis Foundation website. http://www.amyloidosis.org/wp-content/uploads/2017/05/2017-ATTR-guide.pdf. Published 2016. Accessed February 14, 2020.
13. Maurer MS, Bokhari S, Damy T, et al. Expert consensus recommendations for the suspicion and diagnosis of transthyretin cardiac amyloidosis. Circ Heart Fail. 2019;12(9).
14. Coutinho P, Martins da Silva A, Lopes Lima J, Resende Barbosa A. Forty years of experience with type I amyloid neuropathy: review of 483 cases. Excerpta Medica. 1980:88-98.
15. Sales-Luís ML, Galvao M, Carvalho M, Sousa G, Alves MM, Serrão R. Treatment of familial amyloidotic polyneuropathy (Portuguese type) by plasma exchange. Muscle Nerve. 1991;14(4):377-378.
16. Onpattro [package insert]. Cambridge, MA: Alnylam Pharmaceuticals, Inc; 2018.
17. Adams D, Gonzalez-Duarte A, O’Riordan WD, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med. 2018;379(1):11-21.
18. Solomon SD, Adams D, Kristen A, et al. Effects of patisiran, an RNA interference therapeutic, on cardiac parameters in patients with hereditary transthyretin-mediated amyloidosis. Circulation. 2019;139(4):431-443.
19. Suhr OB, Coelho T, Buades J, et al. Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study. Orphanet J Rare Dis. 2015;10(1):109.
20. Garber K. Alnylam terminates revusiran program, stock plunges. Nat Biotechnol. 2016;34(12):1213-1214.
21. Tegsedi [package insert]. Boston, MA: Akcea Therapeutics, Inc; 2018.
22. Benson MD, Waddington-Cruz M, Berk JL, et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med. 2018;379(1):22-31.
23. US Food and Drug Administration. Tegsedi (Inotersen). Approved Risk Evaluation and Mitigation Strategies (REMS) website. https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm?event=IndvRemsDetails.page&REMS=383. Accessed February 14, 2020.
24. Vyndaquel and Vyndamax [package insert]. New York, NY: Pfizer Inc; 2019.
25. Kerschen P, Planté-Bordeneuve V. Current and future treatment approaches in transthyretin familial amyloid polyneuropathy. Curr Treat Options Neurol. 2016;18(12):53.
26. Maurer MS, Schwartz JH, Gundapaneni B, et al; ATTR-ACT Study Investigators. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med. 2018;379(11):1007-1016.
27. Coelho T, Maia LF, da Silva AM, et al. Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy. J Neurol. 2013;260(11):2802-2814. 
28. Müller ML, Butler J, Heidecker B. Emerging therapies in transthyretin amyloidosis – a new wave of hope after years of stagnancy? Eur J Heart Fail. 2020;22(1):39-52. 
29. Merlini G, Planté-Bordeneuve V, Judge DP, et al. Effects of tafamidis on transthyretin stabilization and clinical outcomes in patients with non-val30met transthyretin amyloidosis. J Cardiovasc Trans Res. 2013;6(6):1011-1020.
30. Klamerus KJ, Watsky E, Moller R, Wang R, Riley S. The effect of tafamidis on the QTc interval in healthy subjects. Br J Clin Pharmacol. 2015;79(6):918-925.
31. Berk JL, Suhr OB, Obici L, et al. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA. 2013;310(24):2658-2667.
32. Castaño A, Helmke S, Alvarez J, Delisle S, Maurer MS. Diflunisal for ATTR cardiac amyloidosis. Congest Heart Fail. 2012;18(6):315-319.
33. Diflunisal [package insert]. Baddi, India: Cadila Healthcare Ltd; 2017.
34. Karlstedt E, Jimenez-Zepeda V, Howlett JG, White JA, Fine NM. Clinical experience with the use of doxycycline and ursodeoxycholic acid for the treatment of transthyretin cardiac amyloidosis. J Card Fail. 2019;25(3):147-153.
35. U.S. National Library of Medicine. HELIOS-A: a study of vutrisiran (ALN-TTRSC02) in patients with hereditary transthyretin amyloidosis (hATTR Amyloidosis). https://clinicaltrials.gov/ct2/show/NCT03759379. Accessed February 14, 2020.
36. U.S. National Library of Medicine. HELIOS-B: A study to evaluate vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy. https://clinicaltrials.gov/ct2/show/NCT04153149. Accessed February 14, 2020.
37. Stewart M, Lenderking W, Loftus J, et al. Evaluating the quality of life and burden of illness in an ultra-rare disease in the U.S.: transthyretin familial amyloid polyneuropathy (TTR-FAP) patients and caregivers. Presented at: the IXth International Symposium on Familial Amyloidotic Polyneuropathy (ISFAP); November 10-13, 2013; Rio de Janeiro, Brazil. Abstract E16.
38. Inês M, Coelho T, Conceição I, Landeiro F, de Carvalho M, Costa J. Societal costs and burden of hereditary transthyretin amyloidosis polyneuropathy. Amyloid. December 2019:1-8.
39. Patient Resources. Amyloidosis Foundation. http://amyloidosis.org/resources. Accessed February 14, 2020.
40. Kapoor M, Rossor AM, Laura M, Reilly MM. Clinical presentation, diagnosis and treatment of TTR amyloidosis. J Neuromuscul Dis. 2019;6(2):189-199.
41. Sequeiros J. Guidelines for genetic counselling in ATTR amyloidosis. Orphanet J Rare Dis. 2015;10(Suppl 1):I20.

Back to Top