• Transthyretin amyloidosis (ATTR) is a severe, progressive, systemic disease characterized by cardiomyopathy (ATTR-CM) and/or neuropathy (ATTR-PN) and associated with high mortality​

• ATTR is caused by misfolding of the TTR protein, either due to (i) an inherited genetic variant of the TTR gene (ATTRv) or (ii) a spontaneous anomaly, known as wild-type ATTR (ATTRwt)¹

• In ATTR amyloidosis, naturally occurring TTR homotetramers dissociate into unstable monomers that misfold and aggregate into insoluble TTR amyloid fibrils²; depending on ATTR type, the amyloid is deposited into various organs and/or nerves, which can lead to permanent damage and organ malfunction​

ATTRwt:​

• Risk Factors and Demographics​

• The cause for the instability of the wild-type TTR homotetramer remains unknown, but age-associated factors are implicated⁴

• Although there are a few cases of people being diagnosed as early as their late 40s; the average age at diagnosis is >75 years⁷

• ATTRwt is more common in males (>85% over age 60⁵); no racial predilection reported​

• ATTRwt may be present in up to 25% of men over age 80; clinically significant disease can occur among 8%-16% of people in this age group⁸

• Epidemiology​

• The true prevalence and incidence of ATTRwt amyloidosis are not known⁹⁻¹⁰

• Recent literature aligns on the hypothesis that the diagnosed prevalence of ATTR-CM will increase due to improvements in non-invasive diagnostics and targeted therapies to treat patients with ATTR-CM ​

• ALEXION’s upper bounds estimate is ~1.8 million individuals in the 7 Major Markets* + China, with most patients undiagnosed⁹

• In Japan, ALEXION estimates the prevalence of ATTRwt is ~68K⁹

• Compare: ATTRv amyloidosis prevalence in Japan is estimated to be ~1,600⁹
   

• Prognosis​

• High mortality: median OS for all patients is ~3.6 years⁶, ⁷

• Debilitating physical symptoms similar to those of heart failure, including exercise intolerance and fatigue³

• Decreased functional capacity and reduced quality of life (QoL)³

• Many initial signs and symptoms are vague and not specific to ATTR, and nonspecific symptoms may be mistaken for signs of aging, resulting in delayed diagnosis and treatment initiation​

• With respect to wild-type ATTR (ATTRwt), cardiomyopathy (CM) is the hallmark – and known as ATTRwt-CM​

• Patients commonly present with cardiac abnormalities, such as heart failure with preserved ejection fraction (HFpEF) and diastolic dysfunction, which are also characteristic of an elderly population​

• Amyloid deposits in the heart make the heart wall stiffen and work inefficiently; eventually this leads to congestive heart failure (HF), with symptoms such as shortness of breath, leg swelling, fatigue, nausea, and an irregular heartbeat or palpitation⁶

• In a Japanese study, HF was both the most common initial symptom reported (49%) and the most common symptom leading to diagnosis (61%)⁸

• HF is often preceded by carpal tunnel syndrome by 5-10 years¹, but it is often misdiagnosed⁷

• Peripheral and autonomic neuropathy can occur but are usually less severe than in patients with ATTRv and often manifest post-heart transplant¹

• Compare hereditary ATTR (ATTRv):​

• Patients may present with autonomic neuropathy, gastrointestinal impairment, cardiomyopathy, nephropathy, or ocular amyloid deposition²

• Cardiac involvement develops in about half of ATTRv patients and usually presents as HF with normal systolic function, conduction blocks, ventricular arrhythmias or sudden cardiac death³

• Classic neuropathic symptoms for early onset patients are related to small nerve fibers associated with pain and temperature; lower limbs usually precede observed symptoms in upper limbs⁴

• Late-onset patients may present with milder autonomic dysfunction; lower and upper limb symptoms may occur simultaneously⁴

• Depending on the symptom(s) experienced, ATTRwt patients may feel concerned or scared, or they may not worry that anything is seriously wrong​

• The patient experience at symptom onset is variable, as symptoms can differ in their nature and severity​

• Some patients describe suddenly noticing a problem they never noticed before, e.g., heart palpitations and dizziness in the middle of an exercise class​

• Other patients describe missing the signs for years, e.g., “For more than a decade, I experienced all the early indicators of ATTR-CM: bilateral carpal tunnel syndrome, ruptured biceps tendon, and lumbar stenosis”​

Delayed Diagnosis:​

• The diagnostic process for ATTRwt-CM may be long and difficult, ranging from months to 10(+) years​

• In a targeted literature review, the weighted means of reported mean and median diagnostic delays were 6.1 and 3.4 years for ATTRwt-CM²

• ATTRwt-CM is now diagnosed more than twice as frequently as hereditary ATTR-CM—presumably reflecting the remarkable sensitivity and increasingly widespread use of cardiac magnetic resonance imaging and bone scintigraphy, which in turn have fueled increased awareness of the condition among cardiologists⁷

• However, a recent report (n=1,069 ATTRwt patients) shows that median time from symptom onset to ATTRwt diagnosis did not change over the past 5 years (>60 months from 2015-2019)⁸

• For comparison: a smaller study (n=122 ATTRwt patients) in France found significantly shorter delays after 2012, averaging ~5-12 months between when cardiac amyloidosis was first suspected and diagnosis³

Misdiagnosis:​

• Patients are also often misdiagnosed, and may even be given inappropriate or even counter-indicated treatments​

• Up to ~40% of ATTRwt patients reported initially being misdiagnosed, and 75% of misdiagnosed patients received treatment for the misdiagnosed condition⁴

• In a larger US cohort, 63% of patients also reported having to see 2 or more cardiologists before diagnosis⁵

• >99% of US cardiologists believe that patients with cardiac amyloidosis (CA) experience diagnostic delays primarily due to low awareness of CA and diagnostic algorithm / tests¹

• Patients with gradual symptom onset may initially dismiss symptoms but will eventually get to a point where they recognize that something may be wrong and seek medical attention​

• Patients and caregivers may become frustrated and fearful due to their long search for answers and perceived “missed” opportunities for earlier intervention​

• Is something wrong with me? Patients may attribute ATTRwt symptoms to the “regular” aging process​

• What is wrong with me? Patients get no answers that seem right about what’s wrong with them and why they are getting worse​

• Poisoned by the wrong therapy. Before correct diagnosis, patients (esp. with cardiac involvement) may receive therapies counter-indicated for ATTRwt​

• Time to Diagnosis = Time to Live! Early diagnosis significantly enhances outcomes​

• A diagnosis of ATTRwt-CM requires 3 key steps:​

1.  Suspicion of cardiac amyloidosis (clinical finding, ultrasonic cardiogram, cardiac MRI)​

2.  Diagnosis of cardiac amyloidosis (PYP, M protein, Congo red staining)​

3.  Confirmation of the type of cardiac amyloidosis (immunostaining, genetic test, bone-marrow examination)​

• Endocardial biopsy has been the gold standard for diagnosing ATTR-CM because of its high sensitivity and specificity—it is currently a standard for diagnosis through the Japan Cardiology Society guidelines but may become less common due to advances in imaging¹

• Bone scintigraphy has revolutionized the diagnosis and recognition of ATTR-CM, being extremely sensitive to detect TTR amyloid deposits in the heart, even prior to clinical manifestations or abnormal findings on CMR or ECHO²

• Currently, there is no universal system of staging ATTR amyloidosis; the following are both used³, ⁴:​

• Mayo Clinic model: soluble cardiac biomarkers are used to stratify ATTRwt patients into three distinct risk groups based on troponin T and NT-proBNP​

• NAC (UK) model: replaces troponin T with eGFR, while keeping NT-proBNP at the same Mayo Clinic model threshold​

• The NAC criteria are based on biomarkers of cardiomyopathy (NT-proBNP) and nephropathy (eGFR) and can determine disease severity​

• Many HCP specialties may be involved in diagnosis of ATTRwt, but cardiologists are primarily the (confirming) diagnosing physicians​

• Upon diagnosis, patients (and caregivers) are oftentimes in shock and overwhelmed by the severity of the diagnosis​

• Some patients are relieved to finally have received a diagnosis and to know what they are dealing with​

• Some patients feel like they are not given enough information about the disease and don’t really understand the implications.  If they have no symptoms, they may not be too worried about it at first. ​

• Shock, devastation, and fear. Upon diagnosis, patients research ATTR and learn about poor survival rates and are in complete shock, and sometimes in despair about their outlook​

• “What is going to happen to me?” After receiving a diagnosis, some patients may be confused about what to expect and what to do, especially if their HCP does not provide enough information for them to fully understand the condition and how it progresses. When they hear that there is no cure, patients may worry that they could die the next day, or they may feel that they don’t need to think about it at all.  ​

• Liver transplant is not an option for ATTRwt, and heart transplant is uncommon for ATTRwt due to generally advanced age of the patients—however, successful outcomes have been reported in selected younger patients¹

• ATTRwt-CM Tx involves both (i) disease modifying agents to treat the underlying condition and (ii) supportive care to manage cardiovascular complications¹, ²

Disease-modifying agents:​

• TTR stabilizers provide kinetic stabilization of TTR tetramer and inhibit the initiation of amyloid formation by preventing dissociation of the TTR tetramer into monomers; preventing TTR tetramer dissociation results in slowing progression of disease and preservation of function, which is also expected to translate to improved QoL​

• Pfizer’s Vyndaqel (tafamidis, approved 2019), a TTR stabilizer, is the first approved disease-modifying treatment for ATTRwt-CM in Japan¹

• TTR silencer Acoramidis (Eidos / Alexion) is currently being evaluated in a phase 3 randomized controlled studies in ATTR-CM and ATTR-PN ​

• TTR Silencers are RNA molecules that inhibit the liver production of TTR by binding to the TTR mRNA, preventing its translation​

• TTR silencers (e.g., Vutrisiran and AKCEA-TTR-LRx [next-generation inotersen]) are currently being evaluated in phase 3 randomized controlled studies in patients with ATTRwt and ATTRv cardiac amyloidosis (CA)​

Supportive care:​

• CA initially exhibits a clinical phenotype akin to heart failure with preserved ejection fraction due to other causes, but most well‐recognized anti‐HF drugs may be harmful due to CA’s unique pathology; therefore, HF therapy for CA is primarily based on correct titration of diuretics³, ⁴

• CA patients have various supraventricular and/or ventricular arrhythmia; HCPs should choose the therapy individually based on CA characteristics ​

• Many ATTR‐CA patients at a high risk of conduction system disorders requiring cardiac pacing for symptomatic atrioventricular block or bradycardia​

• Common causes of death in patients with cardiac amyloidosis are a (rapidly) progressive heart failure and sudden cardiac death³

• However, recent emergence of effective therapies that slow disease progression and improve clinical outcomes promises to render ATTR-CM a treatable disease⁵

• Receiving a diagnosis of ATTR-CM does not guarantee that the patient will receive appropriate treatment, e.g., “[HCPs] prescribed Metoprolol and Lisinopril, and those are not appropriate drugs for amyloidosis”​

• Patients and caregivers feel frustrated by a lack of information from their HCPs, e.g., “his cardiologist admitted he didn’t know anything about it, either”​

• Patients and caregivers often feel helpless, which can also cause feelings of resignation and depression; “My husband is suffering. Much difficulty breathing and can’t walk. Coughing is extremely painful. I need help and feel hopeless. How do I change this endless situation of hospital admissions for everything?”​

• “There is nothing I can do.” Being told that you have a condition that will worsen and for which there is no cure available is extremely difficult to accept ​

• A change in perspective; a positive outlook. Each patient must come to terms with how to live with their disease, which may be a resolution to make the most of what they have with the realization that although there is no cure, there are still things that patients can do to improve the way they live​

• This is beyond me. Local HCP refers patient to amyloidosis center of excellence  ​

• The natural individual course of ATTR is difficult to assess due to the multitude of factors influencing the disease¹; but in both ATTRwt and ATTRv, the degree of cardiac involvement is closely associated with prognosis and survival¹

• Earlier reports suggested that the median survival of patients with ATTRwt was greater than 5 years, but contemporary studies demonstrate worse outcomes with a median survival (without treatment] of 3.5 years from initial evaluation³; ATTRwt-CM typically progresses more slowly than ATTRv²

• An accurate prognostic prediction method has not yet been established⁴

• The following prognostic factors have been identified: age, NYHA functional class, biomarkers (e.g., BNP/NT-proBNP, troponin, renal function, uric acid), echocardiographic indices (e.g., LVEF, relative wall thickness, strain), and CMR (e.g., LGE, ECV)⁴

• There are few prognostic data for Japanese patients with ATTR, and further large-scale investigations are needed⁴

• Vyndaqel (tafamidis), the only disease-modifying ATTRwt therapy currently approved in Japan, demonstrated a 30% reduction in risk of death⁴

• Patients’ options are limited as far as what they can do to affect their disease course​

• As patients experience changes that affect their functioning and independence, this can cause feelings of frustration, fear, and loss​

• Patients, especially those with cardiac manifestations, LIVE EACH DAY IN FEAR as they are unsure whether their organ will sustain until treatment response is achieved (if at all); all the while they live in a severely diminished physical state​

• Day-to-day and year-to-year uncertainty. Patients and their caregivers worry about what is to come. They don’t know the rate at which their disease will progress, or how it will progress, and their doctors cannot predict this for them either.​

• Taking things as they come and trying to stay positive about the future. Patients try to make the most of what they have in the “here and now”​

• Both ATTRv-CM and ATTRwt-CM are associated with markedly poor QOL at the time of diagnosis, and the direction of change of QOL scores was overwhelmingly negative ​

• Investigations into the QOL of people living with ATTR typically employ approaches utilizing validated quantitative instruments, and have reported a lower QOL vs. the general population and to people living with other long-term, chronic diseases​

• However, scales or PROMs for ATTR amyloidosis would be useful to better characterize newly diagnosed patients, and assess disease progression and Tx response, as no specific tools for QoL assessment in ATTR amyloidosis currently exist​

PHYSICAL IMPACT / IMPACT ON ACTIVITIES OF DAILY LIVING:​

• Physical impact is substantial and evolves throughout the patient journey; every stage poses different challenges; patients never return to normal and must give up many (in some cases all) activities they once used to love;  “new normal” can be physically extremely challenging for many with many simple activities of daily life becoming impossible for them​

• “If there's any hills, you get very breathless. You can't dance like you used to. You have to cope with that. I mean, that's a limitation that won't go away.”​

PSYCHOLOGICAL / EMOTIONAL IMPACT:​

• Patients are constantly challenged emotionally by the disease and implications on daily life; impact can vary over time, and amongst patients; some days are good, others bad, some patients experience DEPRESSION and/or ANXIETY​

• “What a change of life for my wife and myself. I had lost my independence. I needed help with almost everything I did. The physical and mental tiredness we all experienced was huge, the extent of which cannot be underestimated.”​

• UNCERTAINTY of a life-threatening illness causes FEAR and significant emotional stress on patients and caregivers; others gain strength from their predicament and use it as an opportunity to live LIFE TO THE FULLEST​

• “Not knowing. Not knowing where I am on the path. Not knowing how things will pan out.”​

• “I try to pull myself out of it, take a deep breath and let that subside and then try to be positive about the next step.”​

SOCIAL / PERSONAL LIFE IMPACT:​

• Patients may be unable to participate in activities they used to enjoy​

• He “becomes easily short of breath, even from a brief stroll or a walk up the stairs and can’t participate in many family activities he once loved, such as camping.”​

FINANCIAL & FAMILY / CAREGIVER IMPACT:​

• Family members and caregivers are deeply affected, financially, emotionally, and physically​

• “My wife had a doubling of her workload as well as dealing with the huge concern of whether I would survive. Our son had to step in and assist with driving and some shopping.”​

• An increasing sense of loss: as more things seem to be taken away from patients, it can feel like loss on top of more loss​

• Finding support can change perspective: patients report that seeking support from other patients, family, and friends can change their perspective on their condition and give them a more positive outlook