Amyloidosis Conferences

Hereditary ATTR (hATTR) amyloidosis affects an estimated 50,000 patients worldwide, with up to 10,000 attributed to cases with a polyneuropathy phenotype1 and 40,000 to cases with a cardiomyopathy phenotype.²

Without treatment, patients with hATTR amyloidosis with polyneuropathy experience rapid progression of neuropathy, with a rate of increase in NIS of ~14 points per year (for patients with a median baseline NIS of 32),3 which is vastly quicker than other neuropathies such as diabetic peripheral neuropathy (~0.15 points per year).⁴

The rate-determining step in transthyretin-mediated (ATTR) amyloidosis disease progression is the dissociation of free TTR tetramer into monomers (these monomers then misfold and aggregate into amyloid fibrils that are deposited throughout the body). Tafamadis, the first disease-modifying drug to be approved for ATTR amyloidosis, targets this step by binding to TTR at the thyroxine-binding sites, stabilising the tetramer and slowing dissociation into monomers.⁵ Tafamadis has been shown to delay progression of neuropathy compared with placebo⁶ and is well-tolerated in the long term.⁷

Speakers in the Pfizer satellite symposium "ATTR amyloidosis - navigating this multifaceted disease" at the 7th Congress of the European Academy of Neurology (EAN) - Virtual 2021, discussed many aspects of ATTR amyloidosis, including the benefits of early diagnosis and early treatment with tafamadis, cardiac involvement and the multidisciplinary team approach.

Treating early with tafamadis

Dr Isabel Conceição, Consultant in Neurology and Clinical Neurophysiology, presented post hoc and subanalyses of the pivotal tafamadis study, in which patients with hATTR amyloidosis with polyneuropathy were randomised 1:1 to 20 mg tafamadis once-daily or placebo for 18 months.

In a subanalysis of the pivotal study, patients with mild neuropathic impairment (NIS-Lower Limbs (NIS-LL) <10 at baseline) experienced minimal levels of neuropathic disease progression over 5.5 years (mean NIS-LL increase from baseline = 5.3) when treated with tafamadis, suggesting that treating patients early, when their neuropathic impairment is low, could help slow the progression of neuropathy. The results from a post hoc analysis further supported this, with baseline NIS-LL shown to be an independent predictor of neuropathic progression; patients with lower scores at baseline showed less neuropathy progression than those with higher scores at baseline. Importantly, treatment with tafamadis showed a reduction in the rate of neuropathic progression versus placebo in all patient groups, even those with the lowest baseline NIS-LL, proving that tafamadis is effective from the early stages of disease.

The importance of early diagnosis

Wolfgang Löscher, Professor of Neurology, and Gerhard Pölzl, Chief of the Heart Failure and Heart Transplant Program, led a mock multidisciplinary assessment of specific patient cases, demonstrating the need for interdisciplinary communication in the early and accurate diagnoses of patients. They highlighted 'red flags' - signs or symptoms that can aid the diagnosis - and issues to keep in mind during patient management.

The first case, that of a 65-year-old Caucasian male, focused on the importance of early diagnosis. The patient initially presented with mild length-dependent sensory and motor polyneuropathy and slight sensory pain in his hands; he was not diagnosed with ATTR amyloidosis. 12 months later the patient’s symptoms had progressed to severe length-dependent sensory and motor polyneuropathy, weakness and numbness in his legs and hands and difficulty walking. Amyloid deposits were identified, and immunostaining confirmed that these were TTR amyloids, not paraprotein.

Professor Löscher classed this rapid progressive neuropathy as a red flag for ATTR amyloidosis and shared his belief that earlier diagnosis of this patient may have resulted in an improved outcome: "The earlier the diagnosis the better, and the earlier we treat the better the treatment response. As a rule of thumb, I would say once the axon is damaged it is hard to recover any function from axonal damage."

Identifying and managing cardiac involvement

The next case was a 58-year-old Caucasian male presenting with dyspnoea on moderate exertion, and mild leg oedema. Red flags for cardiac involvement - family history of progressive cardiomyopathy, prior history of carpal tunnel syndrome and signs of cardiac weakness - prompted Professor Löscher to refer this patient to Professor Pölzl for a cardiac evaluation.

An electrocardiogram indicated a pseudo-infarct pattern in the precordial leads, suggestive of cardiac amyloidosis, which was then confirmed by the presence of:

• transthoracic echocardiogram showing restrictive phenotype, concentric LV hypertrophy, preserved systolic reduced diastolic dysfunction and reduced global longitudinal strain with apical sparing
• pronounced cardiac uptake of 99mTcDPD (Perugini grade III)
• elevated NTproBNP and troponin

In patients with ATTR amyloidosis with polyneuropathy (ATTR-PN), those with additional cardiomyopathy have a reduced life expectancy versus those without and Professor Pölzl explained one of the ways in which their disease management should differ; the treatment of choice for patients with ATTR amyloidosis with cardiomyopathy (ATTR-CM) is tafamadis at 61 mg once-daily, compared with 20 mg once-daily in patients with ATTR-PN.

In the phase III ATTR-ACT study, 441 patients with ATTR-CM received placebo, 20 mg tafamadis once-daily or 80 mg tafamadis once-daily. A long-term extension of ATTR-ACT, where all patients were transitioned to 61 mg tafamadis once-daily, found a significant survival benefit in those patients initially treated with the 80 mg dose versus the 20 mg dose (30% reduction in relative risk of death; p=0.0374, median follow-up 51 months).⁸

This difference in treatment, and the survival benefits it confers, emphasises the importance of identifying patients who have ATTR-CM, or ATTR amyloidosis with a mixed phenotype of polyneuropathy and cardiomyopathy. Dr Conceição concluded the session by summarising this: "It's very important that we think about this and we ask for cardiac evaluation in every patient, to change and to switch the dose of tafamadis."

Based on: Conceição I. Management of ATTR amyloidosis: the benefit of early diagnosis. Presented at the 7th Congress of the European Academy of Neurology (EAN) – Virtual 2021, 19-22 June 2021; Löscher W. Inside the multidisciplinary team: a practical approach to managing ATTR amyloidosis. Presented at the 7th Congress of the European Academy of Neurology (EAN) – Virtual 2021, 19-22 June 2021

99mTcDPD: technetium-99m-3,3-diphosphono-1,2 propanodicarboxylic acid; CV: cardiovascular; LV: left ventricular; NIS: Neuropathy Impairment Score; NTproBNP: N-terminal-pro hormone brain natriuretic peptide