Transthyretin amyloid heart disease: causes and new treatments

Serum amyloid P (SAP) component scintigraphy, a quantitative diagnostic and monitoring tool for visceral amyloid deposits,⁴ and cardiac magnetic resonance imaging, a means of tracking cardiac amyloid burden via serial measurement of extracellular volume,⁵ have demonstrated that amyloid deposits exist in a state of dynamic equilibrium dependent upon the rates of ongoing amyloid formation and natural amyloid clearance.^5,6 Because amyloid clearance in vivo is consistently slow, amyloid formation in untreated patients likely outpaces its clearance, resulting in progressive accumulation and a decline in organ function.

Therapies that suppress the circulating concentration of the respective amyloid fibril precursor protein reduce the substrate available required for new amyloid formation.¹ In the case of ATTR amyloidosis, ongoing amyloid formation can also be inhibited by drugs that stabilize the normal soluble TTR tetramer, thereby reducing the availability of misfolded TTR species that serve as the substrate for ATTR amyloid fibril formation.⁷ There are currently no biological assays that specifically measure the rate of amyloid formation or the rate of amyloid clearance in vivo.⁸ However, serial quantitative imaging in patients with systemic light-chain (AL) amyloidosis who have achieved a complete haematological response⁹ as well as in patients with hereditary fibrinogen A α-chain amyloidosis who have undergone liver transplantation such that they have no ongoing amyloid formation¹⁰ has demonstrated that, although the rate of amyloid clearance is consistently slow, it varies substantially between patients and even between different organs in the same patient. For example, amyloid clearance from the liver and spleen typically occurs more rapidly than it does from the heart and tongue.⁹

It is perhaps surprising that the clearance of amyloid, with its acquired highly abnormal structure, occurs so slowly; the reasons for this and mechanisms of clearance remain uncertain. Histological evaluation of patients' biopsies shows that amyloid deposits usually, but not always, elicit a very limited inflammatory response.¹¹ In contrast, studies in mice with experimentally induced AA amyloidosis¹² and in humans with various types of systemic amyloidosis^13,14 have shown that clearance of visceral amyloid can be markedly accelerated following administration of antibodies targeting specifically the amyloid deposits. Based on evidence from the murine model, accelerated antibody-mediated amyloid clearance involves activation of the classical complement pathway, recruitment of macrophages, and formation of multinucleated giant cells that engulf surrounding amyloid. This process is abrogated when there is a deficiency in complement and/or macrophages.¹² These experimental findings were supported by human evidence, as complement activation was observed in patients with systemic amyloidosis who experienced rapid visceral amyloid clearance following administration of the anti-SAP antibody dezamizumab.¹⁵ The fact that age at disease onset in carriers of the pathogenic p.Val50Met TTR variant is influenced by functional variants of C1q lends further support to the potential role of the complement pathway in amyloid pathogenesis.¹⁶

Modest ATTR amyloid deposition is common in the elderly,¹⁷ yet only a small proportion develop sufficient deposition to cause clinically significant cardiomyopathy.¹⁸ Amyloid accumulation can result from increased production, reduced clearance, or both. Potential mechanisms include age-related changes that reduce TTR tetramer stability or alter its tissue interactions, leading to increased deposition, and/or reduced amyloid clearance. Further research is needed to clarify these mechanisms and their relative contributions in different patient subsets.

The primary goal of all approved therapies for amyloidosis is preventing further amyloid deposition in tissues to slow or halt disease progression. In ATTR amyloidosis, this can be achieved by stabilizing TTR (Figure 1) or by reducing its synthesis (Figure 2).

A relationship between greater reduction in circulating TTR and better clinical outcomes could be hypothesized based on data from other forms of amyloidosis. For example, there is a clear relationship between the magnitude of serum amyloid A (SAA) knockdown and risk of death in AA amyloidosis.⁶ The relative risk of death is nearly four times higher among patients with a median SAA concentration between 4 and 9 mg/L compared with those with a median SAA of <4 mg/L (i.e. a normal SAA concentration), underscoring the importance of normaling the production of the amyloid fibril precursor protein. Persistence of excessive inflammation as measured by a median SAA concentration of >155 mg/L was associated with a near 18-fold risk of death.⁶ Similarly, in AL amyloidosis, outcomes are significantly better in patients who achieve a haematological complete response with chemotherapy (equivalent to 100% knockdown of the circulating amyloidogenic protein) than in patients who achieve a very good partial response (equivalent to at least 90% knockdown). In turn, patients who achieve a very good partial response do better than those who achieve a partial response, equivalent to 50–90% knockdown, who do better than those who achieve <50% knockdown. Most notably, in patients with AL amyloidosis, those who achieve a complete haematological response (characterized by undetectable levels of the precursor protein) demonstrate the best survival rates compared with those with lesser degrees of reduction in circulating fibril precursor protein concentration following chemotherapy.⁴² An association between the magnitude of reduction in circulating TTR achieved with patisiran and change in neuropathy score as a measure of clinical outcome has been demonstrated in patients with ATTRv-PN.⁴³ On the other hand, an association between the magnitude of TTR reduction and the improvement in cardiac parameters or cardiac outcome has never been reported in patients with ATTR-CM.

To summarize, we propose a conceptual framework, informed by experience with AL and AA amyloidosis as well as preliminary data in ATTRv-PN amyloidosis, suggesting that a greater magnitude and consistency of reduction in serum TTR concentration will lead to better clinical outcomes in patients with ATTR-CM (Figure 3).

The natural mechanisms of amyloid removal described in the previous section are intriguing, but their relative contribution in the heart and for preventing build-up of ATTR amyloid is unclear. Strategies that enhance amyloid removal by eliciting a targeted immune response hold considerable promise.

ALXN2220 (formerly NI006) is a human-derived monoclonal IgG1 antibody that binds to the linear epitope WEPFA, which is only accessible on misfolded TTR and ATTR deposits, triggering phagocytosis of ATTR aggregates by human macrophages thereby accelerating fibril removal.⁴⁴ In the first-in-human, randomized, double-blind, placebo-controlled, Phase 1 trial, patients with ATTR cardiomyopathy and chronic HF received intravenous ALXN2220/NI006 infusions or placebo every 4 weeks over a 4-month period, followed by an 8-month open-label extension phase.⁴⁵ Participants were assigned to increasing dose levels ranging from 0.3 to 60 mg/kg. All enrolled patients had a confirmed diagnosis of ATTR-CM, a minimum left ventricular wall thickness of 14 mm, preserved ejection fraction of at least 40%, and a range of mild-to-moderate HF symptoms. The majority were receiving concomitant treatment with tafamidis, but no other ATTR-specific therapies were permitted. Safety and tolerability served as the primary objectives, with dose escalation contingent on the absence of clinically significant adverse events. Among 40 enrolled patients, there were no clearly drug-related serious adverse events, and no antidrug antibodies were detected. Most adverse events were mild or moderate and considered typical of the disease in this patient population. A few patients showed mild cytokine release syndrome or transient musculoskeletal symptoms, such as arthralgias, which generally resolved with standard symptomatic management. Some patients had transient asymptomatic thrombocytopenia, one case leading to trial discontinuation. Pharmacokinetic assessments indicated that ALXN2220/NI006 behaved like a typical human IgG antibody with a half-life of 2–3 weeks. Imaging studies revealed dose-dependent reductions in cardiac amyloid load over time. Patients receiving at least 10 mg/kg of ALXN2220/NI006 every 4 weeks for up to 1 year showed reduced extracellular volume, suggesting a decreased amyloid burden. Conversely, those receiving placebo showed no such improvements until they too switched to active treatment in the extension phase. Additional analyses suggested that high doses of ALXN2220/NI006 might be associated with improvements in cardiac biomarkers such as NT-proBNP and troponin T, which are linked to disease severity and prognosis in ATTR-CM.⁴⁵ Although these findings were based on a small sample and must be interpreted with caution, they are consistent with an accelerated removal of pathogenic amyloid deposits leading to potential improvements in cardiac function. ALXN2220 is being investigated in a Phase 3 trial (NCT06183931).

NNC6019-0001 (former known as PRX004) is a humanized monoclonal antibody that targets misfolded monomeric and aggregated forms of TTR, promoting antibody-mediated phagocytosis and amyloid clearance. A Phase 2 trial initiated in 2022 aims to evaluate the efficacy and safety of NNC6019-0001 in 99 patients with ATTR-CM. Participants are receiving either NNC6019-0001 at 30 or 100 mg/kg, or placebo on top of standard-of-care treatment. The study will examine changes in the 6MWD and NT-proBNP levels at Week 52 along with changes in structural and functional cardiac parameters, the incidence of cardiovascular hospitalizations and urgent HF visits, and patient-reported quality of life.⁴⁶

Several therapeutic options for ATTR-CM are currently under investigation (Table 1 and Figure 4). Pharmacologic TTR stabilizers and silencers have already shown that slowing amyloid deposition can prolong survival and enhance quality of life. However, critical questions remain—namely, which therapy offers the greatest benefit, how best to tailor treatment to each patient, and what criteria should define a clinically meaningful response. The absence of direct, head-to-head comparisons only underscores the importance of specialized, multidisciplinary care that tailors therapy to individual patient needs.

An emerging strategy to maximize efficacy involves combination therapies that address multiple disease mechanisms. For example, agents that reduce amyloid formation via TTR knockdown can be paired with stabilizers targeting the remaining circulating TTR to curb new deposition. Yet, the notion that fully halting amyloid formation would shift the balance towards net amyloid clearance remains unproven, as no current intervention completely blocks deposition. Forthcoming clinical trials, particularly those evaluating next-generation agents such as nucresiran and gene-editing approaches, will help clarify whether deeper TTR suppression leads to larger reductions in amyloid load and more significant clinical gains. If gene editing is shown to be both safe and durable as a one-time intervention, it could redefine the treatment landscape, contingent on robust long-term outcomes and feasibility analyses. At the same time, insights into intrinsic amyloid clearance pathways might unlock new therapeutic avenues, whether by harnessing or augmenting these endogenous processes. Whether these or other modalities can achieve rapid and complete amyloid clearance (a result that could simplify or shorten the duration of therapy) remains to be seen.

Pursuing such innovative treatments also raises concerns regarding cost, access, and equity. High-complexity interventions, like gene editing in conjunction with amyloid clearance, could carry substantial financial implications, making careful patient selection essential to ensure both cost-effectiveness and avoidance of futile therapy. Younger individuals, those with earlier-stage disease, or those poised to benefit from sustained improvements in cardiac function may emerge as prime candidates. Striking a balance between therapeutic ambition and fiscal reality is crucial to ensure equitable access for all who stand to benefit.

Supportive HF therapies are likewise central to symptom management in ATTR-CM. Along with disease-specific treatments, established HF regimens (such as renin–angiotensin–aldosterone system blockers, beta-blockers, and mineralocorticoid receptor antagonists) continue to play a key role in symptom control and improving outcomes.⁴⁷ Notably, sodium–glucose cotransporter-2 inhibitors have shown promise in reducing hospitalizations and mortality in HF,⁴⁸ highlighting the value of a comprehensive strategy that merges targeted and supportive interventions.

In summary, while therapeutic innovations have markedly broadened the range of options for patients with ATTR-CM, pressing questions about optimal treatment, patient selection, and response metrics highlight the need for ongoing research and direct clinical comparisons. Until those data become available, individualized, interdisciplinary management remains paramount for delivering effective, patient-centered care.