Monoclonal antibodies and amyloid removal as a therapeutic strategy for cardiac amyloidosis

Emdin, Michele; Morfino, Paolo; Crosta, Lucia; Aimo, Alberto; Vergaro, Giuseppe; Castiglione, Vincenzo

doi:10.1093/eurheartjsupp/suad079

Cited by 12 publications

(4 citation statements)

References 15 publications

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“…AT-02 is a full-length, humanized, recombinant immunoglobulin 1 (IgG1)-like glycoprotein monoclonal antibody (mAb) engineered by fusion with the PAR p5R peptide. AT-02 is part of a group of new pan-amyloid agents designed for amyloid removal [ 100 ]. AT-02 is undergoing a multicenter, international, three-part Phase 1 study (NCT05521022).…”

Section: Treatment Of Al Amyloidosismentioning

confidence: 99%

Renal AL Amyloidosis: Updates on Diagnosis, Staging, and Management

Shafqat,

Elmaleh,

Mushtaq

et al. 2024

JCM

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AL amyloidosis is caused by the excessive production of nonfunctional immunoglobulins, leading to the formation of amyloid fibrils that damage vital organs, especially the heart and kidneys. AL amyloidosis presents with non-specific symptoms such as fatigue, weight loss, numbness, pain, and nephrotic syndrome. Consequently, diagnosis is often delayed, and patients typically present with advanced disease at diagnosis. The Pavia renal staging model stratifies patients based on their likelihood of progressing to dialysis. Treatment with daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (i.e., Dara-CyBorD) was effective in inducing renal response in the landmark phase III ANDROMEDA trial and reducing early mortality. However, determining the most appropriate treatment regimen for relapsed or refractory cases remains a challenge due to various patient- and disease-related factors. Encouragingly, t(11:14) may be a positive indicator of therapy responses to the anti-BCL2 therapy venetoclax. Moreover, it is increasingly possible—for the first time—to clear AL amyloid fibrils from peripheral organs by leveraging novel anti-fibril immunotherapeutic approaches, although these medications are still under investigation in clinical trials. Given these advancements, this review provides a comprehensive overview of the current strategies for diagnosing, staging, treating, and monitoring AL amyloidosis, emphasizing renal involvement.

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Section: Treatment Of Al Amyloidosismentioning

confidence: 99%

Renal AL Amyloidosis: Updates on Diagnosis, Staging, and Management

Shafqat,

Elmaleh,

Mushtaq

et al. 2024

JCM

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“…A monoclonal antibody-based therapy is under evaluation that has the capability of selectively binding to and removing the pre-existing amyloid deposits. Such therapies have a tremendous potential to alter the course of this fatal disease [ 80 ]. It also remains to be seen whether advancements in therapies for both ATTR and AL have a favorable impact on the prevention of life-threatening arrhythmias and also on the mitigation of stroke risk in AF.…”

Section: Ventricular Tachyarrhythmiasmentioning

confidence: 99%

Arrhythmias and Device Therapies in Cardiac Amyloidosis

Bukhari,

Khan,

Ghoweba

et al. 2024

JCM

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Cardiac amyloidosis is caused by amyloid fibrils that deposit in the myocardial interstitium, causing restrictive cardiomyopathy and eventually death. The electromechanical, inflammatory, and autonomic changes due to amyloid deposition result in arrhythmias. Atrial fibrillation is by far the most common arrhythmia. The rate control strategy is generally poorly tolerated due to restrictive filling physiology and heart rate dependance, favoring adoption of the rhythm control strategy. Anticoagulation for stroke prophylaxis is warranted, irrespective of CHA2DS2-VASc score in patients with a favorable bleeding profile; data on left appendage closure devices are still insufficient. Ventricular arrhythmias are also not uncommon, and the role of implantable cardioverter-defibrillator in cardiac amyloidosis is controversial. There is no evidence of improvement in outcomes when used for primary prevention in these patients. Bradyarrhythmia is most commonly associated with sudden cardiac death in cardiac amyloidosis. Pacemaker implantation can help provide symptomatic relief but does not confer mortality benefit.

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“…In vivo, DNA editing technologies and anti-TTR monoclonal antibody therapies are on the rise and may prove to be potential competition for Tafamidis in the treatment of ATTR-CM [ 62 ]. Most of these drugs are in Phase I or II of development.…”

Section: Real-world Evidence (Table 2 )mentioning

confidence: 99%

Tafamidis therapy in transthyretin amyloid cardiomyopathy: a narrative review from clinical trials and real-world evidence

Ogieuhi,

Ugiomoh,

Muzofa

et al. 2024

Egypt Heart J

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Background Amyloidosis is a heterogeneous group of disorders caused by the extracellular deposition of insoluble misfolded proteins, leading to end-organ damage. Transthyretin amyloid cardiomyopathy (ATTR-CM) is a subtype in which a protein known as transthyretin accumulates within the heart tissue, progressively resulting in restrictive cardiomyopathy and heart failure. Due to the progressive nature of ATTR-CM, clinical management requires efficacious regimens to manage the debilitating condition and Tafamidis shows promising results in this regard. Main body ATTR-CM poses a significant challenge due to its nature and limited therapeutic options. Tafamidis is a novel therapy designed to stabilize the transthyretin tetramers, inhibiting the formation of amyloid fibrils. It has emerged as a promising treatment and the only FDA-approved drug for ATTR-CM. Tafamidis' role in slowing disease progression and improving outcomes in patients with ATTR-CM has been demonstrated in the major randomized control trial ATTR-ACT with promising open-label extension studies, some still ongoing. Additionally, real-world evidence supports its use in clinical practice, showing its role in reducing morbidity and mortality associated with this condition. Clinical evidence shows its efficacy in improving symptoms and cardiac function in patients. Case studies also reveal significant benefits to patients like reducing myocardial damage, reversal of atrial fibrillation, and resolution of heart failure symptoms. Real-world outcomes and clinical trials show a consistent reduction in amyloid deposition, cardiovascular-related hospitalizations, and all-cause mortality with Tafamidis therapy. Conclusion Tafamidis is an essential component of the treatment of ATTR-CM and this narrative review synthesizes the current evidence regarding safety, efficacy, and utilization in real practice. While it shows promising effects, its effectiveness may also vary and high cost precludes real-world large-scale studies. Overall, Tafamidis emerges as a valuable therapeutic option for managing ATTR-CM.

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Monoclonal antibodies and amyloid removal as a therapeutic strategy for cardiac amyloidosis

Cited by 12 publications

References 15 publications

Renal AL Amyloidosis: Updates on Diagnosis, Staging, and Management

Renal AL Amyloidosis: Updates on Diagnosis, Staging, and Management

Arrhythmias and Device Therapies in Cardiac Amyloidosis

Tafamidis therapy in transthyretin amyloid cardiomyopathy: a narrative review from clinical trials and real-world evidence

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