What treatment options are available today?

Transthyretin-associated amyloidosis (ATTR) is hereditary (hATTR) or acquired (wATTR). In patients with unclear left ventricular hypertrophy and characteristic findings, it is recommended to investigate the presence of cardiac amyloidosis. In hATTR amyloidosis, there is the option of gene silencing in addition to transthyretin-stabilizing therapy. In addition, further innovative therapeutic approaches are currently being researched.

In the phenotype with cardiomyopathy, the deposits preferentially affect the myocardium, in the phenotype with polyneuropathy the peripheral nervous system. However, there are also mixed phenotypes. If ATTR is detected by myocardial biopsy or non-invasive diagnostic algorithm, genetic testing of the transthyretin gene should be performed regardless of the patient’s age [1]. For many years, the only treatment available for ATTR cardiomyopathy was symptomatic heart failure therapy or, in severe and advanced cases, transplantation [2,3]. This has changed in the meantime.

Transthyretin-stabilizing therapy

The active ingredient tafamidis (Vyndaqel®) prevents the dissociation of transthyretin tetramers into monomers by occupying the binding sites of thyroid hormones and thus counteracts fibril formation and amyloid deposition [4]. Tafamidis is taken orally, side effects are rare. Liver values may increase, which is why they should be monitored at the start of therapy [5]. Other active substances for transthyretin stabilization are being investigated in current studies, including tolcapone and acoramidis [6,7].

Supportive therapy for ATTR
In patients with ATTR, optimal volume management is required due to the primarily diastolic dysfunction with reduced stroke volume and restrictive ventricle [1]. Therefore, in addition to specific disease-modifying treatment options, supportive heart failure therapy is an important factor. Loop diuretics and mineralocorticoid receptor antagonists are usually used as part of closely monitored diuretic therapy. Traditional heart failure therapy with ACE inhibitors, ARNI and beta-blockers is often poorly tolerated due to a tendency to hypotension or bradycardia [3,15]. Most heart failure studies on these agents to date have excluded patients with cardiac amyloidosis, so the data is limited [3,15].

Transthyretin gene silencing

The active principle of gene silencers is to inhibit the expression of the transthyretin gene, which leads to reduced synthesis of transthyretin [2,3]. The following three substances are currently approved for the treatment of patients with hATTR with polyneuropathy (stages 1 and 2)**:

Patisiran (^Onpattro®) [5]
Vutrisiran (^Amvuttra®) [5]
Inotersen (^Tegsedi®) [5]

** No approval for cardiac manifestation alone

Patisiran and vutrisiran are small interfering RNA (si-RNA), which inhibit the translation of the transthyretin protein. Inotersen is a gene silencer with an alternative mechanism of action: it is an antisense oligonucleotide that selectively binds to transthyretin mRNA and prevents its translation into transthyretin [5]. Patisiran is administered intravenously, the other two gene silencers subcutaneously.

In addition to the neurological outcome, the APOLLO study, which is relevant for the approval of patisiran, investigated the effect on cardiac involvement in a pre-specified subgroup analysis [9,10]. Around half of the study population had left ventricular hypertrophy ≥13 mm without other triggers, with patisiran showing an improvement in NT-proBNP values and echocardiographic parameters after 18 months. Based on these results, the APOLLO-B study was initiated [8]. This Phase III study is investigating the efficacy and safety of patisiran in patients with ATTR cardiomyopathy [1,11]. The efficacy of vutrisiran in ATTR cardiomyopathy (hATTR and wtATTR) is being investigated in the HELIOS-B study [5].

The pivotal study for inotersen (NEURO-TTR study) showed an improvement in neurological outcome and slower disease progression in hATTR and polyneuropathy [5,12]. In contrast to patisiran, no improvement in echocardiographic parameters could be demonstrated for inotersen in the subpopulation of patients with cardiac involvement. Vitamin A supplementation is recommended for Patisiran, Vutrisiran and Inotersen. Eplontersen is another antisense oligonucleotide that is currently being researched [13].

Further active substances in the pipeline

The CRISPR (“clustered regularly interspaced short palindromic repeats”)-Cas9 (CRISPR-associated protein 9) method is a gene-based therapeutic approach for hATTR [6]. In a Phase I pilot study, the effects of the drug candidate NTLA2001 after intravenous injection – which induces a permanent knockout of transthyretin using the CRISPR-Cas9 method – are being analyzed in 6 patients with hereditary ATTR neuropathy [14]. Another therapeutic approach is based on immunotherapy with monoclonal, humanized anti-transthyretin antibodies [6]. The mechanism of action is that the antibody-TTR complexes promote degradation by macrophages through specific binding of misfolded transthyretin [15]. Phase I studies are underway for the antibodies PRX004 (Prothena) and NI006 [6,15,16].

Literature:

Knoll K, Fuchs P, Trenkwalder T: Kardiale Amyloidose: Aktuelle und zukünftige Therapieoptionen. CV 2023; 23(2): 39–43.
Yilmaz A, et al.: Diagnosis and treatment of cardiac amyloidosis: position statement of the German Cardiac Society (DGK). Clin Res Cardiol 2021; 110: 479–506.
Garcia-Pavia P, et al.: Diagnosis and treatment of cardiac amyloidosis: a position statement of the ESC Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2021; 42: 1554–1568.
Maurer MS, et al.: Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med 2018; 379: 1007–1016.
Swissmedic: Arzneimittelinformation,
www.swissmedicinfo.ch,(last accessed 08.03.2024).
Stern LK, Patel J: Cardiac Amyloidosis Treatment. Methodist Debakey Cardiovasc J 2022; 18(2): 59–72.
Nelson LT, et al.: Blinded potency comparison of transthyretin kinetic stabilisers by subunit exchange in human plasma. Amyloid 2021; 28(1): 24–29.
Clinical Trials (NCT03997383), https://clinicaltrials.gov/ct2/show/NCT03997383,(last accessed 08.03.2024)
Adams D, et al.: Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med 2018; 379(1): 11–21.
Solomon SD, 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.
Maurer M, et al.: Primary results from APOLLO-B, a phase 3 study of patisiran in patients with transthyretin-mediated amyloidosis with cardiomyopathy. Presented at the International Symposium of Amyloidosis; September 4–8, 2022; Heidelberg, Germany.
Benson MD, et al.: Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis. N Engl J Med 2018; 379(1): 22–31.
Gorevic P, et al.: Indirect treatment comparison of the efficacy of patisiran and inotersen for hereditary transthyretin-mediated amyloidosis with polyneuropathy. Expert Opin Pharmacother 2021; 22(1): 121–129.
Gillmore JD, et al.: CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis. N Engl J Med 2021; 385(6): 493–502.
Tschöpe C, Elsanhoury A: Treatment of Transthyretin Amyloid Cardiomyopathy: The Current Options, the Future, and the Challenges. J Clin Med 2022; 11(8): 2148
Clinical Trials (NCT04360434), https://clinicaltrials.gov/ct2/show/NCT04360434,(last accessed 08.03.2024)