4. Utility of Genetic Testing for the Initiation of a Specific Treatment
There is an increasing availability of novel, effective, and targeted therapeutic options for ATTRv, as well as for ATTRwt. As therapy is more effective in the early stages of the disease, a prompt diagnosis is key to enable the timely management of neurological, cardiac, and other systemic manifestations. The objective of such therapies is to decrease the production of overall and mutated TTR or to stabilize the circulating TTR molecule by preventing the dissociation of the molecule into amyloidogenic fragments
[1].
Treatment alternatives vary according to the variant (ATTRwt versus ATTRv) and are also different within ATTRv patients, depending on the presence of cardiomyopathy, polyneuropathy, or both.
Tafamidis, a benzoxazole derivative without nonsteroidal anti-inflammatory activity, is a stabilizing molecule that selectively binds to the thyroxine-binding sites of TTR and inhibits the dissociation of tetramers into monomers. In the ATTR-ACT study, tafamidis was associated with a lower all-cause mortality than placebo and a lower rate of cardiovascular-related hospitalizations. It was also associated with a lower rate of decline in distance for the 6 minutes walk test and a lower rate of decline in the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score
[19]. Rapezzi et al. further analysed data from the ATTR-ACT in an attempt to determine whether the treatment effects were different between the ATTRv and ATTRwt groups. In fact, they found that the reduction in all-cause mortality following treatment with tafamidis compared with placebo was not different in the ATTRwt and ATTRv groups. In addition, tafamidis was associated with a similar reduction in the 6 min walk test distance and the KCCQ-OS score in both groups
[20]. At present, tafamidis can be readily considered the agent of choice in both ATTRwt and ATTRv patients with a reasonable life expectancy who present with cardiac manifestations or stage 1 polyneuropathy
[19]. Acoramidis is a new TTR stabilizer. Two phase 3 studies are ongoing to evaluate the efficacy and safety of acoramidis in patients with ATTR-CM (NCT03860935 and NCT04622046).
Ribonucleic acid (RNA) interference is an innate mechanism used to regulate gene expression. This process leads to the fragmentation of specific messenger RNA (mRNA) targets through the interaction of small interfering RNAs bound to the RNA-induced silencing complex. The genetic silencers decrease the production of transthyretin by targeting the transthyretin mRNA, causing the catalytic degradation of TTR mRNA in the liver. Patisiran and inotersen are two approved genetic silencers for ATTRv patients with polyneuropathy.
Patisiran is an interfering RNA encapsulated in a lipid nanoparticle that is delivered to the intracellular compartments of hepatocytes by intravenous infusion
[21]. Patisiran has shown to improve multiple clinical manifestations of ATTRv. The favorable impacts of patisiran therapy on polyneuropathy and overall quality of life remained consistent across all primary subgroups, including age, gender, race, region, genotype, initial neuropathy impairment score, familial amyloid polyneuropathy stage, prior use of TTR stabilizers, and cardiac involvement, as observed in the APOLLO-A study
[22].
Patisiran has also demonstrated that it is safe and effective in improving both the neurological and cardiovascular symptoms of ATTRv amyloidosis, and it can help patients maintain a good quality of life, regardless of the disease stage or the specific mutation involved
[23].
Vutrisiran, a novel RNA interference agent, reduces serum TTR levels by curtailing TTR synthesis, and it has been recently approved for the treatment of ATTRv amyloidosis-related polyneuropathy in adults. This molecule is targeted to the liver, the primary site of TTR synthesis, by binding to a triantennary N-acetylgalactosamine ligand that attaches to the asialoglycoprotein receptor on hepatocyte surfaces. This binding design incorporates an enhanced stabilization chemistry, which enhances its potency and metabolic stability, thereby enabling subcutaneous injections once every three months
[24].
Antisense oligonucleotides (ASOs) are single-stranded amphipathic molecules that bind to proteins present in serum, on cell surfaces, and within cells. Within the nucleus of the target cell, ASOs bind to the target mRNA, initiating mRNA degradation
[25].
Inotersen, a 2′-O-methoxyethyl–modified antisense oligonucleotide inhibitor, specifically targets the hepatic production of the transthyretin protein. Studies have indicated its ability to enhance the course of neurological disease and improve the quality of life in patients with hereditary transthyretin amyloidosis. These improvements were observed independently of the disease stage, mutation type, or the presence of cardiomyopathy
[1][26]. Inotersen has also demonstrated a stabilization effect on the disease progression of ATTR cardiomyopathy patients
[27]. Inotersen is a reasonable option for ATTRv patients with early-stage polyneuropathy involvement (stages 1 or 2 polyneuropathy)
[21]. Gene silencers are only indicated for patients with ATTRv. The cost of these drugs, along with the cost of the genetic test, makes it difficult to generalise the use of these drugs for all healthcare systems.
Eplontersen represents a new generation of antisense oligonucleotide inhibitors that are linked to triantennary N-acetyl galactosamine. This linkage enhances uptake by hepatocytes, reducing immunogenic reactions and facilitating a reduction in TTR gene expression. Currently, a phase 3 study is underway to assess its effectiveness and safety in patients diagnosed with ATTR-CM (NCT04136171).
The application of genomic editing through CRISPR Cas9 is a promising therapeutic approach in managing ATTR amyloidosis. This technique involves using a nuclease (Cas9) combined with a single-stranded RNA, leading to the irreversible suppression of the TTR gene. A phase 1 clinical trial is ongoing in patients affected by ATTRv polyneuropathy, ATTRv, and ATTRwt CM (NCT04601051)
[28].
Overall, patients diagnosed with stage 1 polyneuropathy survive longer
[29]. Although therapy can delay disease progression, the recovery of established neurological deficits should not be expected
[2]. At present, there is no consensus on what is considered the minimum level of organ damage needed to initiate treatment. This is important because classifying a carrier as affected usually prompts treatment initiation
[2][11]. In general, disease-modifying therapies, like tafamidis, have significantly improved the survival of amyloidosis-affected patients
[30].
5. Utility of Genetic Testing in Prognosis Assessment
The prognosis for ATTR amyloidosis exhibits variability based on factors such as mutation type, phenotype, and the delay in diagnosis
[7]. Advances in diagnostic imaging, alongside the emergence of novel therapies targeting TTR, are contributing to an improved prognosis for ATTR-CM. In cases of ATTRwt and ATTRv with cardiac involvement, whether associated with neurological symptoms or not, the disease typically progresses, resulting in heart failure and mortality within approximately 10 years from the disease’s onset. However, in ATTRv patients with a pure neurological phenotype, the overall survival tends to be longer
[31]. Specifically, the median survival time for untreated patients experiencing cardiomyopathy or a mixed cardiac-neurological presentation is estimated at 2.5 years for ATTRv and 3.6 years for ATTRwt
[19].
Prognostic methods for cardiac amyloidosis patients include multiparametric biomarker scores and biomarker-based staging systems, primarily developed for AL and ATTR cardiac amyloidosis. Current scoring systems acknowledge several presentation parameters
[1]. Gilmore et al. described a score for ATTRwt and ATTRv using glomerular filtration (< or >45 mL/min/1.73 m
2) and NT-proBNP levels (< or >3000 pg/mL)
[31]. Patients in stage 1 (zero parameters) had a median survival of 69.2 months, patients in stage 2 (one parameter) had a median survival of 46.7 months, and patients in stage 3 (two parameters) had a median survival of 24.1 months
[1]. For the Mayo risk model
[7], a group of ATTRwt patients underwent classification into three distinct prognostic stages determined by the levels of troponin T (>0.05 ng/mL) and N-terminal proB-type natriuretic peptide (>3000 pg/mL) biomarkers. Stage 1 comprised patients without elevated biomarkers, stage 2 included individuals with an elevation in one biomarker, and stage 3 encompassed those with elevations in both biomarkers. Patients in stage 3 exhibited a significantly poorer median survival compared to those in stage 1. The median survival times for patients in stages 1, 2, and 3 were 66, 40, and 20 months, respectively
[32].