Amyloid Polyneuropathy Research Articles

Impact of Baseline Neuropathy Severity on Vutrisiran Treatment Response in the Phase 3 HELIOS-A Study.

Hereditary transthyretin (ATTRv, v for variant) amyloidosis is a rare, progressive, fatal disease with multisystem manifestations, caused by pathogenic variants in the transthyretin (TTR) gene. Vutrisiran, an RNA interference therapeutic that results in rapid TTR knockdown, improved neuropathy and quality of life (QOL) versus external placebo in patients with ATTRv amyloidosis with polyneuropathy in the phase 3 HELIOS-A study (NCT03759379). This post hoc analysis evaluates the impact of baseline neuropathy severity on response to vutrisiran treatment. Patients were randomized (3:1) to vutrisiran (n=122; 25mg subcutaneous injection once every 3months) or patisiran (n=42; 0.3mg/kg intravenous infusion once every 3weeks), which served as a reference group. In this post hoc analysis, patients were grouped into quartiles of increasing baseline Neuropathy Impairment Score (NIS): Quartile (Q)1≥5.0 to≤20.5; Q2>20.5 to≤44.1; Q3>44.1 to≤73.1; Q4>73.1 to≤127.0. Mean change from baseline to Month 18 was summarized by quartile for a range of efficacy endpoints. Across all baseline NIS quartiles, vutrisiran demonstrated benefit versus external placebo in measures of neuropathy severity (modified NIS+7), QOL (Norfolk Quality of Life-Diabetic Neuropathy), disability (Rasch-built Overall Disability Scale), gait speed (10-m walk test), and nutritional status (modified body mass index). Overall, patients in lower versus higher NIS quartiles (less severe neuropathy) at baseline maintained better scores at Month 18. The external placebo group progressively worsened in all measures at Month 18. Vutrisiran demonstrated benefit in neurologic function and other key efficacy measures versus external placebo across all four baseline neuropathy severity quartiles. Patients initiating vutrisiran earlier in their disease course retained the highest neurologic function level after 18months, highlighting the importance of early diagnosis and treatment. ClinicalTrials.gov: NCT03759379.

Abstract P159: Echocardiographic Cardiac Phenotype in Val122Ile Variant Transthyretin Amyloidosis Among Hispanics/Latinos: Results From the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)

Background: Transthyretin amyloidosis, most often caused by Val122Ile mutation, is linked to a higher risk of heart failure (HF) and mortality. Subclinical abnormalities in cardiac structure and function linked to Val122Ile mutations are less well defined in Hispanics/Latinos. We studied the cardiac phenotype of Hispanic/Latino Val122Ile carriers versus non-carriers. Methods: Val122Ile carrier status was determined with genome-wide data. We analyzed echocardiographic data from adults 45 years or older (unweighted n= 6376) from HCHS/SOL and the Echocardiographic Study of Latinos, Echo-SOL. Measures of cardiac structure and function (Table) were compared among Val122Ile carriers and non-carriers using age-and-sex-adjusted least square means (continuous variables) and proportions (categorical variables). Prevalence of pre-HF, identified by the presence of at least one abnormal echocardiographic parameter, was also compared among those with vs. without Val122Ile mutation. Complex survey statistics and sample weights are utilized for all analyses. Results: Val122Ile carriers (0.8%; unweighted n= 40) were younger (mean ±SE, 55.5 years ±1.7), had higher systolic blood pressure (mean ±SE, 130 mmHg ±3.6), but lower body mass index (mean ±SE, 28.5 kg/m 2 ±1.4) than non-carriers, p <0.0001. Lower mean values of left ventricle (LV) ejection fraction, LV end diastolic volume, right ventricle (RV) fractional area change, lateral peak e’ velocity and lower pre-HF prevalence was seen among carriers vs non-carriers. Val122Ile carriers also had higher LV mass, worse concentric remodeling, and worse measures of diastolic function than non-carriers. Most measures of RV function were higher among carriers vs non-carriers (Table) . However, none of the differences found in cardiac phenotype of carriers vs non-carriers were statistically significant (p >0.05). Conclusion: There is a lack of difference in the echocardiographic cardiac phenotype among Hispanic/Latinos who carry the Val122Ile mutation versus non-carriers.

Structures and Dynamics of β-Rich Oligomers of ATTR (105-115) Assembly.

Transthyretin (TTR) is a tetrameric homologous protein that can dissociate into monomers. Misfolding and aggregation of TTR can lead to amyloid transthyretin amyloidosis (ATTR), which can cause many diseases (e.g., senile systemic amyloidosis, familial amyloid cardiomyopathy, and familial amyloid polyneuropathy). Despite growing evidence indicating that small oligomers play a critical role in regulating cytotoxicity, the structures of these oligomeric intermediates and their conformational transformations are still unclear, impeding our understanding of neurodegenerative mechanisms and the development of therapeutics targeting early aggregation species. The TTR monomer protein consists of various fragments prone to self-aggregation, including the residue 105-115 sequence. Therefore, our study investigated the assembly progress of ATTR (105-115) peptides using all-atom molecular dynamics simulations. The findings indicate that the probability of β-sheet content increases with increasing numbers of peptides. Additionally, interactions between hydrophobic residues L110 and L111 are crucial for the formation of a β-rich oligomer formation. These β-rich oligomers may adopt β-barrel conformations, potentially toxic oligomer species. Free-energy analysis reveals that β-barrel conformations serve as intermediates for these β-rich oligomers. Our insights into the structural ensemble dynamics of ATTR (105-115) contribute to understanding the physical mechanisms underlying the β-barrel oligomers of ATTR. These findings may shed light on the pathological role of ATTR in neurodegenerative diseases and offer potential therapeutic targets.

Duodenal amyloidosis: a clinical case

BACKGROUND: Amyloidosis is a chronic systemic disease that, in some cases, affects the organs of the gastrointestinal tract.
 CLINICAL CASE DESCRIPTION: A 62-year-old patient complained of painless enlargement of the lymph nodes in the supraclavicular region on the left side according to the puncture biopsy of the lymph node — reactive lymphoid hyperplasia. During the examination, duodenal amyloidosis was accidentally detected. The results of additional studies to determine the type of amyloid were nonspecific. The patient refused to continue the examination.
 CONCLUSION: This clinical case of duodenal amyloidosis is unusual and clearly demonstrates the difficulties of diagnosis, including the absence of a clinic and the nonspecificity of the endoscopic and radiological picture during the examination. In addition, the absence of an established chronic disease characteristic of amyloid A amyloidosis and the results of laboratory and instrumental research methods, excluding amyloid light chain amyloidosis and transthyretin amyloidosis, emphasise the main role of clinicians in diagnosing the underlying disease.

Altered gut microbiota in Taiwanese A97S predominant transthyretin amyloidosis with polyneuropathy

Increasing evidence suggests that gut microbiota alterations are related to development and phenotypes of many neuropsychiatric diseases. Here, we evaluated the fecal microbiota and its clinical correlates in patients with hereditary transthyretin amyloidosis (ATTRv) and polyneuropathy. Fecal microbiota from 38 ATTRv patients and 39 age-matched controls was analyzed by sequencing 16S V3–V4 ribosomal RNA, and its relationships with clinical characteristics of polyneuropathy and cardiomyopathy were explored. The familial amyloidotic polyneuropathy stage was stage I, II, and III in 13, 18, and 7 patients. 99mTc-PYP SPECT showed a visual score of 2 in 15 and 3 in 21 patients. The gut microbiota of ATTRv patients showed higher alpha diversity (ASV richness and Shannon effective numbers) and dissimilar beta diversity compared to controls. Relative abundance of microbiota was dominated by Firmicutes and decreased in Bacteroidetes in ATTRv patients than in controls. Patients with more myocardial amyloid deposition were associated with increased alpha diversity, and the abundance of Clostridia was significantly correlated with pathophysiology of polyneuropathy in ATTRv patients. These findings demonstrated alterations in the gut microbiota, especially Firmicutes, in ATTRv. The association between altered microbiota and phenotypes of cardiomyopathy and polyneuropathy might suggest potential contributions of gut microbiota to ATTRv pathogenesis.

Longitudinal analysis of serum neurofilament light chain levels as marker for neuronal damage in hereditary transthyretin amyloidosis

Objective To evaluate serum neurofilament light chain (sNfL) as biomarker of disease onset, progression and treatment effect in hereditary transthyretin (ATTRv) amyloidosis patients and TTR variant (TTRv) carriers. Methods sNfL levels were assessed longitudinally in persistently asymptomatic TTRv carriers (N = 12), persistently asymptomatic ATTRv amyloidosis patients (defined as asymptomatic patients but with amyloid detectable in subcutaneous abdominal fat tissue) (N = 8), in TTRv carriers who developed polyneuropathy (N = 7) and in ATTRv amyloidosis patients with polyneuropathy on treatment (TTR-stabiliser (N = 20) or TTR-silencer (N = 18)). Polyneuropathy was confirmed by nerve conduction studies or quantitative sensory testing. sNfL was analysed using a single-molecule array assay. Results sNfL increased over 2 years in persistently asymptomatic ATTRv amyloidosis patients, but did not change in persistently asymptomatic TTRv carriers. In all TTRv carriers who developed polyneuropathy, sNfL increased from 8.4 to 49.8 pg/mL before the onset of symptoms and before polyneuropathy could be confirmed neurophysiologically. In symptomatic ATTRv amyloidosis patients on a TTR-stabiliser, sNfL remained stable over 2 years. In patients on a TTR-silencer, sNfL decreased after 1 year of treatment. Conclusion sNfL is a biomarker of early neuronal damage in ATTRv amyloidosis already before the onset of polyneuropathy. Current data support the use of sNfL in screening asymptomatic TTRv carriers and in monitoring of disease progression and treatment effect.

Role of Multimodality Imaging in the Diagnostic work-up for Cardiac Amyloidosis

Cardiac amyloidosis is caused by the deposition of transthyretin or light-chain fibrils into the myocardium, leading to restrictive cardiomyopathy, and eventually death if untreated. The improvement in diagnostic modalities has seen a recent surge in the number of patients being diagnosed with cardiac amyloidosis, particularly transthyretin amyloidosis. The diagnostic workup often starts with echocardiogram, followed by cardiac magnetic resonance and finally pyrophosphate scintigraphy. It is important to know that while transthyretin amyloidosis is often diagnosed non-invasively with technetium pyrophosphate scan in the contemporary practice, the diagnosis of light-chain amyloidosis still needs tissue confirmation.

Cardiopulmonary Exercise Testing in Evaluating Transthyretin Amyloidosis.

Cardiopulmonary exercise testing (CPET) has an established role in the assessment of patients with heart failure. However, data are lacking in patients with transthyretin (ATTR) amyloidosis. To use CPET to characterize the spectrum of functional phenotypes in patients with ATTR amyloidosis and assess their association with the cardiac amyloid burden as well as the association between CPET parameters and prognosis. This single-center study evaluated patients diagnosed with ATTR amyloidosis from May 2019 to September 2022 who underwent CPET at the National Amyloidosis Centre. Of 1045 patients approached, 506 were included and completed the study. Patients were excluded if they had an absolute contraindication to CPET or declined participation. The mean (SD) follow-up period was 22.4 (11.6) months. Comparison of CPET parameters across disease phenotypes (ATTR with cardiomyopathy [ATTR-CM], polyneuropathy, or both [ATTR-mixed]), differences in CPET parameters based on degree of amyloid infiltration (as measured by cardiovascular magnetic resonance [CMR] with extracellular volume mapping), and association between CPET parameters and prognosis. Among the 506 patients with ATTR amyloidosis included in this study, the mean (SD) age was 73.5 (10.2) years, and 457 participants (90.3%) were male. Impairment in functional capacity was highly prevalent. Functional impairment in ATTR-CM and ATTR-mixed phenotypes (peak mean [SD] oxygen consumption [VO2], 14.5 [4.3] mL/kg/min and 15.7 [6.2] mL/kg/min, respectively) was observed alongside impairment in the oxygen pulse, with ventilatory efficiency highest in ATTR-CM (mean [SD] ventilatory efficiency/volume of carbon dioxide expired slope, 38.1 [8.6]). Chronotropic incompetence and exercise oscillatory ventilation (EOV) were highly prevalent across all phenotypes, with both the prevalence and severity being higher than in heart failure from different etiologies. Worsening of amyloid burden on CMR was associated with decline in multiple CPET parameters, although chronotropic response and EOV remained abnormal irrespective of amyloid burden. On multivariable Cox regression analysis, peak VO2 and peak systolic blood pressure (SBP) were independently associated with prognosis (peak VO2: hazard ratio, 0.89 [95% CI, 0.81-0.99; P = .03]; peak SBP: hazard ratio, 0.98 [95% CI, 0.97-0.99; P < .001]). In this study, ATTR amyloidosis was characterized by distinct patterns of functional impairment between all disease phenotypes. A high prevalence of chronotropic incompetence, EOV, and ventilatory inefficiency were characteristic of this population. CPET parameters were associated with amyloid burden by CMR and with peak VO2, and SBP, which have been shown to be independent predictors of mortality. These findings suggest that CPET may be useful in characterizing distinct patterns of functional impairment across the spectrum of amyloid infiltration and predicting outcomes, and potentially offers a more comprehensive method of evaluating functional capacity for future prospective studies.

Patisiran, an RNAi therapeutic for hereditary transthyretin-mediated amyloidosis: Sub-analysis in Taiwanese patients from the APOLLO study

BackgroundTo examine the efficacy and safety of patisiran, an RNA interference therapeutic, in patients from Taiwan with hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy. MethodsThe APOLLO phase 3 trial included patients from Taiwan who received patisiran 0.3 mg/kg intravenously or placebo once every 3 weeks (q3w) for 18 months (18 M), followed by patisiran 0.3 mg/kg q3w in an ongoing global open-label extension (OLE) study. The primary endpoint was change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) at 18 M. ResultsEighteen Taiwanese patients were enrolled in APOLLO (patisiran, n = 8; placebo, n = 10; all A97S gene variant) and 14 continued in the global OLE. In this Taiwanese sub-population, beneficial treatment effects at 18 M were observed in mNIS+7 (least squares mean difference in change from baseline [patisiran-placebo], −26.5 points; 95% confidence interval: −45.5, −7.5). Patients who switched from placebo to patisiran demonstrated slowing of polyneuropathy progression at month 12 in the global OLE, while those who received patisiran in APOLLO maintained the beneficial treatment effects. Patisiran had an acceptable safety profile in the Taiwanese sub-population. ConclusionThis analysis suggests that patisiran is well tolerated and may provide a substantial clinical benefit for Taiwanese patients with hATTR amyloidosis with polyneuropathy. Trial registration informationThe studies were registered on the ClinicalTrials.gov. The APOLLO study ClinicalTrials.gov identifier is NCT01960348 (https://clinicaltrials.gov/ct2/show/NCT01960348), with the registration date of October 10, 2013, and the first patient was enrolled on December 13, 2013. For the global OLE, the ClinicalTrials.gov identifier is NCT02510261 (https://clinicaltrials.gov/ct2/show/NCT02510261) with the registration date of July 29, 2015, and the first patient was enrolled on July 13, 2015. Classification of evidenceThis study provides Class II evidence that treatment with patisiran is safe and efficacious in Taiwanese patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy.

Biceps Tendon Rupture as an Early Manifestation of Hereditary Transthyretin Amyloidosis

Biceps Tendon Rupture as an Early Manifestation of Hereditary Transthyretin Amyloidosis

A clinical case of transthyretin amyloidosis with manifestations of seronegative arthritis

A clinical case of transthyretin amyloidosis with manifestations of seronegative arthritis

Origin of Transthyretin in Cerebral Amyloid Angiopathy

This case series evaluates the correlation between transthyretin and cerebral amyloid angiopathy progression in individuals with hereditary transthyretin amyloidosis.

RNA Drug As Therapeutic Agents: A Review Based On Literature.

Small RNA targeted drugs have received significant interest from the public and researches in the last decade due to their capability in treating different illnesses. RNA drugs corresponds to the small molecules which interact with and regulate the expression of particular genes at the level of RNA. Unlike ordinary small molecular chemicals, RNA drugs act directly on the nucleus and gene to produce very efficient and effective curative functions. Some of the RNA drugs are siRNA, ASOs, and mRNA, although the last one is used in vaccines. Both compounds, SiRNA and ASOs, act by attaching to the target mRNA chain and, as a result, the latter can be degraded or prevented from being translated into a protein. Onc the other hand, mRNA vaccines involve introducing a particular mRNA sequence into cells, and the outcome is that cells synthesize a certain protein that can be a viral antigen to spark an immune response. The RNA drugs have demonstrated quite significant outcomes with initial trials for diseases like cancer, genetic disorders as well as certain infections. For instance, siRNA based drugs are introduced for the treatment of hereditary transthyretin amyloidosis which is a rare genetic disease and ASO based drugs for spinal muscular atrophy. mRNA vaccines have also been developed to fight against the epidemic such as COVID-19. However, there are few major issues that have to be considered with regard to RNA drugs These are: These are; problems of drug delivery and stability; and issues to do with side or off-target effects. Despite of these hurdles, RNA drugs are a promising new category of drugs for diseases that can be treated by this technique. As the research work in the field of RNA medicine grows, the public might observe more RNA-based drugs being approved for the clinical use in the future years. Keywords: RNA Drug, Therapeutic Agents, A Review

Current Perspectives on Atrial Amyloidosis: A Narrative Review.

Amyloidosis is a systemic disease caused by low molecular weight protein accumulation in the extracellular space, which can lead to different degrees of damage, depending of the organ or tissue involved. The condition is defined cardiac amyloidosis (CA) when heart is affected, and it is associated with an unfavorable outcome. Different types of CA have been recognized, the most common (98%) are those associated with deposition of light chain (AL-CA), and the form secondary to transthyretin deposit. The latter can be classified into two types, a wild type (transthyretin amyloidosis wild type (ATTRwt)-CA), which mainly affects older adults, and the hereditary or variant type (ATTRh-CA or ATTRv-CA), which instead affects more often young people and is associated with genetic alterations. The atrial involvement can be isolated or linked to CA with a nonspecific clinical presentation represented by new onset atrial fibrillation (AF), diastolic dysfunction and heart failure with preserved ejection fraction, or thromboembolism and stroke. Untreated patients have a median survival rate of 9 years for AL-CA and 7 years for ATTR-CA. By contrast, AL-CA and ATTR-CA treated patients have a median survival rate of 24 and 10 years, respectively. Atrial involvement in CA is a common but poor studied event, and alterations of performance can anticipate the anatomical damage. Recently, numerous advances have been made in the diagnostic field with improvements in the available techniques. An early diagnosis therefore allows a more effective therapeutic strategy with a positive impact on prognosis and mortality rate. A multimodality approach to the diagnosis of atrial involvement from CA is therefore recommended, and standard echocardiography, advanced Doppler-echocardiography (DE) and cardiac magnetic resonance (CMR) can be useful to detect early signs of CA and to estabilish an appropriate treatment.

Inhibitors of Transthyretin Amyloidosis: How to Rank Drug Candidates Using X-ray Crystallography Data.

Amyloidosis is a group of protein misfolding diseases, which include spongiform encephalopathies, Alzheimer's disease and transthyretin (TTR) amyloidosis; all of them are characterized by extracellular deposits of an insoluble fibrillar protein. TTR amyloidosis is a highly debilitating and life-threatening disease. Patients carry less stable TTR homotetramers that are prone to dissociation into non-native monomers, which in turn rapidly self-assemble into oligomers and, ultimately, amyloid fibrils. Liver transplantation to induce the production of wild-type TTR was the only therapeutic strategy until recently. A promising approach to ameliorate transthyretin (TTR) amyloidosis is based on the so-called TTR kinetic stabilizers. More than 1000 TTR stabilizers have already been tested by many research groups, but the diversity of experimental techniques and conditions used hampers an objective prioritization of the compounds. One of the most reliable and unambiguous techniques applied to determine the structures of the TTR/drug complexes is X-ray diffraction. Most of the potential inhibitors bind in the TTR channel and the crystal structures reveal the atomic details of the interaction between the protein and the compound. Here we suggest that the stabilization effect is associated with a compaction of the quaternary structure of the protein and propose a scoring function to rank drugs based on X-ray crystallography data.

Historic characteristics and mortality of patients in the Swiss Amyloidosis Registry.

Systemic amyloidoses are rare protein-folding diseases with heterogeneous, often nonspecific clinical presentations. To better understand systemic amyloidoses and to apply state-of-the-art diagnostic pathways and treatment, the interdisciplinary Amyloidosis Network was founded in 2013 at University Hospital Zurich. In this respect, a registry was implemented to study the characteristics and life expectancy of patients with amyloidosis within the area covered by the network. Patient data were collected retrospectively for the period 2005-2014 and prospectively from 2015 onwards. Patients aged 18 years or older diagnosed with any subtype of systemic amyloidosis were eligible for inclusion if they were treated in one of the four referring centres (Zurich, Chur, St Gallen, Bellinzona). Baseline data were captured at the time of diagnosis. Follow-up data were assessed half-yearly for the first two years, then annually. Between January 2005 and March 2020, 247 patients were screened, and 155 patients with confirmed systemic amyloidosis were included in the present analysis. The most common amyloidosis type was light-chain (49.7%, n = 77), followed by transthyretin amyloidosis (40%, n = 62) and amyloid A amyloidosis (5.2%, n = 8). Most patients (61.9%, n = 96) presented with multiorgan involvement. Nevertheless, single organ involvement was seen in all types of amyloidosis, most commonly in amyloid A amyloidosis (75%, n = 6). The median observation time of the surviving patients was calculated by the reverse Kaplan-Meier method and was 3.29 years (95% confidence interval [CI] 2.33-4.87); it was 4.87 years (95% CI 3.14-7.22) in light-chain amyloidosis patients and 1.85 years (95% CI 1.48-3.66) in transthyretin amyloidosis patients, respectively. The 1-, 3- and 5-year survival rates were 87.0% (95% CI 79.4-95.3%), 68.5% (95% CI 57.4-81.7%) and 66.0% (95% CI 54.6-79.9%) respectively for light-chain amyloidosis patients and 91.2% (95% CI 83.2-99.8%), 77.0% (95% CI 63.4-93.7%) and 50.6% (95% CI 31.8-80.3%) respectively for transthyretin amyloidosis patients. There was no significant difference between the two groups (p = 0.81). During registry set-up, a more comprehensive work-up of our patients suffering mainly from light-chain amyloidosis and transthyretin amyloidosis was implemented.Survival rates were remarkably high and similar between light-chain amyloidosis and transthyretin amyloidosis, a finding which was noted in similar historic registries of international centres. However, further studies are needed to depict morbidity and mortality as the amyloidosis landscape is changing rapidly.

Detection of TTR Amyloid in the Conjunctiva Using a Novel Fluorescent Ocular Tracer.

Transthyretin amyloidosis (ATTR) is a significant cause of cardiomyopathy and other morbidities in the elderly and Black Americans. ATTR can be treated with new disease-modifying therapies, but large shortfalls exist in its diagnosis. The objective of this study was to test whether TTR amyloid can be detected and imaged in the conjunctiva using a novel small-molecule fluorescent ocular tracer, with the implication that ATTR might be diagnosable by a simple eye examination. Three approaches were used in this study. First, AMDX-9101 was incubated with in vitro aggregated TTR protein, and changes in its excitation and emission spectra were quantified. Second, a cadaver eye from a patient with familial amyloid polyneuropathy type II TTR mutation and a vitrectomy sample from an hATTR patient were incubated with AMDX-9101 and counterstained with Congo Red and antibodies to TTR to determine whether AMDX-9101 labels disease-related TTR amyloid deposits in human conjunctiva and eye. Last, imaging of in vitro aggregated TTR amyloid labeled with AMDX-9101 was tested in a porcine ex vivo model, using a widely available clinical ophthalmic imaging device. AMDX-9101 hyper-fluoresced in the presence of TTR amyloid in vitro, labeled TTR amyloid deposits in postmortem human conjunctiva and other ocular tissues and could be detected under the conjunctiva of a porcine eye using commercially available ophthalmic imaging equipment. AMDX-9101 enabled detection of TTR amyloid in the conjunctiva, and the fluorescent binding signal can be visualized using commercially available ophthalmic imaging equipment. AMDX-9101 detection of TTR amyloid may provide a potential new and noninvasive test for ATTR that could lead to earlier ATTR diagnosis, as well as facilitate development of new therapeutics.

Vutrisiran (Amvuttra)

&#x0D; CADTH recommends that Amvuttra be reimbursed by public drug plans for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin-mediated (hATTR) amyloidosis if certain conditions are met.&#x0D; Amvuttra should only be covered to treat adults with stage 1 or stage 2 genetically confirmed hATTR amyloidosis with polyneuropathy (hATTR-PN) who are symptomatic with early-stage neuropathy, do not have severe heart failure symptoms, and have not had a liver transplant. A patient’s response to treatment with Amvuttra should be assessed at least every 6 months to determine whether they would benefit from continued treatment. Treatment with Amvuttra should not be continued in patients who are permanently bedridden and dependent on assistance for basic activities of daily living or who are receiving end-of-life care.&#x0D; Amvuttra should only be reimbursed if the patient is under the care of a specialist with experience in the diagnosis and management of hATTR-PN and should not be reimbursed if it is used in combination with interfering ribonucleic acid drugs or transthyretin stabilizers. The cost of Amvuttra should be reduced so that it does not cost more than other drugs for hATTR amyloidosis.&#x0D;

Complexities of Coexisting Cardiac Amyloidosis and Coronary Artery Disease: A Contemporary Review of Diagnostic and Treatment Approaches.

Cardiac amyloidosis (CA) represents an emerging challenge in cardiovascular medicine, with notable clinical overlaps and diagnostic complexities when coexisting with coronary artery disease (CAD). This integrative review navigates the intricate terrain of CA and CAD, elucidating epidemiology, clinical presentations, and diagnostic considerations. Examining both immunoglobulin light chain amyloidosis (AL) and transthyretin amyloidosis, we underscore their shared demographic associations, diagnostic intricacies, and potential diagnostic confounders with CAD. Notably, we emphasize the impact of CA on epicardial coronary arteries and the consequential implications for coronary microcirculation. Further exploration reveals the connection between CA and acute myocardial infarction, emphasizing early recognition as pivotal. In terms of differential diagnosis, we underscore the significance of clinical symptoms, electrocardiography, echocardiography, cardiac magnetic resonance, and bone scintigraphy. Additionally, we scrutinize the intricate realm of treatment, encompassing medication selection, antithrombotic strategies, and revascularization modalities. Our review addresses the distinctive challenges posed by CA patients' limited tolerance for conventional therapies. This comprehensive synthesis serves as an invaluable resource for clinicians confronting the intricate intersection of CA and CAD. By offering insights into diagnostic refinement and innovative therapeutic avenues, we aim to enhance patient outcomes and quality of life within this complex clinical landscape.

2023 FDA TIDES (Peptides and Oligonucleotides) Harvest.

A total of nine TIDES (pepTIDES and oligonucleoTIDES) were approved by the FDA during 2023. The four approved oligonucleotides are indicated for various types of disorders, including amyotrophic lateral sclerosis, geographic atrophy, primary hyperoxaluria type 1, and polyneuropathy of hereditary transthyretin-mediated amyloidosis. All oligonucleotides show chemically modified structures to enhance their stability and therapeutic effectiveness as antisense or aptamer oligomers. Some of them demonstrate various types of conjugation to driving ligands. The approved peptides comprise various structures, including linear, cyclic, and lipopeptides, and have diverse applications. Interestingly, the FDA has granted its first orphan drug designation for a peptide-based drug as a highly selective chemokine antagonist. Furthermore, Rett syndrome has found its first-ever core symptoms treatment, which is also peptide-based. Here, we analyze the TIDES approved in 2023 on the basis of their chemical structure, medical target, mode of action, administration route, and common adverse effects.