Liver Directed Drugs for Transthyretin-Mediated Amyloidosis

AIM: Transthyretin-mediated amyloidosis (ATTR) is a rare, under-recognized, progressively debilitating, fatal disease caused by the aggregation and extracellular deposition of amyloid transthyretin (TTR) fibrils in multiple organs and tissues throughout the body. TTR is predominantly synthesized by the liver, and normally circulates as a homotetramer, while misfolded monomers aggregate to form amyloid fibrils. One strategy to treat ATTR amyloidosis is to reduce the amount of TTR produced by the liver using drugs that directly target the TTR mRNA or gene. METHODS: This narrative review focuses on how TTR gene silencing tools act to reduce TTR production, describing strategies for improved targeted delivery of these agents to hepatocytes where TTR is preferentially expressed. RESULTS: Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), termed RNA silencers, cause selective degradation of TTR mRNA, while a TTR gene editing tool reduces TTR expression by introducing nonsense mutations into the TTR gene. Two strategies to facilitate tissue-specific delivery of these nucleic acid-based drugs employ endogenous receptors expressed by hepatocytes. Lipid nanoparticles (LNPs) that recruit apolipoprotein E support low density lipoprotein receptor-mediated uptake of unconjugated siRNA and is now used for CRISPR gene editing tools. Additionally, conjugating N-acetylgalactosamine (GalNAc) moieties to ASOs or siRNAs facilitates receptor-mediated uptake by the asialoglycoprotein receptor. CONCLUSION: ATTR is a progressive disease with various clinical manifestations due to TTR aggregation, deposition, and amyloid formation. Receptor-targeted ligands (e.g., GalNAc) and nanoparticle encapsulation (e.g., LNPs) are technologies to deliver ASOs, siRNAs, and gene editing tools to hepatocytes, the primary location of TTR synthesis

Design and Rationale of the Global Phase 3 NEURO-TTRansform Study of Antisense Oligonucleotide AKCEA-TTR-LRx (ION-682884-CS3) in Hereditary Transthyretin-Mediated Amyloid Polyneuropathy

Introduction: AKCEA-TTR-LRx is a ligand-conjugated antisense (LICA) drug in development for the treatment of hereditary transthyretin amyloidosis (hATTR), a fatal disease caused by mutations in the transthyretin (TTR) gene. AKCEA-TTR-LRx shares the same nucleotide sequence as inotersen, an antisense medicine approved for use in hATTR polyneuropathy (hATTR-PN). Unlike inotersen, AKCEA-TTR-LRx is conjugated to a triantennary N-acetylgalactosamine moiety that supports receptor-mediated uptake by hepatocytes, the primary source of circulating TTR. This advanced design increases drug potency to allow for lower and less frequent dosing. The NEURO-TTRansform study will investigate whether AKCEA-TTR-LRx is safe and efficacious, with the aim of improving neurologic function and quality of life in hATTR-PN patients. Methods/design: Approximately 140 adults with stage 1 (independent ambulation) or 2 (requires ambulatory support) hATTR-PN are anticipated to enroll in this multicenter, open-label, randomized, phase 3 study. Patients will be assigned 6:1 to AKCEA-TTR-LRx 45 mg subcutaneously every 4 weeks or inotersen 300 mg once weekly until the prespecified week 35 interim efficacy analysis, after which patients receiving inotersen will receive AKCEA-TTR-LRx 45 mg subcutaneously every 4 weeks. All patients will then receive AKCEA-TTR-LRx through the remainder of the study treatment period. The final efficacy analysis at week 66 will compare the AKCEA-TTR-LRx arm with the historical placebo arm from the phase 3 trial of inotersen (NEURO-TTR). The primary outcome measures are between-group differences in the change from baseline in serum TTR, modified Neuropathy Impairment Score + 7, and Norfolk Quality of Life-Diabetic Neuropathy questionnaire. Conclusion: NEURO-TTRansform is designed to determine whether targeted delivery of AKCEA-TTR-LRx to hepatocytes with lower and less frequent doses will translate into clinical and quality-of-life benefits for patients with hATTR-PN

Amiodarone and digitalis: An odd couple in a tachycardiomyopathic patient

Amiodarone is one of the most used anti-arrhythmic drug for rate and rhythm control in atrial fibrillation. Unfortunately, it has also well-known pro-arrhythmic properties and it has been reported as a common cause of malignant ventricular tachyarrhytmias, especially torsade de pointes. Proarrhytmic effects of amiodarone are greatly increased by other concomitant factors, such as ventricular dysfunction and concomitant treatment with digitalis. Current evidence shows how amiodarone and digitalis together are associated with torsade de pointes in ischemic patients with heart failure. The present case report describes, for the first time, how amiodarone and digital can concur in producing torsade de pointes also in a tachycardiomyopathic patient with no coronary artery disease

The value of Stanford integrated psychosocial assessment for transplantation (SIPAT) in prediction of clinical outcomes following left ventricular assist device (LVAD) implantation

Background: The Stanford integrated psychosocial assessment for transplantation (SIPAT) is a validated psychosocial evaluation tool in the transplant population. Objective: We evaluated SIPAT in predicting post-left ventricular assist device (LVAD) outcomes, including cumulative re-admissions, driveline infections, pump malfunction, pump thrombosis, gastrointestinal bleeding, major bleeding, stroke and right ventricular failure. Methods: This retrospective study included 50 LVAD patients at an academic institution in the United States who had a pre-implant SIPAT score during the years 2015-2017. Patients were split into two groups based on SIPAT score, separating a “excellent”/“good” from a “minimally acceptable”/“poor” candidate. Poisson regression, using SIPAT as both a categorical and continuous variable, was used to compare the incidence rates of the primary outcome of cumulative re-admissions and secondary outcomes of LVAD complications. Results: The patient cohort was predominantly male 93.5% vs 89.4% (p = 0.629) with a median age of 67.0 vs 58.0 years (p = 0.037), planned destination therapy 48.4% vs 68.4% (p = 0.242) and median LVAD follow-up time of 241 vs 379 days (p = 0.10) in the low- and high- SIPAT groups, respectively. SIPAT was not a significant predictor for cumulative re-admissions, but there was an association between higher SIPAT scores and major bleeding. Conclusion: In this single-center retrospective study, SIPAT did not predict cumulative re-admissions. Further study is required to validate SIPAT before clinical implementation

[Primary cardiac lymphoma in an immunocompetent young adult: outcome with chemotherapy]

Primitive cardiac lymphoma (PCL) is a rare disease accounting for only 1-2% of primary cardiac tumors. Diffuse large B cell lymphoma is the most common type and shows a rapid progression with poor prognosis. The clinical presentation of PCL is nonspecific, and echocardiographic study is essential to the initial work-up. Magnetic resonance imaging and computed tomography scan are the methods of choice for the assessment of tumor extension. The definitive diagnosis is histopathology examination. Chemotherapy and radiotherapy represent the best treatment and should be started promptly after PCL diagnosis. We here report a case of PCL in a 59-year-old man complicated by pulmonary microembolism, atrial fibrillation and signs of right outflow tract obstruction

Kidney Function Following Left Ventricular Assist Device Implantation: An Observational Cohort Study

Rationale & objectiveNearly half the patients with heart failure have chronic kidney disease. Implantation of a left ventricular assist device (LVAD) improves kidney function in some but not all patients, and lack of improvement is associated with worse outcomes. Preimplantation factors that predict change in kidney function after LVAD placement are not well described.Study designSingle-center observational study.Setting & participantsConsecutive patients undergoing LVAD implantation.Predictors48 diverse preimplantation variables including demographic, clinical, laboratory, hemodynamic, and echocardiographic variables.OutcomesThe primary outcome was change in estimated glomerular filtration rate (eGFR) at 1 month after implantation. Secondary outcomes included eGFR changes at 3, 6, and 12 months.Analytic approachUnivariable and multivariable linear regression.ResultsAmong 131 patients, average age was 60 ± 13 years, 83% were men, 47% had pre-existing chronic kidney disease, and mean preimplantation eGFR was 57 ± 23 mL/min/1.73 m2. At 1-month following LVAD implantation, eGFR improved in 98 (75%) patients. Variables associated with 1-month increases in eGFR were younger age, absence of diabetes mellitus (DM), use of inotropes, lower implantation eGFR, and higher implantation serum urea nitrogen, alanine aminotransferase, bilirubin, and creatinine levels. In multivariable models, younger age (β = 7.14 mL/min/1.73 m2 per SD; 95% CI, 3.17-11.10), lower eGFR (β = 7.72 mL/min/1.73 m2 per SD; 95% CI, 3.10-12.34), and absence of DM (β = 10.36 mL/min/1.73 m2; 95% CI, 2.99-17.74) were each independently associated with 1-month improvement in eGFR. Only younger age and lower eGFR were associated with improvements in eGFR at later months.LimitationsSingle-center study. Loss to follow-up from heart transplantation and death over duration of study.ConclusionsOnly younger age, lower eGFR, and absence of DM were associated with improvement in eGFR at 1 month. Thus, prediction of eGFR change at 1 month and beyond is limited by using preimplantation variables