Search Results (6)

Transthyretin-related (ATTR) amyloidosis is a progressive, multisystem disease caused by the extracellular deposition of misfolded transthyretin (TTR) monomers as insoluble amyloid fibrils. Clinical manifestations vary widely and may include cardiomyopathy (ATTR-CM), polyneuropathy (ATTR-PN), or mixed phenotypes. The condition is increasingly recognized as an underdiagnosed contributor to heart failure, particularly in elderly patients. ATTR amyloidosis exists in two major forms: hereditary (ATTRv), resulting from mutations in the TTR gene, and wild-type (ATTRwt), typically affecting men over 70 years of age. Advances in disease understanding have led to a paradigm shift in management, with the introduction of targeted therapies that slow disease progression and improve prognosis. First-generation therapies such as tafamidis have demonstrated survival benefits in ATTR-CM. More recently, second-generation agents—such as the TTR stabilizer acoramidis and RNA silencers including vutrisiran and eplontersen—have shown promising efficacy in clinical trials. Additional strategies under investigation include gene editing and monoclonal antibodies targeting TTR amyloid deposits. This review outlines current diagnostic strategies and therapeutic options for ATTR amyloidosis, emphasizing the need for early detection and individualized treatment approaches. The expanding therapeutic landscape highlights the importance of accurate phenotyping and timely intervention to optimize clinical outcomes. Full article

The hypertrophic cardiomyopathy (HCM) clinical phenotype includes sarcomeric HCM, which is the most common form of inherited cardiomyopathy with a population prevalence of 1:500, and phenocopies such as cardiac amyloidosis and Anderson–Fabry disease, which are considered rare diseases. Identification of cardiac and non-cardiac red flags in the context of multi-organ syndrome, multimodality imaging, including echocardiography, cardiac magnetic resonance, and genetic testing, has a central role in the diagnostic pathway. Identifying the specific disease underlying the hypertrophic phenotype is very important since many disease-modifying therapies are currently available, and phase 3 trials for new treatments have been completed or are ongoing. In particular, many chemotherapy agents (alkylating agents, proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies targeting clonal cells) allowing one to treat AL amyloidosis, transthyretin stabilizers (tafamidis and acoramidis), and gene silencers (patisiran and vutrisiran) are available in transthyretin cardiac amyloidosis, and enzyme replacement therapies (agalsidase-alpha, agalsidase-beta, and pegunigalsidase-alpha) or oral chaperone therapy (migalastat) can be used in Anderson–Fabry disease. In addition, the introduction of cardiac myosin inhibitors (mavacamten and aficamten) has deeply modified the treatment of hypertrophic obstructive cardiomyopathy. The aim of this review is to describe the new disease-modifying treatments available in HCM and phenocopies in light of current scientific evidence. Full article

Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a progressive disease that has emerged as a significant cause of heart failure. Advances in the understanding of ATTR-CM pathophysiology have revolutionised its therapeutic landscape over the past decade, with the development of targeted therapies that are able to improve survival and quality of life. TTR stabilizers, such as tafamidis and acoramidis, can reduce TTR instability and subsequent amyloid fibril formation. Clinical trials have demonstrated their efficacy both in improving survival and quality of life in patients with ATTR-CM. Gene-silencing therapies using small interfering RNAs (siRNAs), such as patisiran and vutrisiran, or antisense oligonucleotide inhibitors (ASOs), such as inotersen and eplontersen, serve as powerful therapeutic options by decreasing TTR production; trials on patients with ATTR-CM have been recently published or are ongoing. Novel, emerging therapies aim to enhance fibril clearance using monoclonal antibodies, such as NI006, that target amyloid deposits in the myocardium, promoting their depletion, plausibly with regression of the structural and functional impairments caused by the disease. Concurrently, advancements in diagnostic modalities have facilitated earlier detection of this disease, allowing the timely initiation of treatment with a more significant impact on patients’ survival and quality of life. Despite these strides, challenges remain, including the high cost of disease-modifying therapy and the need for response criteria to monitor treatment’s efficacy. Future directions will involve improving patients’ screening to achieve earlier diagnoses, optimising patients’ selection for disease-modifying therapy and identifying criteria for the treatment’s response or lack thereof to possibly consider therapy switch or associations. In this review, we will explore the more recent therapeutic advancements in ATTR-CM, starting from traditional heart failure therapies and moving to disease-modifying therapies with a detailed evaluation of the registration trials to explore the strengths and shortcomings of each treatment. Full article

Small interfering RNA (siRNA)-based medications offer the ability to target previously undruggable targets and have now received FDA approval in five instances for orphan or uncommon diseases. The current siRNA “-sirans” are directed towards hepatic molecular targets. Because they are not conventional drug formulae, their ultimate clinical success will require overcoming multiple barriers beyond their pharmacology. The minimal patient numbers leave fewer patients to bear the costs of R&D and manufacture; therefore, the cost of these drugs, questionable third-party reimbursement, and competition from other drug classes for the same low number of patients are impediments to patient access. The parenteral route of administration, as well as emerging safety restrictions, are also drawbacks to siRNA. With this review, we document currently approved siRNA drugs by condition, approval date, administration route and frequencies. We have estimated the available patient populations for siran therapies using the U.S. Medicaid and Medicare populations and sought to identify the frequency with which large Medicaid formularies list siRNA drugs. Current comparative costs between the siRNA drugs and alternatives have been presented, and the review summarizes current adverse events as reported to the FDA’s Adverse Event Reporting System. Our review and data indicate that sirans are extremely expensive and seldom recognized in posted Medicaid formularies. However, alternative treatments for these conditions are no less costly, usually do not have significantly different adverse events, and are often less convenient for the patient. Full article

The global statistics of bone disorders, skeletal defects, and fractures are frightening. Several therapeutic strategies are being used to fix them; however, RNAi-based siRNA therapy is starting to prove to be a promising approach for the prevention of bone disorders because of its advanced capabilities to deliver siRNA or siRNA drug conjugate to the target tissue. Despite its ‘bench-to-bedside’ usefulness and approval by food and drug administration for five siRNA-based therapeutic medicines: Patisiran, Vutrisiran, Inclisiran, Lumasiran, and Givosiran, its use for the other diseases still remains to be resolved. By correcting the complications and complexities involved in siRNA delivery for its sustained release, better absorption, and toxicity-free activity, siRNA therapy can be harnessed as an experimental tool for the prevention of complex and undruggable diseases with a personalized medicine approach. The present review summarizes the findings of notable research to address the implications of siRNA in bone health for the restoration of bone mass, recovery of bone loss, and recuperation of bone fractures. Full article

A total of 37 new drug entities were approved in 2022; although that year registered the lowest number of drug approvals since 2016, the TIDES class consolidated its presence with a total of five authorizations (four peptides and one oligonucleotide). Interestingly, 23 out of 37 drugs were first-in-class and thus received fast-track designation by the FDA in categories such as breakthrough therapy, priority review voucher, orphan drug, accelerated approval, and so on. Here, we analyze the TIDES approved in 2022 on the basis of their chemical structure, medical target, mode of action, administration route, and common adverse effects. Full article