Tegsedi (inotersen) / Ionis, PTC Therapeutics, SOBI - LARVOL DELTA

Precision medicine with pioneering RNAi therapeutics in ATTR amyloidosis: from bench to bedside. (PubMed, Eur J Intern Med) - "Major clinical trials evaluating first- and second-generation RNA-targeted agents-including patisiran, vutrisiran, inotersen, and eplontersen-are summarized, highlighting efficacy, safety profiles, dosing regimens, and relevance across different ATTR phenotypes. As RNA-based therapies continue to evolve, integration of molecular insights with clinical phenotyping and real-world evidence will be essential to fully realize the potential of precision medicine for patients with ATTR amyloidosis."

Journal • Review • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular • CNS Disorders • Developmental Disorders • Pain

Predictors of poor prognosis in a large cohort of patients with hereditary cardiac transthyretin amyloidosis. (PubMed, Rev Esp Cardiol (Engl Ed)) - "This national cohort-the largest reported to date-highlights the clinical and genetic heterogeneity of hATTR -CA in Spain. Early diagnosis and disease-specific therapies are essential to improving prognosis."

Clinical • Journal • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • Pain • Transplantation

Small RNA or oligonucleotide drugs and challenges in evaluating drug-drug interactions. (PubMed, Front Pharmacol) - "Widespread adoption of these strategies has further enabled the application of oligonucleotides as viable drugs and expanded the class of RNA therapeutics, with thirteen antisense oligonucleotides (ASOs) (fomiversen, mipomersen, nusinersen, inotersen, eteplirsen, golodirsen, casimersen, viltolarsen, tofersen, eplontersen, olezarsen, and donidalorsen), seven small interfering RNAs (siRNAs) (patisiran, givosiran, lumasiran, inclisiran, vutrisiran, nedosiran, and fitusiran), and two aptamers (pegaptanib and avacincaptad pegol) that have been approved by the United States Food and Drug Administration (FDA). This article provides an overview of FDA-approved oligonucleotide therapies, emphasizing chemical modifications, molecular targets for mechanistic actions, and available ADME and PK/PD properties, followed by the discussion of critical needs for risk assessment strategies suited for this unique modality that focuses on possible DDIs with concomitant drugs. The latter may..."

Journal • Review

Anti-PF4 antibodies are a potential mediator of antisense oligonucleotide (ASO)-induced thrombocytopenia. (ASH 2025) - "Twelve ASOs, Inotersen, Eplontersen,Olezarsen, Fomivirsen, Mipomersen, Tofersen, Nusinersen, Eteplirsen, Golodirsen, Viltolarsen,Casimersen (all FDA approved) and Volanesorsen (EMA approved) were evaluated in this study. With two ASOs, Fomivirsen and Eteplirsen, direct activation of platelets was noted. Studieswith additional ASOs revealed a novel immune mechanism involving ASO-PF4 complex formation andanti-PF4 antibody recognition that can plausibly mediate ASO-induced thrombocytopenia. These findingshighlight the key role PS linkages may play in ASO immunogenicity and provide a mechanistic frameworkfor risk mitigation in ASO drug design, supporting the safer development and broader application of ASOtherapeutics."

Hematological Disorders • Thrombocytopenia

Long-term follow-up with magnetic resonance neurography in a patient with hereditary transthyretin amyloidosis treated with inotersen. (PubMed, J Neurol Sci) - No abstract available

Journal • Amyloidosis • Cardiac Amyloidosis

RNA Interference Therapeutics for Hereditary Transthyretin-Mediated Amyloidosis with Neuropathy: A Systematic Review (ASH 2024) - "Currently, limited treatment options are available for ATTRv, which include orthotopic liver transplantation and transthyretin tetramer stabilizers (tafamidis or diflunisal)...The most common cause of death reported was cardiac failure.Conclusion : RNA interference therapies, including Eplontersen, Inotersen, Vutrisiran, and Patisiran, have demonstrated significant benefits in enhancing the quality of life for patients with ATTRv and associated polyneuropathy...While RNAi therapies offer substantial symptomatic relief, vigilant surveillance for side effects is crucial to optimize patient outcomes and ensure safety. Further studies, including comparative studies, are essential to establish therapeutic protocols and ensure improved quality of life for patients with ATTRv."

Review • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular • CNS Disorders • Congestive Heart Failure • Diabetic Neuropathy • Glomerulonephritis • Heart Failure • Hematological Disorders • Lupus Nephritis • Nephrology • Pain • Renal Disease • Thrombocytopenia

Neurological efficacy and safety of RNA therapeutics in hereditary transthyretin amyloidosis: a systematic review and meta-analysis of randomized controlled trials. (PubMed, Ther Adv Cardiovasc Dis) - "RNA therapeutics are effective and well-tolerated in patients with hATTR, significantly improving quality of life and the progression of neurological impairment. siRNAs demonstrate better outcomes compared to ASOs."

Journal • Retrospective data • Review • Amyloidosis • Cardiac Amyloidosis • Diabetic Neuropathy • Gastrointestinal Disorder • Pain

Association of TTR-Targeted Therapies with Cardiovascular Outcomes in Transthyretin Amyloid Cardiomyopathy: A Real-World Analysis (AHA 2025) - "Adults with a diagnosis of ATTR-CM were categorized into three groups based on prescription records: TTR stabilizers (e.g., tafamidis, acoramidis), TTR gene silencers (e.g., vutrisiran, eplontersen, patisiran, inotersen), or standard medical therapy. In this large, real-world analysis of patients with ATTR-CM, use of TTR stabilizers was associated with a lower incidence of major cardiovascular events compared with standard care. TTR gene silencers showed a similar directional association, though limited by a smaller sample size. These findings support further investigation in prospective studies to better understand the relationship between TTR-targeted therapies and clinical outcomes."

Clinical • Real-world • Real-world evidence • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular • Ventricular Tachycardia

Gastrointestinal Amyloidosis: Unmasking the Hidden Culprit of Chronic Epigastric Pain and Weight Loss (ACG 2025) - "Recent trials support daratumumab for AL and patisiran/inotersen for ATTR amyloidosis. Early, accurate diagnosis is key to initiating appropriate therapy and improving outcomes, with multidisciplinary involvement crucial for optimal care."

Amyloidosis • Cardiovascular • Constipation • Gastroenterology • Gastroesophageal Reflux Disease • Gastrointestinal Disorder • Heart Failure • Hematological Malignancies • Hepatitis B • Hepatology • Infectious Disease • Lymphoma • Monoclonal Gammopathy • Pain • Renal Disease

Cardiac Amyloidosis: Tribulations and New Frontiers. (PubMed, J Pers Med) - "Critically, it is imperative that physicians develop close relationships with the patient that addresses not only their individual health needs but also their unique psychosocial situation. Therefore, more clinical trials, protocols and patient resources are needed to better inform and guide providers managing these complex patient needs."

Journal • Review • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • Transplantation

Disease-Modifying Therapies for Transthyretin Amyloid Cardiomyopathy: A Systematic Review and Meta-Analysis. (PubMed, Arq Bras Cardiol) - "TTR stabilizers significantly reduced all-cause mortality and hospitalizations in patients with ATTR-CM compared with placebo. These benefits were not observed with TTR silencers, potentially due to shorter follow-up durations in the studies evaluated. Both therapies improved functional status and serum levels of NT-proBNP."

Biomarker • Clinical • Journal • Retrospective data • Review • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular

Comparative Study on Cardiac Findings in Patients with Transthyretin Amyloidosis Before and After Treatment with a Transthyretin Silencer. (PubMed, J Cardiovasc Dev Dis) - "Although this may be an incurable disease, there are various treatments that are currently available for patients with ATTR, including transthyretin (TTR) silencers such as inotersen and patisiran. By undergoing these scans, the effectiveness of this treatment could be determined by observing any improvements in the signs of CM. A decrease in the H/CL ratio and/or the PYP grade would indicate that the TTR silencer has been effective in alleviating the signs and symptoms of CM, and that the patients should continue with their treatment plan."

Journal • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular • Pain • Rare Diseases

Real-world treatment management in hereditary transthyretin amyloidosis - an experience report and proposal for therapy switch decision criteria. (PubMed, Neurol Res Pract) - "In this study, reasons for treatment switches were manifold, encompassing disease progression, the occurrence of adverse events, patient preferences and/or the availability of newly approved drugs. Hence, multidimensional consideration of these reasons remains pivotal in guiding the subsequent choice of medication in particular and managing hereditary transthyretin amyloidosis in general."

HEOR • Journal • Real-world evidence • Amyloidosis • Cardiac Amyloidosis

Impact of disease-modifying drugs in patients with transthyretin amyloidosis after liver transplantation: a systematic review. (PubMed, Transplant Rev (Orlando)) - "Disease-modifying therapies may offer clinical benefits in post-OLT ATTRv patients. However, robust prospective studies and randomized trials are needed to confirm efficacy and ensure safety in this population."

Journal • Review • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular • CNS Disorders • Congestive Heart Failure • Heart Failure • Pain • Transplantation

Transthyretin-related amyloid cardiomyopathy: A single-center experience in southern Poland, an endemic area. (PubMed, Kardiol Pol) - P=N/A | "A comprehensive diagnostic approach is crucial for timely initiation of disease-modifying therapies. Our study suggests that, in this region, there is a high rate of the Phe53Leu TTR variant; however, further research is needed to validate these findings (NCT05814380)."

Journal • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular • Pain

Pharmacological Management of Transthyretin Amyloid Cardiomyopathy: Where We Are and Where We Are Going. (PubMed, J Clin Med) - "TTR stabilizers, such as tafamidis and acoramidis, can reduce TTR instability and subsequent amyloid fibril formation...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...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..."

Journal • Review • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure

Current and emerging treatment options for transthyretin amyloid cardiomyopathy. (PubMed, Heart) - "Treatments available in clinical practice include TTR stabilisers (tafamidis and acoramidis), which prevent the dissociation of TTR tetramer into monomers and oligomers that subsequently form amyloid fibrils, and gene-silencing therapies (patisiran, inotersen and vutrisiran), which suppress the hepatic synthesis of TTR, which is the amyloid precursor protein. Novel treatment strategies that are at various stages of development include Clustered Regularly Interspaced Short Palindromic Repeats-Cas9 gene-editing technology (nexiguran ziclumeran), which, if successful, offers the prospect of a single-dose treatment, and monoclonal (cormitug and ALXN220) and pan-amyloid antibodies (AT-02) that seek to target and remove amyloid fibrils that have deposited in the myocardium...The success of ATTR-specific disease-modifying therapies has already altered the treatment landscape and changed the perception of ATTR amyloidosis from a progressive and fatal disease to one that is..."

Journal • Review • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • APP

A Study to Characterize Adverse Events Occurring Within One Day of TEGSEDI Administration to Adult Participants With hATTR-PN (clinicaltrials.gov) - P4 | N=8 | Terminated | Sponsor: Akcea Therapeutics | Completed ➔ Terminated; Withdrawal of TEGSEDI from sale was not related to any safety issues.

Adverse events • Trial termination • Amyloidosis • Cardiac Amyloidosis • Pain

IMPROVEMENT IN MEASURES OF QUALITY OF LIFE AMONG PATIENTS RECEIVING TARGETTED THERAPY FOR ATTR AMYLOIDOSIS: A META-ANALYSIS OF DATA FROM RANDOMIZED CONTROLLED TRIALS - Shubhashis Saha (ACC 2025) - "Background: Novel drugs like patisiran, vutrisiran, tafamidis, acoramidis, eplontersen, and inotersen reduce the synthesis and deposition of TTR amyloid fibrils in patients with cardiac amyloidosis. Contemporary drugs for cardiac amyloidosis improved quality of life and 6MWT, while having a good safety profile. Although they are usually classified as secondary outcomes in many clinical trials, these improvements would be more relevant to the patients in short to medium term."

HEOR • Retrospective data • Amyloidosis • Cardiac Amyloidosis • Cardiovascular

LACK OF IMPROVEMENT IN CARDIAC FUNCTION AMONG PATIENTS RECEIVING TARGETTED THERAPY FOR ATTR AMYLOIDOSIS: A META-ANALYSIS OF DATA FROM RANDOMIZED CONTROLLED TRIALS - Revati Varma (ACC 2025) - "Background: Novel drugs like patisiran, vutrisiran, tafamidis, acoramidis, eplontersen, and inotersen reduce the synthesis and deposition of TTR amyloid fibrils in patients with cardiac amyloidosis (CA). Contemporary drugs for CA did not result in changes in the cardiac structure on echocardiographic parameters while having a good safety profile."

Retrospective data • Amyloidosis • Cardiac Amyloidosis • Cardiovascular

GEOGRAPHIC DISPARITIES IN CARDIAC AMYLOIDOSIS PRESCRIBING PATTERNS: INSIGHTS FROM EPIC COSMOS - Mirza S. Khan (ACC 2025) - "Medications included novel amyloid therapies tafamidis, vutrisiran, patisiran, eplontersen, inotersen and diflunisal. The highest prescription rates for cardiac amyloidosis therapies were in the Northeast U.S., known to have a high density of dedicated amyloidosis centers. Our findings underscore the need for efforts to improve recognition and diagnosis of cardiac amyloidosis and improve treatment access in underserved regions."

Amyloidosis • Cardiac Amyloidosis • Cardiovascular • Congestive Heart Failure • Heart Failure

Impact on efficacy of target reduction of two FDA-approved ASO drugs by intracellular glucose levels in in vitro cell models. (PubMed, Mol Ther Nucleic Acids) - "Reducing intracellular glucose levels in HepG2 cells, either by knocking down the glucose transporter GLUT2 or by treating with the antidiabetic drug metformin, reversed the decreased silencing efficacy of inotersen and mipomersen. This study brings to light the first indication about the significant impact of intracellular glucose levels on the silencing efficacy of the FDA-approved ASO drugs in an in vitro model."

FDA event • Journal • Preclinical • Diabetes • Metabolic Disorders

RNAi-based Therapies for Hereditary Transthyretin Amyloidosis with Polyneuropathy: A Meta-analysis of Randomized Clinical Trials (AAN 2025) - "Subgroup analysis is performed based on individual RNAi drugs.We included 5 trials involving 595 patients received Patisiran, Eplontersen, Inotersen, or Vutisiran. Our results suggest that RNAi-based therapies are promising for hATTR with polyneuropathy treatment, showing improvements in neurological function, quality of life, and an acceptable safety profile. However, evidence is limited, with heterogeneity in long-term safety and effectiveness across studies. Further randomized trials are needed to clarify the role of RNAi therapeutics and optimize patient outcomes."

Retrospective data • Amyloidosis • Cardiac Amyloidosis • Genetic Disorders • Pain

Efficacy of Pharmacological Interventions for Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP): A Systematic Review and Network Meta-Analysis (AAN 2025) - "Patisiran and Inotersen demonstrated superior efficacy with significant results, while Vutrisiran and Diflunisal also showed notable outcomes. In contrast, Tafamidis did not yield significant results. Further research is needed to confirm these findings."

Retrospective data • Review • Amyloidosis • CNS Disorders • Diabetic Neuropathy • Pain

Patisiran in ATTRv amyloidosis with polyneuropathy: "PatisiranItaly" multicenter observational study. (PubMed, J Neurol) - "Patisiran can be considered a valid therapeutic option for the management of patients with ATTRv amyloidosis. Considering its mechanism of action, similar outcomes could also be expected with the wider utilization of newly approved gene silencers for ATTRv therapy, such as vutrisiran."

Journal • Observational data • Amyloidosis • Cardiac Amyloidosis • CNS Disorders • Diabetic Neuropathy • Pain