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

Case Report: Inotersen reintroduction after thrombocytopenia in hereditary transthyretin amyloidosis: a case series. (PubMed, Front Pharmacol) - "In this small case series, inotersen reintroduction after thrombocytopenia was feasible in two ATTRv patients when implemented with a structured stepwise protocol and close platelet monitoring, but these findings are hypothesis-generating and not generalizable. One reintroduction occurred outside prescribing recommendations for severe thrombocytopenia and should not be interpreted as a recommended strategy."

Journal • Amyloidosis • Cardiac Amyloidosis • Hematological Disorders • Pain • Thrombocytopenia

ESCRT-I complex enhances therapeutic efficacy of ASO drugs by regulating endosomal escape and glucose homeostasis. (PubMed, Mol Ther Nucleic Acids) - "Using human hepatocyte-derived cell models and FDA-approved ASO drugs inotersen and mipomersen, we demonstrate that suppression of specific ESCRT-I subunits, VPS23 and VPS28, markedly enhances ASO-mediated target silencing, whereas depletion of other subunits has minimal effect. Notably, this regulatory effect extends beyond ASOs to small interfering RNA (siRNA) therapeutics, indicating a broader role for ESCRT-I in RNA drug biology. Together, these findings uncover a metabolic-endosomal axis controlling nucleic acid drug efficacy and provide new mechanistic insight into intracellular determinants of RNA-based therapeutics."

Journal • TSG101

Real-world effectiveness and clinical predictors of response to first-generation TTR silencers in variant ATTR amyloidosis with polyneuropathy. (PubMed, Sci Rep) - "Total responders had higher baseline CMAP amplitudes (p = 0.045), while baseline neurophysiological measures showed modest discriminatory capacity overall, with electrochemical skin conductance providing the strongest signal...Compared with inotersen, patisiran showed a higher total response rate (59.3% vs. 23.5%), slower NIS progression (median + 0.31 vs. +4.00 points/year; p = 0.011), and greater treatment persistence (log-rank p = 0.0005)...Baseline neurological preservation, particularly motor and small-fiber measures, may help identify patients more likely to benefit from treatment. However, these findings should be interpreted with caution due to the limited sample-size and the observational nature of the study."

Journal • Real-world evidence • Amyloidosis • Cardiac Amyloidosis • CNS Disorders • Pain

Disease-Modifying Therapies for Hereditary Transthyretin Amyloidosis with Polyneuropathy: Current Status and Future Perspectives. (PubMed, Neurol Ther) - "These therapies include TTR stabilizers, such as tafamidis, diflunisal, and acoramidis, as well as RNA-silencing agents, such as patisiran, vutrisiran, inotersen, and eplontersen, which reduce hepatic production of TTR and slow disease progression...Emerging gene-editing approaches, including CRISPR-based therapies like NTLA-2001, may provide a one-time treatment and long-term disease control, representing a promising future direction for managing ATTRv-PN...These include high treatment costs, limited global accessibility, uncertainty regarding optimal treatment selection and sequencing, and the need for long-term real-world, patient-centered outcome data. This review summarizes current disease-modifying therapies for ATTRv-PN, compares their mechanisms and clinical evidence, and discusses unmet needs and future research directions, with the aim of providing a practical and comprehensive overview for clinicians treating patients with ATTRv-PN."

Journal • Review • Amyloidosis • Cardiac Amyloidosis • Developmental Disorders • Gene Therapies • Pain • Transplantation

Pharmacological Interventions for Hereditary Transthyretin-Related Amyloidosis With Polyneuropathy: Systematic Review and Network Meta-Analysis. (PubMed, Eur J Neurol) - "Gene-silencing therapies were more efficacious, although these findings should be regarded as hypothesis-generating given the scarcity of data, lack of head-to-head trials, and clinical heterogeneity across trials."

Journal • Retrospective data • Review • Amyloidosis • CNS Disorders • Pain

First-Generation TTR Silencing Therapies in Hereditary Transthyretin Amyloidosis With Polyneuropathy: Real-World Insights From a German Single-Referral Center. (PubMed, Eur J Neurol) - "Our findings confirm long-term treatment with TTR silencers in a real-world setting is safe, consistently reducing serum TTR levels, stabilizing neurologic symptoms, cardiac and renal functions, and nutritional parameters."

Journal • Real-world evidence • Amyloidosis • Cardiac Amyloidosis • CNS Disorders • Hematological Disorders • Pain • Thrombocytopenia

Unraveling the Stereochemical Complexity of Phosphorothioate-Modified Oligonucleotides Using Analytical Technologies. (PubMed, Nucleic Acid Ther) - "Here, we used a suite of analytical techniques-ultraviolet (UV) thermal denaturation, circular dichroism (CD), and nuclear magnetic resonance (NMR) spectroscopy-to evaluate the PS diastereomer distribution using Tegsedi, a Food and Drug Administration-approved PS-containing antisense oligonucleotide, and with other synthetic inotersen samples having varied PS diastereomer distributions...The univariate metric of 31P integration was shown to be insufficient for this quality metric evaluation; application of principal component analysis to both 1D 31P and 2D 1H,13C spectra revealed distinct PS changes that arose from the different activators used during manufacturing. This comprehensive evaluation highlights the necessity of advanced analytical techniques in ensuring the quality and consistency of PS-containing oligonucleotide therapeutics."

Journal

Case Report: A rare presentation of gastrointestinal amyloidosis: unmasking the hidden culprit of chronic epigastric pain and weight loss. (PubMed, Front Gastroenterol (Lausanne)) - "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."

Journal • Amyloidosis • Cardiovascular • CNS Disorders • Constipation • Gastroenterology • Gastroesophageal Reflux Disease • Gastrointestinal Disorder • Heart Failure • Hematological Malignancies • Hepatitis B • Infectious Disease • Inflammation • Lymphoma • Monoclonal Gammopathy • Oncology • Pain • Renal Disease

Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy: An Exploratory Analysis of Treatment Effect in Male and Female Patients. (PubMed, Muscle Nerve) - P2/3, P3 | "Eplontersen halted neuropathy impairment and improved quality of life versus placebo to a similar degree in both male and female patients with ATTRv-PN, including those with cardiomyopathy. These findings support the use of eplontersen as an effective treatment for ATTRv-PN regardless of sex."

Journal • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular • Diabetic Neuropathy • Pain

Oligonucleotides: Evolution of Carcinogenicity and Risk Assessment Strategy. (PubMed, Toxicol Pathol) - "Nevertheless, for eplontersen and olezarsen, carcinogenicity assessment was limited to a single Tg.rasH2 mouse study or fully waived, supported by prior two-species carcinogenicity data from inotersen and volanesorsen. With the recent ICH S1B(R1) addendum, sponsors now have a defined pathway to pursue carcinogenicity strategies, including potential waivers of the 2-year rat study when supported by the totality of evidence. This article reviews the evolving landscape of ASO carcinogenicity testing and highlights opportunities to reduce or waive long-term studies."

Journal • Review • Oncology

TAFAMIDIS IN TRANSTHYRETIN AMYLOID CARDIOMYOPATHY: MORTALITY AND CARDIOVASCULAR OUTCOMES IN A LARGE REAL-WORLD NETWORK (ACC 2026) - "Adults with ATTR-CM (2002-2025) were identified; Cohort A received Tafamidis only, Cohort B never received Tafamidis, Inotersen, Patisiran, or Vutrisiran. In this large, propensity-matched real-world cohort, Tafamidis use correlated with lower mortality, major cardiovascular events, and resource utilization. These findings reinforce its efficacy in routine practice, though retrospective design and residual confounding warrant confirmation in prospective studies."

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

Detecting Polyneuropathy in Patients with Hereditary Transthyretin Amyloid Cardiomyopathy. (PubMed, CJC Open) - "Based on the systematic neurologic assessment, 36 patients in our study were identified as having a mixed hATTR phenotype, and they are to receive specific disease-modifying therapies, either patisiran or inotersen. Patients with hATTR-CM should be systematically referred to a specialized neurologist for routine assessment, especially patients who report neurologic symptoms (ie, numbness and burning sensation in extremities)."

Journal • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular

ION-682884 in Patients With TTR Amyloid Cardiomyopathy (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: Brigham and Women's Hospital | N=17 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular • Congestive Heart Failure

24 Month Open Label Study of the Tolerability and Efficacy of Inotersen in TTR Amyloid Cardiomyopathy Patients (clinicaltrials.gov) - P2 | N=31 | Terminated | Sponsor: Brigham and Women's Hospital | N=50 ➔ 31 | Active, not recruiting ➔ Terminated; recruitment of new patients not possible during Covid 19 epidemic

Enrollment change • Trial termination • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular • Congestive Heart Failure

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