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

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

Antisense oligonucleotide as novel therapies for neurogenetic disorders (PubMed, Zhonghua Yi Xue Yi Chuan Xue Za Zhi) - "Some of these therapeutics, including eteplirsen, golodirsen, viltolarsen, nusinersen and inotersen, have been approved by the Food and Drug Administration (FDA) and begun to draw the public's attention as an effective therapeutic approach. This review has elaborated the mechanism of ASO therapies, including basic rationales, modifications, side effects and delivery routes. It also systemically summarized the FDA-approved ASO therapeutics and their applications for various neurological disorders, and discussed the limitations and challenges the real-world market may face and issues genetic counselor should take into consideration in the near future."

Journal • Review • CNS Disorders • Genetic Disorders

A retrospective observational analysis of the real-world care pathway of people with hereditary transthyretin amyloidosis with polyneuropathy in Italy. (PubMed, Expert Rev Pharmacoecon Outcomes Res) - "From the Fondazione ReS (Ricerca e Salute) administrative healthcare database (~5.5 million inhabitants in 2021), patients were identified as having ATTRv-PN in 2021 if they had received treatments for ATTRv-PN under SSN reimbursement (i.e. tafamidis, patisiran or inotersen) from 1 January 2014 to 12/31/2021 (index date in 2021). The per patient mean annual cost was € 122,017; drugs for ATTRv-PN accounted for 94.7% of the total expenditure. This study of real-world patients with ATTRv-PN showed a high rate of comorbidities, and substantial direct healthcare and economic burdens on the SSN."

Journal • Real-world evidence • Retrospective data • Amyloidosis • Cardiac Amyloidosis • Pain

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 • Hepatology • Lupus Nephritis • Nephrology • Pain • Renal Disease • Thrombocytopenia

Carcinogenicity Assessment of Inotersen in Tg.rasH2 Mice and Sprague-Dawley Rats: Implications for 2'-MOE Antisense Oligonucleotides. (PubMed, Regul Toxicol Pharmacol) - "There was no evidence of genotoxicity in vitro or in vivo at limit doses. Collectively, these data support a conclusion that a single carcinogenicity assessment in the Tg.rasH2 mouse, along with data from chronic toxicology studies in the rodent and nonrodent, is sufficient to assess carcinogenic potential for this drug class."

Journal • Preclinical • Amyloidosis • Fibrosarcoma • Kidney Cancer • Oncology • Renal Cell Carcinoma • Renal Disease • Sarcoma • Solid Tumor

Cost-Effectiveness of Inotersen in Combination With Standard Care vs Standard Care for the Treatment of Stage I or II Polyneuropathy in Adult Patients With Hereditary Transthyretin Amyloidosis in Colombia (ISPOR-EU 2024) - "Inotersen + BSC offers significant health gains, with more total life years, more time in stages 1 and 2, and less time in stage 3 and QALYs. The results are consistent with those obtained by health agencies such as NICE, ICER, and CADTH. The intervention did not prove to be cost-effective, a common phenomenon in treatments for rare diseases."

Clinical • Combination therapy • Cost effectiveness • HEOR • Amyloidosis • Cardiac Amyloidosis • Pain • Rare Diseases

ATTRv Neuropathy (ICNMD 2024) - "Transthyretin protein stabilisers diflunisal, tafamidis and acoramidis, can delay the progression of the disease, if treated early in the course. Additionally, TTR gene silencing medications, patisiran and inotersen, and second-generation silencers vutrisiran and eplontersen, have resulted in up to 80% reduction in TTR production leading to stabilisation or improvement of peripheral neuropathy and cardiac dysfunction, as well as improvement in quality of life and functional outcomes...Furthermore, current management strategies do not modify occular or CNS TTR production, and as such late occurrence of the disease in these compartments is becoming more prevalent. As such, novel treatment strategies or optimised CNS and ocular penetrance of existing treatments are required to treat these emerging manifestations."

Amyloidosis • Cardiac Amyloidosis • Musculoskeletal Pain • Pain

An Accurate and Fast 31P qNMR Assay Method for Oligonucleotide Therapeutics. (PubMed, Anal Chem) - "The 31P qNMR method showed 7 ± 2%, 8 ± 1%, and 12 ± 1% lower concentration values compared with drug product labels for eteplirsen, inotersen, and inclisiran, respectively. The underestimate of UV results for eteplirsen, which has a phosphorodiamidate morpholino oligomer (PMO) structure, suggests that the UV-260 nm extinction coefficient may need to be re-established for the PMO based oligonucleotide. Therefore, the 31P qNMR method could be a primary assay method for the oligonucleotide drug and reference standard."

Journal

Drug-Related Glomerular Phenotypes: A Global Pharmacovigilance Perspective. (PubMed, J Clin Med) - "Among the evaluated medications, Inotersen (IC025 of 8.3), Penicillamine (IC025 6.8), Bevacizumab (IC025 5.9) and Lenvatinib (IC025 5.4) were identified as having the strongest association with these glomerular disorders. Drug-induced glomerular disorders were significantly associated with medications that had no established nephrotoxic role but demonstrated a high disproportionality index in VigiBase. These newly alleged nephrotoxic drugs warrant further evaluation in dedicated studies to assess their true nephrotoxic potential."

Adverse events • Journal • Nephrology • Renal Disease

Switching from inotersen to eplontersen in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: analysis from NEURO-TTRansform. (PubMed, J Neurol) - "Switching from inotersen to eplontersen further reduced serum TTR, halted disease progression, stabilized QoL, restored platelet count, and improved tolerability, without deterioration in nutritional status. This supports a positive benefit-risk profile for patients with ATTRv-PN who switch from inotersen to eplontersen."

Journal • Amyloidosis • Pain

Drug-Associated Acute Kidney Disease: Data From a World Pharmacovigilance Database. (PubMed, Cureus) - "Among the most notable medications collected, 8.3% were classified as "non-nephrotoxic," 16.7% as "potentially nephrotoxic," and 75% as "known nephrotoxic." Notable active ingredients included cobicistat + elvitegravir + emtricitabine + tenofovir disoproxil (IC025 8.7; ROR 786.96), inotersen (IC025 7.7; ROR 604.57), emtricitabine + tenofovir disoproxil (IC025 7.9; ROR 432.36), esomeprazole (IC025 6.8; ROR 184.23), and pantoprazole (IC025 6.3; ROR 109.86), with proton pump inhibitors dominating the top four positions among the most frequently involved medications. We also highlight the potential nephrotoxic role of less suspected medications. This study emphasizes the need to consider AKD as a condition potentially associated with iatrogenic etiology, highlighting various medications and their respective involvement in the various possible manifestations of AKD."

Adverse events • Journal • Nephrology • Renal Disease

RNA Interference Therapeutics for Hereditary Amyloidosis: A Narrative Review of Clinical Trial Outcomes and Future Directions. (PubMed, Cureus) - "This study reviews patisiran, vutrisiran, inotersen, and eplontersen, developed for the treatment of ATTR. It provides an overview of the clinical trial outcomes, focusing mainly on quality of life, adverse reactions, and the future of RNAi-based therapies."

Journal • Review • Amyloidosis • Atrial Fibrillation • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Genetic Disorders • Heart Failure • Hepatology • Pain • Transplantation

A Clinical Study to Characterize Adverse Events Occurring Within One Day of TEGSEDI Administration to Adult Patients With hATTR-PN (clinicaltrials.gov) - P4 | N=8 | Completed | Sponsor: Akcea Therapeutics | Recruiting ➔ Completed | N=75 ➔ 8 | Trial completion date: Mar 2025 ➔ Mar 2024 | Trial primary completion date: Mar 2025 ➔ Mar 2024

Adverse events • Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Amyloidosis • Cardiac Amyloidosis • Pain

Novel treatments in hereditary neuropathies (EAN 2024) - "Phase 3 study was conducted to evaluate a combination of baclofen, naltrexone, and sorbitol in CMT1A...Safety and efficacy of tafamidis, TTR stabilizer, in early- stage polyneuropathy have been demonstrated. Inotersen is an antisense oligonucleotide that proved its efficacy in a phase 3 trial conducted on patients hATTR polyneuropathy. Eplontersen is an antisense oligonucleotide conjugated to N- acetylgalactosamine which improves its distribution...Vutrisiran is a subcutaneous siRNA that was more efficacious than patisiran in a phase 3 open- label study. Another siRNA, givosiran, that silences the expression of the gene ALAS1, has been approved for the treatment of acute hepatic porphyrias...Idebenone has been approved for treatment of Leber neuropathy. In conclusion, hereditary neuropathies have recently entered a therapeutic era."

Amyloidosis • Cardiac Amyloidosis • Fabry Disease • Genetic Disorders • Hematological Disorders • Hepatology • Metabolic Disorders • Pain • AKR1B1

Patisiran in ATTRv amyloidosis with polyneuropathy: “PatisiranItaly” multicenter observational study (EAN 2024) - "In 70% of patients, patisiran was the first treatment while in 30% it was switched from tafamidis or inotersen. Our data show that patisiran is effective and safe and that this drug stabilizes neurological symptoms, and QoL, of ATTRv amyloidosis patients."

Clinical • Observational data • Amyloidosis • Cardiac Amyloidosis • Diabetic Neuropathy • Pain

Mechanisms of Action of the US Food and Drug Administration-Approved Antisense Oligonucleotide Drugs. (PubMed, BioDrugs) - "RNase H-dependent ASOs include inotersen and eplontersen (for hereditary transthyretin amyloidosis), fomiversen (for opportunistic cytomegalovirus infection), mipomersen (for familial hypercholesterolemia), and tofersen [for amyotrophic lateral sclerosis (ALS)]. Splice modulating ASOs include nursinersen (for spinal muscular atrophy) and eteplirsen, golodirsen, viltolarsen, and casimersen (all for the treatment of Duchenne muscular dystrophy). In addition, a designer ASO, milasen, was used to treat a single individual afflicted with Batten disease. Since ASO design relies principally upon knowledge of mRNA sequence, the bench to bedside pipeline for ASOs is expedient compared with protein-directed drugs. [Graphical abstract available.]."

FDA event • Journal • Review • Amyloidosis • Amyotrophic Lateral Sclerosis • Cardiac Amyloidosis • CNS Disorders • Cytomegalovirus Infection • Duchenne Muscular Dystrophy • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Infectious Disease • Metabolic Disorders • Movement Disorders • Muscular Dystrophy • Rare Diseases

Early tolerance of SGLT2i therapy in patients with ATTR V30M amyloidosis: staging the disease to establish standard of care. (ERA-EDTA 2024) - " Eight patients were followed on median of 7 months [IQR 5.6 -9.4]; 7 treated with dapagliflozin, 1 with empagliflozin...4 were treated with tafamidis, 1 inotersen and 1 patisiran... In this pilot study, we evidenced that ATTR V30M patients meet the criteria for SGLT2i therapy. Dysautonomia and neurogenic bladder were not an impediment for therapy. In addition to disease modifying drugs, SGLT2i may improve kidney and cardiovascular outcomes in ATTR V30M amyloidosis."

Clinical • Amyloidosis • Atrial Fibrillation • Cardiomyopathy • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Diabetes • Diabetic Nephropathy • Fabry Disease • Genetic Disorders • Heart Failure • Hypotension • Infectious Disease • Nephrology • Renal Disease • Type 2 Diabetes Mellitus • CST3

A real-world pharmacovigilance analysis for transthyretin inhibitors: findings from the FDA adverse event reporting database. (PubMed, Front Pharmacol) - "The top three reported AEs for patisiran were fatigue, asthenia, and fall, with the most unexpectedly strong association being nonspecific reaction. The top three reported AEs for vutrisiran were fall, pain in extremity and malaise, with the most unexpectedly strong association being subdural haematoma. The top three reported AEs for inotersen were platelet count decreased, blood creatinine increased, and fatigue, with the most unexpectedly strong association being blood albumin decreased...The results indicate that not only do these three drugs share common AEs, but they also exhibit differences in drug safety profiles. This study contributes to enhancing the understanding of medical professionals regarding the safety of TTR inhibitors."

Adverse events • Journal • Real-world • Real-world evidence • Fatigue • Musculoskeletal Pain • Pain • Pulmonary Disease