Wainua (eplontersen) / Ionis, AstraZeneca - LARVOL DELTA

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

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

Gastric Transthyretin Amyloidosis: A Unique Case of Gastric Outlet Obstruction and Gastroparesis (ACG 2025) - "After the EGD, her symptoms initially improved, and on discharge, she continued Tafamidis and Eplontersen. Moreover, a gastric simulator is used as a last resort for patients with gastric ATTR complicated with gastroparesis who haven't responded to other treatments. Due to the rare co-occurring complications and underreported incidence, we aim to raise awareness and strongly advocate for the need for large, multi-center, prospective studies to capture the impact of gastric ATTR and its burden on the US healthcare system."

Clinical • Amyloidosis • Cardiac Amyloidosis • Cardiovascular • Gastrointestinal Disorder • Infectious Disease • Metabolic Disorders

Neuropathy impairment and nutritional status with eplontersen in patients with hereditary transthyretin-mediated amyloidosis. (PubMed, Amyloid) - No abstract available

Journal • Amyloidosis • Pain

Recent Highlights – Partnered Medicines (Businesswire) - "WAINUA (eplontersen) (WAINZUA in EU) for the treatment of adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis (ATTRv-PN) generated sales of $59 million and $143 million resulting in royalty revenue of $13 million and $33 million in the third quarter and the nine months ended September 30, 2025, respectively."

Sales • Amyloidosis

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

Data from the CARDIO-TTRansform study of eplontersen for transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) are expected in H2 (Ionis Pharmaceuticals Press Release)

P3 data • Amyloidosis • Cardiomyopathy

EPPRO: The Eplontersen Pregnancy and Lactation Outcomes Study (clinicaltrials.gov) - P=N/A | N=10 | Not yet recruiting | Sponsor: AstraZeneca

New trial • Amyloidosis • Cardiac Amyloidosis

Atrial structure and function in patients with amyloidosis: findings from the NEURO-TTRansform study. (ESC-WCC 2025) - " Patients enrolled in the NEURO-TTRansform study, an open label study with historical control, randomized to eplontersen vs inotersen, then cross over from inotersen to eplontersen of adult patients with Coutinho Stage 1 OR 2 disease, were studied... In a population of patients with amyloid polyneuropathy, abnormalities of LA strain were highly prevalent, even in patients without known cardiac involvement. This suggests LA strain can be used as a marker of early amyloid cardiac disease and should be looked for in patients with known genetic variants.Figure: A. Number of strain abnormalities by Cardiac Status. B."

Clinical • Atherosclerosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular • Heart Failure

A review of Eplontersen use in hereditary transthyretin amyloidosis. (PubMed, Neurodegener Dis Manag) - "Eplontersen is suitable for long term use in patients with disease related polyneuropathy and is currently being studied for use in patients with cardiomyopathy. In this review, we discuss the clinical efficacy, mechanism of action, pharmacology, tolerability, and social determinants of health affecting the use of Eplontersen."

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

Transthyretin Amyloid Cardiomyopathy-2025 Update: Current Diagnostic Approaches and Emerging Therapeutic Options. (PubMed, J Clin Med) - "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...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."

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

An Extension Study to Assess Long-Term Safety of Eplontersen in Adults With Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR-CM) (clinicaltrials.gov) - P3 | N=1400 | Enrolling by invitation | Sponsor: Ionis Pharmaceuticals, Inc. | Recruiting ➔ Enrolling by invitation | Trial primary completion date: Apr 2029 ➔ Aug 2029

Enrollment status • Trial primary completion date • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular

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

Ionis reports first quarter 2025 financial results (Businesswire) - "WAINUA (eplontersen) (WAINZUA in EU) for the treatment of adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis (ATTRv-PN) achieved commercial and regulatory milestones: Generated sales of $39 million resulting in royalty revenue of $9 million in the first quarter of 2025; Launch underway in numerous countries, including the EU following approval by the European Commission (EC); additional global submissions in progress to expand WAINUA access. SPINRAZA (nusinersen) for the treatment of spinal muscular atrophy (SMA) generated global sales of $424 million resulting in royalty revenue of $48 million in the first quarter of 2025: Higher dose nusinersen under review for marketing approval in U.S. (PDUFA date of September 22, 2025) and EU."

EMA approval • PDUFA • Sales • Amyloidosis • Muscular Atrophy

EPIC-ATTR: A Study to Evaluate the Effect of Eplontersen on the Transthyretin Reduction and Long-term Safety in Chinese Subjects With Transthyretin Amyloid Cardiomyopathy (clinicaltrials.gov) - P3 | N=64 | Active, not recruiting | Sponsor: AstraZeneca | Trial primary completion date: Mar 2025 ➔ Apr 2026

Trial primary completion date • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular

eplontersen (Wainzua) is accepted for use within NHSScotland (Scottish Medicines Consortium) - "Indication under review: for the treatment of hereditary transthyretin-mediated amyloidosis (ATTRv amyloidosis) in adult patients with Stage 1 and 2 polyneuropathy. Eplontersen offers an additional treatment choice of transthyretin (TTR) gene silencer for this indication. Another TTR gene silencer was accepted for use under the ultra-orphan process."

Reimbursement • Amyloidosis

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

Hope on the horizon: FDA approves eplontersen for hereditary transthyretin-mediated amyloidosis. (PubMed, Ann Med Surg (Lond)) - No abstract available

FDA event • Journal • Amyloidosis

WAINZUA (eplontersen) approved in the EU for the treatment of hereditary transthyretin-mediated amyloidosis in adults with stage 1 or stage 2 polyneuropathy (Businesswire) - "Ionis Pharmaceuticals, Inc...announced today that Ionis and AstraZeneca’s WAINZUA (eplontersen) has been approved in the European Union (EU) for the treatment of hereditary transthyretin-mediated amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy, commonly referred to as hATTR-PN or ATTRv-PN. WAINZUA is the only approved medicine in the EU for the treatment of ATTRv-PN that can be self-administered monthly via an auto-injector...The approval is based on the positive NEURO-TTRansform Phase 3 trial which showed that through 66 weeks, patients treated with WAINZUA demonstrated consistent and sustained benefit on the co-primary endpoints of serum transthyretin (TTR) concentration and neuropathy impairment measured by modified Neuropathy Impairment Score +7 (mNIS+7), and key secondary endpoint of quality of life (QoL) on the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) versus external placebo."

EMA approval • Amyloidosis • CNS 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

Ionis reports fourth quarter and full year 2024 financial results (Businesswire) - "'Over the next three years, we expect three more independent launches, including donidalorsen later this year for hereditary angioedema and olezarsen for severe hypertriglyceridemia in 2026, pending Phase 3 results in the second half of this year. Additionally, our partners are on track to launch four Ionis-discovered medicines over the same time period, including several that address broad patient populations'...WAINUA...Generated sales of $85 million resulting in royalty revenue of $20 million in the year ended December 31, 2024...SPINRAZA...generated global sales of $1.6 billion resulting in royalty revenue of $216 million in year ended December 31, 2024...Higher dose nusinersen under regulatory review in U.S. (PDUFA date of September 22, 2025) and EU. QALSODY (tofersen) for the treatment of SOD1-ALS generated global sales of $32 million resulting in royalty revenue of $4 million in the year ended December 31, 2024."

Launch • P3 data • PDUFA • Sales • Amyloidosis • Amyotrophic Lateral Sclerosis • Cardiovascular • Genetic Disorders • Hereditary Angioedema • Muscular Atrophy • Severe Hypertriglyceridemia