ALBERT

Description: Background: Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is a life-threatening, irreversible condition, which can lead to heart failure (HF) and, ultimately, heart transplant or death. Despite the recent approval in United States of a TTR stabilizer (VYNDAQEL®-tafamidis meglumine;VYNDAMAX™-tafamidis) for the treatment of ATTR-CM, disease progression still occurs. This study aims to determine if treatment with AKCEA-TTR-LRx (ION-682884), an antisense oligonucleotide (ASO), is safe and superior to placebo in reducing the risk of cardiovascular (CV) death or CV clinical events in patients with hereditary (hATTR-CM) or wild-type ATTR-CM (wtATTR-CM). Study Design and Methods: AKCEA-TTR-LRx (ION-682884) is a follow-on compound that incorporates the Ligand-Conjugated Antisense (LICA) technology; in this case, a triantennary N-acetyl galactosamine (GalNAc) moiety which targets the asialoglycoprotein receptors (ASGPR) expressed abundantly on the hepatocyte cell surface. In comparison to inotersen, its parent compound, ION-682884 requires a lower dose and frequency of administration (27-fold smaller; 45mg SC Q4W) to achieve a similar reduction in ATTR, providing greater patient convenience. ION-682884-CS2 (EudraCT No: 2019-002835-27) is a Phase 3 global, double-blind, randomized, placebo-controlled study assessing the efficacy and safety of AKCEA-TTR-LRx (ION-682884) in hATTR-CM or wtATTR-CM patients receiving available background standard of care (SoC) therapy. Approximately 750 patients with a history of HF due to ATTR-CM will be randomized 1:1 to receive AKCEA-TTR-LRx (ION-682884) or placebo administered by subcutaneous injection once every 4 weeks. The main inclusion criteria include confirmed diagnosis of ATTR-CM by tissue biopsy or positive PYP/DPD scan, end-diastolic interventricular septum thickness of 〉12mm, NT-proBNP 〉600 pg/mL, NYHA class I-III and 6-minute walk distance (6MWD) 〉150 m. The main exclusion criteria include estimated glomerular filtration rate (eGFR) 〈 30 mL/min/1.73m2, platelet count below the low limit of normality and urine protein/creatinine ratio (UPCR) ≥ 1000 mg/g. Patients are allowed to concomitantly receive tafamidis/tafamidis meglumine as SoC for ATTR-CM, if locally approved and available, per physician's discretion. The study consists of a 120-week Treatment Period and a 20-week Post-Treatment Evaluation Period. During each study visit, subjects will undergo laboratory tests, cardiac assessments (echocardiography), and functional evaluations. Patient-reported outcomes (PRO) will also be collected. Primary efficacy endpoint is the composite of CV mortality and frequency of CV clinical events (HF-related urgent visits requiring administration of IV diuretics and/or CV-related hospitalizations) at Week 120 study visit, analyzed by the Finkelstein-Shoenfeld method. This test is based on the principle of each patient in the study being compared with every other patient in a pairwise manner in hierarchical fashion. Secondary endpoints include the change from baseline in the 6MWD, Kansas City Cardiomyopathy Questionnaire score, rate of CV mortality, CV clinical events, and all-cause of mortality at Week 120. Additional exploratory endpoints include a change from baseline in cardiac imaging parameters, renal function, biomarkers, and PROs questionnaires and disease scores. An interim analysis on change from baseline in 6MWD is also planned at Week 60. All deaths and CV clinical events will be adjudicated by an independent, blinded Clinical Adjudication Committee, using predefined endpoint criteria. Conclusions: Despite recent advances, there is still a need for more efficacious, safe and convenient treatment options for ATTR-CM. The ION-682884-CS2 is a large Phase 3 trial designed to evaluate the clinical efficacy and safety of AKCEA-TTR-LRx (ION-682884) compared to placebo for the treatment of ATTR-CM. Figure Disclosures Falk: Ionis Pharmaceuticals: Consultancy. Gertz:Ionis/Akcea: Consultancy; Alnylam: Consultancy; Proclara: Membership on an entity's Board of Directors or advisory committees; Prothena Biosciences Inc: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Annexon: Consultancy; Appellis: Consultancy; Amgen: Consultancy; Medscape: Consultancy, Speakers Bureau; Physicians Education Resource: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Research to Practice: Consultancy; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; i3Health: Other: Development of educational programs and materials; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding. Benson:Ionis Pharmaceuticals: Research Funding. Buchele:Ionis Pharmaceuticals: Employment. Brambatti:Ionis Pharmaceuticals: Employment. Tsimikas:Ionis Pharmaceuticals: Employment. Viney:Ionis Pharmaceuticals: Employment. Tai:Ionis Pharmaceuticals: Employment. Monteiro:Ionis Pharmaceuticals: Employment. Yang:Ionis Pharmaceuticals: Employment. O'Dea:Akcea Therapeutics: Employment. Karwatowska-Prokopczuk:Akcea Therapeutics: Employment. Schneider:Ionis Pharmaceuticals: Employment. Geary:Ionis Pharmaceuticals: Employment. Monia:Ionis Pharmaceuticals: Employment.

Description: Variants of fibrinogen A α-chain (AFib) cause the most common type of hereditary renal amyloidosis in Europe and, possibly, the United States as well. Variant fibrinogen is produced in the liver, and solitary renal allografts fail within 1 to 7 years with recurrent amyloidosis. We assessed 22 AFib patients for combined liver and kidney transplantation (LKT) and report the clinical features and outcome. Twenty-one had E526V and 1, the R554L variant. Coronary atherosclerosis was identified in 68% and systemic atheromatosis in 55%. Vascular atheroma excised at endarterectomy and endomyocardial biopsies contained purely variant fibrinogen amyloid. Half had autonomic neuropathy. Six of 9 patients who underwent LKT are alive (67%), with good allograft function and no amyloidosis at median 67 months (range, 33-155 months) of follow-up. Serial technetium-99m–labeled dimercaptosuccinic acid (99mTc-DMSA) renal scintigraphy in 2 cases of preemptive LKT demonstrated preserved native kidney residual function at 5 years. Four explanted livers were used successfully for domino transplantation. Fibrinogen amyloidosis is a systemic amyloid disease with visceral, vascular, cardiac, and neurologic involvement. LKT is curative; however, cardiovascular amyloidosis may preclude this option. Our data encourage evaluation of preemptive solitary liver transplantation early in the course of amyloid nephropathy to prevent hemodialysis and kidney transplantation.

Description: Background: Hereditary transthyretin amyloidosis (hATTR) is a rare, progressive, and fatal disease caused by the buildup of transthyretin-derived amyloid protein in major organs, predominantly affecting the peripheral nerves and heart. Inotersen, a second-generation antisense oligonucleotide targeting TTR mRNA, has shown efficacy and safety in patients with hATTR in a randomized, double-blind, placebo-controlled, phase 3 study, NEURO-TTR (ClinicalTrials.gov, NCT01737398; Benson NEJM 2018). Patients with hATTR amyloidosis who completed the NEURO-TTR study were eligible to receive inotersen for up to 5 years in a phase 3 open-label extension study (ClinicalTrials.gov, NCT02175004). Methods: In NEURO-TTR, patients were randomized 2:1 to receive inotersen (300-mg weekly subcutaneous doses) or placebo. In the open-label extension, patients continued inotersen (inotersen-inotersen) or switched from placebo to inotersen (placebo-inotersen). Evaluations included modified Neuropathy Impairment Score +7 neurophysiologic tests composite score (mNIS+7; higher scores indicate worse neuropathy), Norfolk Quality of Life-Diabetic Neuropathy questionnaire total score (Norfolk QoL-DN; higher scores indicate worse QoL), and adverse events (AEs). Cardiomyopathy (CM) was defined by a diagnosis of hATTR-CM at trial entry or by an interventricular wall thickness of 13 mm or more on transthoracic echocardiography at baseline, as ascertained by a central reader, or no known history of persistent hypertension (systolic blood pressure, ≥150 mm Hg) within 12 months before screening. Results : In the placebo-controlled, double-blind, phase 3 NEURO-TTR study, 112/172 patients were randomized and received inotersen. At baseline, patients were predominantly white (91.9%) males (68.6%) with a mean age of 59.2 years. A total of 67.4% had stage I (ambulatory) and 32.6% had stage II (ambulatory with assistance) disease. Inotersen-treated patients who had stage II disease had a longer duration of disease from diagnosis (40.9 vs 24.8 months, respectively) and from onset (72.6 vs 63.2 months, respectively) of hATTR polyneuropathy symptoms compared with placebo-treated patients who had stage II disease, indicating more advanced disease. A higher proportion of inotersen-treated patients had CM at baseline (67% vs 55%, respectively), and more severe CM, measured by higher NT-proBNP levels and longer duration of disease from hATTR-CM symptom onset, compared with placebo-treated patients. In the phase 3 open-label extension study as of Sept 15, 2017, 134 of 135 patients enrolled received ≥1 dose of inotersen. The mean age was 60.4 years and most patients were male (69.4%). Extended dosing with inotersen up to 27 months continued to improve mNIS+7 and Norfolk QoL-DN in the open-label extension compared to placebo-treated patients at week 66 in the double-blind NEURO-TTR study; mean changes from open-label extension baseline to open-label extension week 52 in the inotersen-inotersen group were 5.1 points for mNIS+7 (vs 25.5 for placebo-treated patients in the double-blind NEURO-TTR study) and 3.9 points for Norfolk QoL-DN (vs 10.7 for placebo-treated patients in the double-blind NEURO-TTR study). Initiation of inotersen in placebo-treated patients (placebo-inotersen) resulted in improvement in mNIS+7 and Norfolk QoL-DN by week 26. Few patients discontinued treatment because of AEs (inotersen-inotersen, 9%; placebo-inotersen, 4%). The rate of treatment-related serious AEs was low in both treatment groups (2% each). There was no evidence of increased risk for grade 4 thrombocytopenia or severe renal events with increased duration of exposure. We will present 2-year follow-up results from the open-label extension study. Conclusions: Results of the open-label extension show continued benefit, measured by mNIS+7 and Norfolk QoL-DN, and confirmed that earlier initiation of treatment is important for optimal clinical outcomes. No new safety concerns were identified. Results from the longer-term follow-up for the open-label extension will further elucidate how inotersen may benefit patients with hATTR amyloidosis. Disclosures Brannagan: Alnylam: Honoraria, Other: Investigator, Speakers Bureau; Ionis: Other: Investigator. Wang:Ionis: Other: Investigator, Speakers Bureau. Coelho:Prothena: Consultancy, Honoraria; Ionis: Consultancy, Other: Investigator; Alnylam: Consultancy, Honoraria, Other: Investigator; Pfizer: Consultancy, Honoraria, Other: Investigator. Waddington Cruz:Ionis: Honoraria; Genzyme/Sanofi: Honoraria; Pfizer: Honoraria. Polydefkis:Pfizer: Honoraria; Alnylam: Honoraria. Dyck:Ionis: Consultancy; Alnylam: Consultancy. Plante-Bordeneuve:Alnylam: Consultancy; Pfizer: Consultancy, Other: reimbursement for travel and meeting; Ionis: Other: reimbursement for travel and meeting. Berk:Ionis: Honoraria, Other: Investigator; Alnylam: Honoraria, Other: Investigator; Pfizer: Other: Investigator. Barroso:Pfizer: Consultancy, Honoraria, Other: Thaos registry, Speakers Bureau; Alnylam: Honoraria, Other: Investigator. Conceição:Alnylam: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau. Hughes:Ionis: Employment. Kwoh:Ionis: Employment. Jung:Ionis: Employment. Guthrie:Akcea: Employment. Pollock:Akcea: Employment. Benson:Ionis: Other: Investigator, Research Funding. Gertz:janssen: Consultancy; Teva: Consultancy; spectrum: Consultancy, Honoraria; Alnylam: Honoraria; Ionis: Honoraria; Amgen: Consultancy; annexon: Consultancy; Prothena: Honoraria; Research to Practice: Consultancy; Apellis: Consultancy; celgene: Consultancy; Abbvie: Consultancy; Medscape: Consultancy; Physicians Education Resource: Consultancy.

Description: Key Points Protein and DNA analyses reveal that mutation in the immunoglobulin κ light-chain constant region gene may cause hereditary amyloidosis. Sequencing of immunoglobulin light-chain constant region genes is indicated for patients with AL amyloidosis and no evidence of a plasma cell dyscrasia.