Wang, Annabel K.

Abstract 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.

ABSTRACTIntroductionPolyneuropathy signs (Neuropathy Impairment Score, NIS), neurophysiologic tests (m+7Ionis), disability, and health scores were assessed in baseline evaluations of 100 patients entered into an oligonucleotide familial amyloidotic polyneuropathy (FAP) trial.MethodsWe assessed: (1) Proficiency of grading neurologic signs and correlation with neurophysiologic tests, and (2) clinometric performance of modified NIS+7 neurophysiologic tests (mNIS+7Ionis) and its subscores and correlation with disability and health scores.ResultsThe mNIS+7Ionis sensitively detected, characterized, and broadly scaled diverse polyneuropathy impairments. Polyneuropathy signs (NIS and subscores) correlated with neurophysiology tests, disability, and health scores. Smart Somatotopic Quantitative Sensation Testing of heat as pain 5 provided a needed measure of small fiber involvement not adequately assessed by other tests.ConclusionsSpecially trained neurologists accurately assessed neuropathy signs as compared to referenced neurophysiologic tests. The score, mNIS+7Ionis, broadly detected, characterized, and scaled polyneuropathy abnormality in FAP, which correlated with disability and health scores. Muscle Nerve 56: 901–911, 2017