Pollock, Michael

AbstractIntroductionInotersen, an antisense oligonucleotide inhibitor of transthyretin (TTR) protein production, demonstrated significant benefit versus placebo in the modified Neuropathy Impairment Score (NIS) +7 neurophysiologic tests (mNIS+7) in patients with hereditary TTR‐mediated amyloidosis (hATTR) with polyneuropathy. This analysis assessed the mNIS+7 components by anatomic location and the lower limb function (LLF) test.MethodsAdults with hATTR in the NEURO‐TTR trial (NCT01737398) were randomly assigned to receive weekly doses of subcutaneous inotersen 300 mg or placebo for 65 weeks. The mNIS+7 and LLF were assessed at 35 and 66 weeks.ResultsAll major mNIS+7 components (muscle weakness, muscle stretch reflexes, sensation) and the LLF showed significant efficacy in patients receiving inotersen versus placebo; however, NIS‐reflexes (upper limb), touch pressure (upper and lower limbs), and heart rate during deep breathing did not show significant effects.DiscussionThe results of this analysis reinforce the beneficial effect of inotersen on slowing neuropathy progression in patients with hATTR polyneuropathy.

AbstractIntroductionHereditary transthyretin‐mediated amyloidosis (hATTR) manifests as multisystem dysfunction, including progressive polyneuropathy. Inotersen, an antisense oligonucleotide, improved the course of neuropathic impairment in patients with hATTR in the pivotal NEURO‐TTR study (NCT01737398). To determine inotersen's impact on symptoms and patients’ neuropathy experience, we performed a post hoc analysis of the Neuropathy Symptoms and Change (NSC) score.MethodsStage 1 or 2 hATTR patients were randomized to receive weekly subcutaneous inotersen or placebo for 65 weeks. NSC score was assessed at baseline and 35 and 66 weeks.ResultsAt 66 weeks, inotersen‐treated patients had symptom stabilization as compared with worsening in patients receiving placebo, based on total NSC score. There were also improvements in the subdomains of muscle weakness, sensory, pain, and autonomic symptoms, and for various individual items.DiscussionInotersen treatment stabilized neuropathy symptoms, including autonomic symptoms, in patients with hATTR according to NSC score. Thus, the NSC may be an effective measure to assess neuropathy progression and patients’ neuropathy experience in clinical practice.

Abstract Background: Hereditary transthyretin amyloidosis (hATTR) is a rare, systemic, progressive, and fatal condition in which misfolded proteins, mainly produced in the liver, deposit in muscle and organ tissues leading to symptoms of peripheral neuropathy, and possible cardiomyopathy and autonomic neuropathy. The Norfolk Quality of Life (QOL)-Diabetic Neuropathy (DN) Questionnaire is a patient-reported measure that has been validated for capturing neuropathic-specific QOL in patients with hATTR amyloidosis. Examination of patients' responses to the items of the Norfolk-QOL-DN can provide important insights into the impact of hATTR amyloidosis, and its treatment, on concrete aspects of patients' daily activities and physical functioning. Objective: To provide a descriptive analysis of item-level responses to the Norfolk-QOL-DN by patients with hATTR amyloidosis with polyneuropathy, who participated in the NEURO-TTR trial, in order to identify the impact of treatment with inotersen versus placebo on concrete aspects of patients' functioning and daily activities. Methods: Data come from the NEURO-TTR trial, a multicenter, multinational, double-blind trial (NCT01737398) of 172 adults with hATTR amyloidosis with polyneuropathy who received 65 weeks of either treatment with the investigational drug inotersen, an antisense oligonucleotide, or a matching placebo. The Norfolk QOL-DN was administered to patients at baseline, week 35, and week 66. The Norfolk QOL-DN is a 35-item measure which captures neuropathic-related QOL. Nineteen items from the scale were determined to elicit concrete information about functioning and daily activities. Each of these 19 items used five response choices: "no problems", "very mild problems", "mild problems", "moderate problems", and "severe problems". Response options were dichotomized such that the latter two options were coded as indicating substantial impairment in functioning or activities. Descriptive analyses compared, for each item, the proportion of patients in the inotersen and placebo arms at baseline and week 66 (and change from baseline to week 66) who indicated substantial impairment. Results: At baseline, there were no differences for any Norfolk QOL-DN items in the proportions of patients who indicated substantial impairment. However, at week 66, patients receiving inotersen were less likely than those receiving placebo to indicate that they had a substantial impairment on several aspects of functioning and daily activities. Patients in the inotersen arm were half as likely as those receiving placebo to indicate a problem of pain keeping them awake at night (15% vs. 37%) and being moderately or severely bothered by the touch of bedsheets (12% vs. 27%). A noticeably smaller percentage of patients receiving inotersen than placebo reported problems with their symptoms affecting their usual activities (37% vs. 50%); having difficulty moving their fingers (47% vs 64%); feeling unsteady on their feet (49% vs 67%); having difficulty getting out of a chair (51% vs. 62%) or walking down stairs (42% vs. 58%); and having difficulty bathing (24% vs. 35%), dressing (21% vs 35%), walking (41% vs 60%), getting on/off the toilet (22% vs. 37%), and utensil use (19% vs. 31%). Percentages of change in patients from baseline to week 66 show larger increases in having substantial impairment in these functions and activities for patients receiving placebo than inotersen, with those receiving inotersen generally showing small increases, and even decreases in substantial impairment over the course of treatment. Conclusion: Following 66 weeks of treatment, hATTR amyloidosis patients receiving inotersen were less likely than those receiving placebo to report substantial impairment in many aspects of functioning and activities of daily living, including moving fingers, balance while standing, getting out of a chair, walking down stairs, bathing, dressing, walking, getting on/off the toilet, and using utensils. Ability to engage in these functions and activities was better preserved in patients treated with inotersen than placebo. These findings present a context for understanding the concrete impact of inotersen treatment on the day-to-day lives of patients with hATTR amyloidosis with polyneuropathy. Disclosures Yarlas: Optum: Employment; Akcea: Research Funding. Merlini:Millenium: Consultancy; Pfizer: Consultancy; Janssen: Consultancy; Prothena: Consultancy; Ionis: Consultancy; Akcea: Consultancy. White:Optum: Employment; Akcea: Research Funding. Sikora Kessler:Optum: Employment; Akcea: Research Funding. Lovley:Optum: Employment; Akcea: Research Funding. Guthrie:Akcea: Employment, Other: Stock Ownership. Pollock:Akcea: Employment. Gertz:Apellis: Consultancy; Amgen: Consultancy; janssen: Consultancy; Alnylam: Honoraria; Prothena: Honoraria; annexon: Consultancy; Abbvie: Consultancy; spectrum: Consultancy, Honoraria; Teva: Consultancy; Ionis: Honoraria; Medscape: Consultancy; Physicians Education Resource: Consultancy; Research to Practice: Consultancy; celgene: Consultancy.

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.

Abstract Background: Hereditary transthyretin amyloidosis (hATTR) is a rare, systemic, progressive, and fatal condition in which misfolded proteins, mainly produced in the liver, deposit in muscle and organ tissues leading to symptoms of peripheral neuropathy, and possible cardiomyopathy and autonomic neuropathy. Primary results from the NEUTO-TTR trial indicated that patients with hATTR amyloidosis who received 65 weeks of treatment with inotersen had better preservation of quality of life (QOL), as measured by the Norfolk QOL-Diabetic Neuropathy (DN) Questionnaire total score and the physical component summary score of the SF-36v2® Health Survey (SF-36v2), than did patients who received placebo. Whether the benefits of inotersen on domains of QOL differ across subgroups of patients has not been previously addressed. Objective: To examine the efficacy of inotersen for preserving QOL in subgroups of patients with hATTR amyloidosis, defined by time of disease onset (early or late) and ambulatory stage (Stage 1 or Stage 2). Methods: Data come from the NEURO-TTR trial, a multicenter, multinational, double-blind trial (NCT01737398) of 172 adults with hATTR amyloidosis with polyneuropathy who received 65 weeks of treatment with either the investigational drug inotersen, which is an antisense oligonucleotide, or matching placebo. The Norfolk QOL-DN and SF-36v2 were administered to patients at baseline, week 35, and week 66. The Norfolk QOL-DN is a 35-item measure which captures neuropathic-related QOL, representing five domains: activities of daily living, autonomic neuropathy, large fiber neuropathy/physical functioning, small fiber neuropathy, and neuropathic symptoms. The SF-36v2 is a 36-item measure which captures generic health-related QOL, representing eight domains: physical functioning, role limitations due to physical health (role-physical), bodily pain, general health, vitality, social functioning, role limitations due to emotional health (role-emotional), and mental health. Patient subgroups were defined by: (1) patients' time of symptom onset: whether symptoms first occurred early (at or before age 50) or late (after age 50) in life; and (2) patients' disease severity, as defined by ambulatory disability - Stage 1 (walking without assistance) or Stage 2 (walking with assistance, such as a cane or walker). Mixed-effects repeated-measures models tested treatment differences (inotersen vs. placebo) in changes of mean Norfolk QOL-DN and SF-36v2 domain scores from baseline to week 66 for each patient subgroup. Results: Inotersen was more effective than placebo for preserving QOL in patients with early onset of symptoms: treatment differences in scores were statistically significant (p<0.05) for four of the five Norfolk QOL-DN domains (all except small fiber neuropathy) and for all eight SF-36v2 domains. In patients with late onset of symptoms: statistically significant treatment differences in scores were observed for no Norfolk QOL-DN domains and only one of eight SF-36v2 domains (physical functioning). Inotersen was more effective than placebo for preserving QOL in patients with Stage 1 severity, treatment differences were statistically significant for three of the five Norfolk QOL-DN domains (all except autonomic neuropathy and small fiber neuropathy) and for five of eight SF-36v2 domains (all except general health, vitality, and mental health). In patients with Stage 2 severity, significant treatment differences in scores were observed for only one Norfolk QOL-DN domain (activities of daily living) and no SF-36v2 domains. Conclusion: Following 66 weeks of treatment, inotersen was more effective than placebo for preserving QOL in patients with hATTR amyloidosis who had early onset of symptoms or who were in Stage 1 of disease severity. Preserving QOL in patients with early onset is critical, as many of these patients are likely to be in the work force, raising children, and leading active lives. The benefits seen for patients in Stage 1 disease severity point to the crucial importance of early diagnosis and treatment, as there may be a window in which treatment can preserve QOL in patients with hATTR amyloidosis prior to the late progressive stages. Disclosures Yarlas: Optum: Employment; Akcea: Research Funding. Merlini:Pfizer: Consultancy; Millenium: Consultancy; Akcea: Consultancy; Prothena: Consultancy; Janssen: Consultancy; Ionis: Consultancy. White:Optum: Employment; Akcea: Research Funding. Sikora Kessler:Optum: Employment; Akcea: Research Funding. Lovley:Optum: Employment; Akcea: Research Funding. Guthrie:Akcea: Employment, Other: Stock Ownership. Pollock:Akcea: Employment. Gertz:Apellis: Consultancy; Research to Practice: Consultancy; Teva: Consultancy; celgene: Consultancy; Amgen: Consultancy; Physicians Education Resource: Consultancy; Ionis: Honoraria; annexon: Consultancy; Alnylam: Honoraria; Medscape: Consultancy; Prothena: Honoraria; janssen: Consultancy; Abbvie: Consultancy; spectrum: Consultancy, Honoraria.

ABSTRACTIntroductionHereditary transthyretin (hATTR) amyloidosis is a progressive, degenerative disease, with peripheral neuropathy, cardiomyopathy, and other clinical manifestations. In this study we examine the impact of hATTR amyloidosis on quality of life (QOL).MethodsNeuropathy‐specific QOL, measured with the Norfolk QOL‐Diabetic Neuropathy questionnaire, was compared between patients with hATTR amyloidosis and patients with type 2 diabetes, whereas generic QOL, measured with the 36‐item Short Form Health Survey version 2 (SF‐36v2), was compared between patients with hATTR amyloidosis, the general population, and patients with chronic diseases.ResultsNeuropathy‐specific QOL for patients with hATTR amyloidosis was nearly equivalent to that of patients with type 2 diabetes with diabetic neuropathy accompanied by a history of ulceration, gangrene, or amputation. Generic QOL was worse than that seen in the general population, with physical functioning worse than that for patients with multiple sclerosis and congestive heart failure.DiscussionPatients with hATTR amyloidosis show significant burden on QOL, particularly in physical functioning. Muscle Nerve 60: 169–175, 2019