Guthrie, Spencer

Nonspecific symptoms and other diagnostic challenges lead to underdiagnosis of cardiac amyloidosis (CA). Artificial intelligence (AI) could help address these challenges, but a summary of the performance of these tools is lacking. This narrative review of published literature describes the performance of AI tools that use data from ECGs and echocardiography to improve identification of CA and challenges that hinder adoption of these tools. Thirteen studies met inclusion criteria with sample sizes ranging from 50 to 2451 patients. Four studies used ECG data, 8 used echocardiography data, and 1 used both. The CA gold standard was typically defined as a CA diagnosis in an institutional or other database but the requirements for these diagnoses were heterogenous across studies, and many did not distinguish among CA subtypes. AI model development varied considerably, and only 4 studies included external validation. The ability of models to predict CA ranged from 0.71 to 1.00, sensitivity ranged from 16% to 100%, and specificity from 75% to 100%. Only 1 study reported model performance across strata of sex, age, race, and CA type. Persistent challenges to AI adoption include usability, cost, value added, electronic health record/information technology interoperability, patient‐related factors, regulation, and privacy and liability. Published studies on AI for improved identification of CA show favorable performance measures but numerous methodologic and other challenges must be addressed before these tools are more widely adopted.

Abstract Amyloid light-chain (AL) amyloidosis is a rare, typically fatal disease characterized by the accumulation of misfolded immunoglobulin light chains (LCs). Birtamimab is an investigational humanized monoclonal antibody designed to neutralize toxic LC aggregates and deplete insoluble organ-deposited amyloid via macrophage-induced phagocytosis. VITAL was a phase 3 randomized, double-blind, placebo-controlled clinical trial assessing the efficacy and safety of birtamimab + standard of care (SOC) in 260 newly diagnosed, treatment-naive patients with AL amyloidosis. Patients received 24 mg/kg IV birtamimab + SOC or placebo + SOC every 28 days. The primary composite end point was the time to all-cause mortality (ACM) or centrally adjudicated cardiac hospitalization ≥91 days after the first study drug infusion. The trial was terminated early after an interim futility analysis; there was no significant difference in the primary composite end point (hazard ratio [HR], 0.826; 95% confidence interval [CI], 0.574-1.189; log-rank P = .303). A post hoc analysis of patients with Mayo stage IV AL amyloidosis, those at the highest risk of early mortality, showed significant improvement in the time to ACM with birtamimab at month 9 (HR, 0.413; 95% CI, 0.191-0.895; log-rank P = .021). At month 9, 74% of patients with Mayo stage IV AL amyloidosis treated with birtamimab and 49% of those given placebo survived. Overall, the rates of treatment-emergent adverse events (TEAEs) and serious TEAEs were generally similar between treatment arms. A confirmatory phase 3 randomized, double-blind, placebo-controlled clinical trial of birtamimab in patients with Mayo stage IV AL amyloidosis (AFFIRM-AL; NCT04973137) is currently enrolling. The VITAL trial was registered at www.clinicaltrials.gov as #NCT02312206.

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.

Background and purposeHereditary transthyretin (hATTR) amyloidosis causes progressive polyneuropathy resulting from transthyretin (TTR) amyloid deposition throughout the body, including the peripheral nerves. The efficacy and safety of inotersen, an antisense oligonucleotide inhibitor of TTR protein production, were demonstrated in the pivotal NEURO‐TTR study in patients with hATTR polyneuropathy. Here, the long‐term efficacy and safety of inotersen are assessed in an ongoing open‐label extension (OLE) study.MethodsPatients who completed NEURO‐TTR were eligible to enroll in the OLE (NCT02175004). Efficacy assessments included the modified Neuropathy Impairment Score plus seven neurophysiological tests composite score (mNIS + 7), the Norfolk Quality of Life – Diabetic Neuropathy (Norfolk QOL‐DN) questionnaire total score and the Short‐Form 36 Health Survey (SF‐36) Physical Component Summary (PCS) score. Safety and tolerability were also assessed.ResultsOverall, 97% (135/139) of patients who completed NEURO‐TTR enrolled in the OLE. Patients who received inotersen for 39 cumulative months in NEURO‐TTR and the OLE continued to show benefit; patients who switched from placebo to inotersen in the OLE demonstrated improvement or stabilization of neurological disease progression by mNIS + 7, Norfolk QOL‐DN and SF‐36 PCS. No new safety concerns were identified. There was no evidence of increased risk for grade 4 thrombocytopenia or severe renal events with increased duration of inotersen exposure.ConclusionInotersen slowed disease progression and reduced deterioration of quality of life in patients with hATTR polyneuropathy. Early treatment with inotersen resulted in greater long‐term disease stabilization than delayed initiation. Routine platelet and renal safety monitoring were effective; no new safety signals were observed.

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.