A real-world prospective observational study of eptinezumab in Asian patients with migraine.

OBJECTIVE: To evaluate the real-world effectiveness of eptinezumab for migraine prevention in Asian patients. BACKGROUND: Eptinezumab is a monoclonal antibody that targets calcitonin gene-related peptide (CGRP), a potent vasodilator with an important role in migraine pathophysiology. Although there is robust clinical evidence from pivotal Phase 3 placebo-controlled trials of the efficacy of eptinezumab for migraine prevention, there are limited data on the real-world effectiveness of eptinezumab in Asian patient cohorts. METHODS: This was a non-interventional, prospective, multisite cohort study of adults with migraine (International Classification of Headache Disorders, 3rd edition criteria) in Singapore who were prescribed eptinezumab (100 mg at baseline and Month 3, administered intravenously) and were followed until Month 6. The primary endpoint was change from baseline in monthly migraine days (MMDs) at Month 3 and Month 6. Secondary endpoints were ≥30% and ≥50% responder rates, and change from baseline in the Headache Impact Test-6 (HIT-6), Migraine Disability Assessment (MIDAS), Migraine-Specific Quality of Life (MSQ), patient-identified most bothersome symptom (PI-MBS), acute medication use at Month 3 and Month 6, and safety. RESULTS: Enrolled patients (completed = 29/30) had on average 3.4 (SD 2.9) previous preventive treatments; 29/30 of the patients had trialed at least one previous preventive treatment without benefit. Most had previously trialed oral preventives (87%, 26/30) and anti-CGRP (70%, 21/30). Relative to baseline, mean MMDs decreased by 4.3 days (95% CI 2.1-6.4; p < 0.001) at Month 3 and 4.9 days (95% CI 2.1-7.7; p < 0.001) at Month 6. At Month 3 and Month 6, 14/30 (47%) and 15/29 (52%) of the patients were ≥30% responders, and 6/30 (20%) and 8/29 (28%) patients were ≥50% responders, respectively. The number of patients with severe life impairment based on the HIT-6 score (total score 60-78) decreased from 24/30 (80%) at baseline to 19/30 (63%) at Month 3 and 19/29 (66%) at Month 6. The mean MIDAS score decreased by 24.6 points (95% CI 2.82-46.38; p = 0.028) at Month 6, and the mean MSQ score increased by 12.2 points (95% CI 5.18-19.20; p = 0.001) at Month 3 and 13.6 points (95% CI 4.58-22.66; p = 0.004) at Month 6. Most patients reported improvement in the PI-MBS at Month 3 (73%, 22/30) and Month 6 (55%, 16/29). Acute medication use for headache relief decreased by 3.3 days/month (95% CI 1.0-5.6; p = 0.007) at Month 3 and 4.7 days/month (95% CI 1.7-7.7; p = 0.003) at Month 6. Treatment-emergent adverse events (TEAEs) were reported in 16/30 (54%) patients, mostly mild/moderate in severity. No serious TEAEs led to treatment discontinuation. CONCLUSION: Quarterly eptinezumab administration was effective and well-tolerated in Asian patients with chronic migraine.

Healthcare resource utilization and costs associated with generalized myasthenia gravis: a retrospective matched cohort study using the National Health Insurance Research Database in Taiwan.

Background: We estimated healthcare resource utilization (HRU) and costs in patients with generalized myasthenia gravis (gMG) in Taiwan. Methods: This retrospective population-based, matched cohort study used the National Health Insurance Research Database to identify prevalent patients with gMG (cases) in 2019. In total, 2537 cases were matched (1:4) by age, sex, and urbanization level to 10148 randomly selected patients without gMG (comparators). A generalized linear regression model predicted the frequency of HRU and costs among service users. Costs attributable to gMG were obtained by subtracting all-cause HRU costs incurred by comparators from cases. Results: The mean age of all patients was 54.99 years and 55.97% were female. Compared with comparators, cases had significantly higher rates of hypertension (33.03%/24.26%), diabetes mellitus (18.92%/11.37%), malignancies (16.00%/4.08%), cardiovascular disease (11.35%/8.12%), thyroid-related conditions (5.99%/1.16%), respiratory illness/disorders (4.38%/1.22%), and neurotic disorders (4.65%/2.6%). Amongst users of healthcare resources, cases had a mean 10 additional outpatient visits, 0.62 inpatient stays, and 0.49 emergency room visits in 2019 compared with comparators (p < 0.0001 for all). The mean (standard deviation) difference in all-cause healthcare costs between cases and comparators was NT$ 94997 (76431) [US$ 3133 (2521)], and was significantly higher for all categories (outpatient, inpatient, emergency room, drugs; p < 0.0001 for all). Among employed persons, 13.18%/7.59% of cases/comparators changed employment status during the study (p < 0.0001). Conclusion: gMG presents a substantial burden on HRU and healthcare costs in Taiwan. A high attrition rate from full-time employment suggests additional societal costs. Improved treatments are needed to alleviate the burden of disease on individuals, healthcare systems, and economies.

The growing burden of generalized myasthenia gravis: a population-based retrospective cohort study in Taiwan.

Background: The prevalence of myasthenia gravis is increasing in many countries, including Asia. As treatment options expand, population-based information about the disease burden can inform health technology assessments. Methods: We conducted a population-based retrospective cohort study using the Taiwan National Healthcare Insurance Research database and Death Registry to describe the epidemiology, disease burden and treatment patterns of generalized myasthenia gravis (gMG) from 2009 to 2019. Episodes of hepatitis B virus (HBV) infection or reactivation were explored. Results: The number of patients with gMG increased from 1,576 in 2009 to 2,638 in 2019 and the mean (standard deviation) age from 51.63 (17.32) to 55.38 (16.29) years. The female:male ratio was 1.3:1. Frequently reported co-morbidities were hypertension (32-34% of patients), diabetes mellitus (16-21%) and malignancies (12-17%). The prevalence of patients with gMG increased annually from 6.83/100,000 population in 2009 to 11.18/100,000 population in 2019 (p < 0.0001). There was no temporal trend in all-cause fatality rates (range 2.76-3.79/100 patients annually) or gMG incidence rates (2.4-3.17/100,000 population annually). First-line treatment was with pyridostigmine (82%), steroids (58%), and azathioprine (11%). There was minimal change in treatment patterns over time. Among 147 new HBV infections, 32 (22%) received ≥4 weeks of antiviral therapy suggesting chronic infection. The HBV reactivation rate was 7.2%. Conclusion: The epidemiology of gMG in Taiwan is evolving rapidly, with higher prevalence rates and increasing involvement of older age-groups suggesting a growing burden of disease and associated healthcare costs. HBV infection or reactivation may pose a previously unrecognized recognized risk for patients with gMG receiving immunosuppressants.

A comparison of real-world effectiveness of vortioxetine along the treatment algorithm for major depressive disorder.

OBJECTIVE: To evaluate the effectiveness of vortioxetine in major depressive disorder (MDD) when used as a first-line versus second-line treatment or later. METHODS: This was a post-hoc analysis of three 3-month non-interventional, prospective studies of vortioxetine in MDD - REVIDA (Malaysia, Philippines, Singapore, Thailand), PREVIDA (Pakistan) and TREVIDA (Taiwan). Improvements in depressive symptoms (PHQ-9, CGI-S), cognitive function (PDQ-D) and work productivity (WPAI) were compared between studies, and in a pooled analysis of patients using vortioxetine as the first line versus second-line treatment or later. Safety was compared between studies. RESULTS: Overall, 798 patients were analyzed (PREVIDA = 425, REVIDA = 130, TREVIDA = 243). Most patients in PREVIDA (60.5%)/REVIDA (57.4%) used vortioxetine as first-line treatment versus TREVIDA (21.8%). Generally, greater improvements from baseline were observed across outcome measures in PREVIDA/REVIDA versus TREVIDA (Month 3, p < .0001). Vortioxetine as first-line treatment was associated with greater improvements in depression severity, cognition, functioning outcomes compared to second-line or later users (PHQ-9: -16.1 [6.4] vs -10.8 [8.9]; CGI-S: -2.7 [1.1] vs -2.0 [1.4]; PDQ-D: -29.5 [17.7] vs -18.5 [21.4]; p < .0001 at Month 3) as well as greater response (PHQ-9: 88.6% vs 61.5%; p < .0001) and remission rates (PHQ-9: 75.4% vs 47.7%; p < .0001). No new adverse events were reported outside of the product label. CONCLUSIONS: In the Asian real-world setting, vortioxetine showed greater improvements in depressive and cognitive symptoms, work functioning, and response and remission rates when used as first-line versus second-line treatment or later. Vortioxetine was well-tolerated irrespective of the study population across Asia.

A Taiwanese study on real-world evidence with vortioxetine in patients with major depression in Asia (TREVIDA).

OBJECTIVE: The TREVIDA study aimed to evaluate vortioxetine for the treatment of major depressive disorder (MDD) in Taiwanese adults. METHODS: Patients with active depressive episode were recruited in this non-interventional, prospective, multi-site study conducted between June 2019 and August 2020 in Taiwan. Patient eligibility was independent of the physician's decision to prescribe vortioxetine for an MDD episode. Vortioxetine was initiated on the first visit. Depression severity, cognitive function, work productivity, functioning and safety were evaluated over 3 months. RESULTS: Overall, 242 patients were analyzed. At baseline, 70.7% and 90.4% of patients had moderately severe-to-severe depression based on PHQ-9 (Patient Health Questionnaire-9) and TDQ (Taiwanese Depression Questionnaire), respectively. By Month 3, significant improvements from baseline in depression severity (mean [SD] changes in PHQ-9, TDQ and CGI-S [Clinical Global Impression-Severity]: -6.3 [7.3]; -13.2 [14.0]; -1.5 [1.3], respectively), cognitive function (mean [SD] change in PDQ-D: -8.0 [17.5]), functioning (mean [SD] change in SDS: -5.4 [7.6]), and presenteeism (38.9% from 56.3%), work productivity loss (40.9% from 58.7%) and activity impairment (43.2% from 61.0%) were observed (p < .001 for all). By month 3, patient-reported (PHQ-9) response and remission rates were 43.4% and 52.9%, respectively; physician-reported (CGI-S) response and remission rates were 29.0% and 31.6%, respectively. Vortioxetine was well-tolerated and no unexpected side effects were reported. CONCLUSIONS: Vortioxetine reduced depression severity and improved cognitive function, work productivity, and functioning in Taiwanese patients with MDD in the real-world setting. Vortioxetine was well-tolerated in this Taiwanese population.

Cognitive dysfunction in Malaysian patients with major depressive disorder: A subgroup analysis of a multicountry, cross-sectional study.

INTRODUCTION: Cognitive dysfunction has been significantly associated with functional impairment in patients with major depressive disorder (MDD). METHODS: This is a subgroup analysis of 211 Malaysian patients recruited from the multicountry, multicenter, cross-sectional Cognitive Dysfunction in Asian patients with Depression (CogDAD) study. Depression severity, cognitive dysfunction, and functional disability were assessed and compared with the overall CogDAD study population. Factors associated with functional disability were also evaluated in this Malaysian patient population. RESULTS: Approximately half of the Malaysian patients were in their first depressive episode, with the majority being treated for mild-to-moderate depression. Furthermore, Malaysian patients experienced cognitive dysfunction, with self-reported Perceived Deficits Questionnaire (PDQ-D) scores falling within the third quartile of PDQ-D severity. Malaysian patients also reported functional disability evidenced by a mean total Sheehan Disability Scale (SDS) score of 11.47 ± 6.68, with the highest SDS score reported in the "Social Life/Leisure Activities" domain. Compared with the overall CogDAD study population, the Malaysian patient population had comparable patient demographics in terms of marital and working status; outcome scores for PHQ-9 (9-item Patient Health Questionnaire for self-reported depression severity), PDQ-D and SDS; and worst perceived cognitive dysfunction reported in the "Attention/Concentration" domain. Factors found to be significantly associated with functional disability were PDQ-D score, sick leave taken, and antidepressant treatment (P < 0.05). DISCUSSION: Findings from this subgroup analysis highlight the significance of treating cognitive dysfunction in patients with MDD and its correlation to functional disability.

Loss of α-catenin elicits a cholestatic response and impairs liver regeneration.

The liver is unique in its capacity to regenerate after injury, during which hepatocytes actively divide and establish cell-cell contacts through cell adhesion complexes. Here, we demonstrate that the loss of α-catenin, a well-established adhesion component, dramatically disrupts liver regeneration. Using a partial hepatectomy model, we show that regenerated livers from α-catenin knockdown mice are grossly larger than control regenerated livers, with an increase in cell size and proliferation. This increased proliferation correlated with increased YAP activation, implicating α-catenin in the Hippo/YAP pathway. Additionally, α-catenin knockdown mice exhibited a phenotype reminiscent of clinical cholestasis, with drastically altered bile canaliculi, elevated levels of bile components and signs of jaundice and inflammation. The disrupted regenerative capacity is a result of actin cytoskeletal disorganisation, leading to a loss of apical microvilli, dilated lumens in the bile canaliculi, and leaky tight junctions. This study illuminates a novel, essential role for α-catenin in liver regeneration.

Stereotyped fetal brain disorganization is induced by hypoxia and requires lysophosphatidic acid receptor 1 (LPA1) signaling.

Fetal hypoxia is a common risk factor that has been associated with a range of CNS disorders including epilepsy, schizophrenia, and autism. Cellular and molecular mechanisms through which hypoxia may damage the developing brain are incompletely understood but are likely to involve disruption of the laminar organization of the cerebral cortex. Lysophosphatidic acid (LPA) is a bioactive lipid capable of cortical influences via one or more of six cognate G protein-coupled receptors, LPA(1-6), several of which are enriched in fetal neural progenitor cells (NPCs). Here we report that fetal hypoxia induces cortical disruption via increased LPA(1) signaling involving stereotyped effects on NPCs: N-cadherin disruption, displacement of mitotic NPCs, and impaired neuronal migration, as assessed both ex vivo and in vivo. Importantly, genetic removal or pharmacological inhibition of LPA(1) prevented the occurrence of these hypoxia-induced phenomena. Hypoxia resulted in overactivation of LPA(1) through selective inhibition of G protein-coupled receptor kinase 2 expression and activation of downstream pathways including G(αi) and Ras-related C3 botulinum toxin substrate 1. These data identify stereotyped and selective hypoxia-induced cerebral cortical disruption requiring LPA(1) signaling, inhibition of which can reduce or prevent disease-associated sequelae, and may take us closer to therapeutic treatment of fetal hypoxia-induced CNS disorders and possibly other forms of hypoxic injury.