Long-Term Safety and Efficacy of Eculizumab in Aquaporin-4 IgG-Positive NMOSD.

OBJECTIVE: During PREVENT (NCT01892345), eculizumab significantly reduced relapse risk versus placebo in patients with aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG+ NMOSD). We report an interim analysis of PREVENT's ongoing open-label extension (OLE; NCT02003144) evaluating eculizumab's long-term safety and efficacy. METHODS: Patients who completed PREVENT could enroll in the OLE to receive eculizumab (maintenance dose = 1,200 mg/2 weeks, after a blinded induction phase). Safety and efficacy data from PREVENT and its OLE (interim data cut, July 31, 2019) were combined for this analysis. RESULTS: Across PREVENT and the OLE, 137 patients received eculizumab and were monitored for a median (range) of 133.3 weeks (5.1-276.9 weeks), for a combined total of 362.3 patient-years (PY). Treatment-related adverse event (AE) and serious adverse event (SAE) rates were 183.5 in 100 PY and 8.6 in 100 PY, respectively. Serious infection rates were 10.2 in 100 PY in eculizumab-treated patients versus 15.1 in 100 PY in the PREVENT placebo group. No patient developed a meningococcal infection. At 192 weeks (3.7 years), 94.4% (95% confidence interval [CI], 88.6-97.3) of patients remained adjudicated relapse-free. The adjudicated annualized relapse rate was 0.025 (95% CI = 0.013-0.048) in all eculizumab-treated patients versus 0.350 (95% CI = 0.199-0.616) in the PREVENT placebo group. During the OLE, 37% of patients (44 of 119 patients) stopped or decreased background immunosuppressive therapy use. INTERPRETATION: This analysis demonstrates that eculizumab's long-term safety profile in NMOSD is consistent with its established profile across other indications. This analysis also demonstrated the sustained ability of long-term eculizumab treatment to reduce relapse risk in patients with AQP4-IgG+ NMOSD. ANN NEUROL 2021;89:1088-1098.

Improved cognitive outcomes in patients with relapsing-remitting multiple sclerosis treated with daclizumab beta: Results from the DECIDE study.

BACKGROUND: Cognitive impairment is common in multiple sclerosis (MS), with cognitive processing speed being the most frequently affected domain. OBJECTIVE: Examine the effects of daclizumab beta versus intramuscular (IM) interferon (IFN) beta-1a on cognitive processing speed as assessed by Symbol Digit Modalities Test (SDMT). METHODS: In DECIDE, patients with relapsing-remitting multiple sclerosis (RRMS) (age: 18-55 years; Expanded Disability Status Scale (EDSS) score 0-5.0) were randomized to daclizumab beta ( n = 919) or IM IFN beta-1a ( n = 922) for 96-144 weeks. SDMT was administered at baseline and at 24-week intervals. RESULTS: At week 96, significantly greater mean improvement from baseline in SDMT was observed with daclizumab beta versus IM IFN beta-1a ( p = 0.0274). Significantly more patients treated with daclizumab beta showed clinically meaningful improvement in SDMT (increase from baseline of ⩾3 points ( p = 0.0153) or ⩾4 points ( p = 0.0366)), and significantly fewer patients showed clinically meaningful worsening (decrease from baseline of ⩾3 points ( p = 0.0103)). Odds representing risk of worsening versus stability or improvement on SDMT were significantly smaller for daclizumab beta ( p = 0.0088 (3-point threshold); p = 0.0267 (4-point threshold)). In patients completing 144 weeks of treatment, the effects of daclizumab beta were generally sustained. CONCLUSION: These results provide evidence for a benefit of daclizumab beta versus IM IFN beta-1a on cognitive processing speed in RRMS. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01064401 (Efficacy and Safety of BIIB019 (Daclizumab High Yield Process) Versus Interferon ß 1a in Participants With Relapsing-Remitting Multiple Sclerosis (DECIDE)): https://clinicaltrials.gov/ct2/show/NCT01064401 .

Efficacy of daclizumab beta versus intramuscular interferon beta-1a on disability progression across patient demographic and disease activity subgroups in DECIDE.

BACKGROUND: Demonstration of clinical benefits on disability progression measures is an important attribute of effective multiple sclerosis (MS) treatments. OBJECTIVE: Examine efficacy of daclizumab beta versus intramuscular (IM) interferon beta-1a on measures of disability progression in patient subgroups from DECIDE. METHODS: Twenty-four-week confirmed disability progression (CDP), 24-week sustained worsening on a modified Multiple Sclerosis Functional Composite (MSFCS) where 3-Second Paced Auditory Serial Addition Test was replaced by Symbol Digit Modalities Test, and proportion of patients with clinically meaningful worsening in 29-Item Multiple Sclerosis Impact Scale physical impact subscale (MSIS-29 PHYS) score from baseline to week 96 were examined in the overall population and subgroups defined by baseline demographic/disease characteristics. RESULTS: Daclizumab beta significantly reduced risk of 24-week CDP (hazard ratio (HR), 0.73; 95% confidence interval (95% CI), 0.55-0.98), risk of 24-week sustained MSFCS progression (HR, 0.80; 95% CI, 0.67-0.95), and odds of clinically meaningful worsening in MSIS-29 PHYS (odds ratio, 0.76; 95% CI, 0.60-0.95) versus IM interferon beta-1a. Point estimates showed trends favoring daclizumab beta over IM interferon beta-1a across several patient subgroups for all three outcome measures. CONCLUSION: Daclizumab beta showed consistent benefit versus IM interferon beta-1a across measures assessing patient disability/function and across a range of clinical baseline characteristics in patients with relapsing-remitting MS.

A single relapse induces worsening of disability and health-related quality of life in patients with neuromyelitis optica spectrum disorder.

Background: Cumulative damage from multiple relapses in neuromyelitis optica spectrum disorder (NMOSD) is associated with poor health-related quality of life (HRQoL) and long-term disability in patients positive for anti-aquaporin 4 antibodies (AQP4+). This study assessed the effect of an individual relapse on HRQoL and disability outcomes in AQP4+ NMOSD. Methods: Post hoc analyses of data pooled from the PREVENT study and its open-label extension, which evaluated the efficacy and safety of eculizumab in AQP4+ NMOSD, examined the effect of a single relapse on 3 disability and 4 HRQoL outcome measures. Assuming the effect of 1 relapse extends to multiple relapses, an extrapolation was done to assess the effect of 2 relapses on these outcomes. Results: In 27 patients (placebo: n = 20; eculizumab: n = 7) experiencing an independently adjudicated relapse, 1 relapse led to significantly worse disability (modified Rankin Scale and Expanded Disability Status Scale [EDSS]) and HRQoL (36-item Short-Form Health Survey mental and physical component summaries; European Quality of Life 5-Dimension questionnaire 3-Level visual analogue scale and utility index) scores. In 4 of 7 outcomes, clinically meaningful worsening was more likely for relapsing versus non-relapsing patients (n = 116). Extrapolating the effect of 2 relapses predicted that clinically meaningful worsening was more likely in 6 out of 7 outcomes, including EDSS, for patients experiencing multiple relapses versus patients experiencing no relapses. Conclusion: Findings from these clinical trial data demonstrate that a single NMOSD relapse can worsen disability and HRQoL, underscoring the role of relapse prevention in improving long-term outcomes in patients with AQP4+ NMOSD.

Proximity of TPR and NTRK1 rearranging loci in human thyrocytes.

Chromosomal rearrangements are frequently associated with cancer; the mechanisms underlying their cell-type specificity are poorly understood. Papillary thyroid carcinomas are marked by a high frequency of chromosome rearrangements involving the RET and NTRK1 tyrosine kinase receptor genes and producing RET and TRK oncogenes. An explanation for the propensity of thyrocytes to undergo gene rearrangements has been recently proposed by Nikiforova and colleagues, who showed that the recombination between RET and H4 is favored by the loci proximity in interphase nuclei. We investigated whether the spatial proximity is a contributing factor also in the generation of the thyroid-specific TRK oncogenes. The distance between NTRK1 and its oncogenic partner TPR was determined by two-color fluorescence in situ hybridization and two-dimensional microscopy. A three-dimensional reconstruction of the data was also done. We show that the two loci in thyrocytes nuclei display a distance reduced with respect to peripheral blood lymphocytes, thus supporting the notion that spatial proximity of translocation-prone gene loci may favor gene rearrangements.

Measuring the impact of multiple sclerosis: Enhancing the measurement performance of the Multiple Sclerosis Impact Scale (MSIS-29) using Rasch Measurement Theory (RMT).

BACKGROUND: Study objectives were to evaluate the Multiple Sclerosis Impact Scale (MSIS-29) and explore an optimized scoring structure based on empirical post-hoc analyses of data from the Phase III ADVANCE clinical trial. METHODS: ADVANCE MSIS-29 data from six time-points were analyzed in a sample of patients with relapsing-remitting multiple sclerosis (RRMS). Rasch Measurement Theory (RMT) analysis was undertaken to examine three broad areas: sample-to-scale targeting, measurement scale properties, and sample measurement validity. Interpretation of results led to an alternative MSIS-29 scoring structure, further evaluated alongside responsiveness of the original and revised scales at Week 48. RESULTS: RMT analysis provided mixed evidence for Physical and Psychological Impact scales that were sub-optimally targeted at the lower functioning end of the scales. Their conceptual basis could also stand to improve based on item fit results. The revised MSIS-29 rescored scales improved but did not resolve the measurement scale properties and targeting of the MSIS-29. In two out of three revised scales, responsiveness analysis indicated strengthened ability to detect change. CONCLUSION: The revised MSIS-29 provides an initial evidence-based improved patient-reported outcome (PRO) instrument for evaluating the impact of MS. Revised scoring improves conceptual clarity and interpretation of scores by refining scale structure to include Symptoms, Psychological Impact, and General Limitations. CLINICAL TRIAL: ADVANCE (ClinicalTrials.gov identifier NCT00906399).

Impact of daclizumab versus interferon beta-1a on patient-reported outcomes in relapsing-remitting multiple sclerosis.

BACKGROUND: Patient-reported outcomes (PROs) provide information on treatment effects from the patient's perspective that complement outcomes on clinical measures. In DECIDE, daclizumab demonstrated superior efficacy in reducing relapses, 24-week confirmed disability progression, and brain lesions (assessed by magnetic resonance imaging [MRI]) versus intramuscular interferon beta-1a in relapsing-remitting multiple sclerosis. OBJECTIVE: To examine the impact of daclizumab versus interferon beta-1a on PROs in DECIDE. METHODS: DECIDE was a randomized, double-blind, active-controlled, phase 3 study comparing daclizumab 150mg subcutaneous every 4 weeks with interferon beta-1a 30mcg intramuscular once weekly. The 29-item Multiple Sclerosis Impact Scale (MSIS-29) and EuroQoL 5-Dimensions (EQ-5D) were assessed at baseline and every 24 weeks. Mean changes from baseline were analyzed using analysis of covariance models. Individual items for the MSIS-29 physical (PHYS) and psychological (PSYCH) subscales were analyzed post hoc. RESULTS: Daclizumab treatment resulted in greater mean improvements relative to baseline in MSIS-29 PHYS and PSYCH scores starting at week 24 that persisted over 96 weeks. Mean improvements from baseline in MSIS-29 PHYS and PSYCH scores were significantly greater for daclizumab versus intramuscular interferon beta-1a at week 96. Daclizumab-treated patients showed steady improvements in EQ-5D health utility index and EQ-5D visual analog scale scores over the study period, with significantly greater improvements versus intramuscular interferon beta-1a at week 96 (p=0.0048 and p=0.0006, respectively). CONCLUSIONS: Improvements in patient-reported physical and psychological functioning and general health status with daclizumab compared with intramuscular interferon beta-1a are consistent with outcomes on clinical and brain MRI lesion measures in DECIDE (NCT01064401).

Subgroup and sensitivity analyses of annualized relapse rate over 2 years in the ADVANCE trial of peginterferon beta-1a in patients with relapsing-remitting multiple sclerosis.

ADVANCE was a 2-year, double-blind, placebo-controlled, Phase 3 study in 1512 patients aged 18-65 years with relapsing-remitting multiple sclerosis, which demonstrated that peginterferon beta-1a 125 mcg administered subcutaneously every 2 or 4 weeks led to significant reductions in annualized relapse rate (ARR) compared with placebo. This analysis examined ARR over 2 years in ADVANCE across subgroups. Patients were treated with peginterferon beta-1a every 2 weeks or every 4 weeks, or placebo during Year 1. Thereafter, patients on placebo were re-randomized to peginterferon beta-1a every 2 weeks or every 4 weeks (delayed treatment). Subgroup analyses were conducted by demographics and baseline disease characteristics. The following results compared ARR in these subgroups for patients in continuous 2-week treatment versus continuous 4-week treatment. ARR was similar in most demographic and baseline disease characteristic subgroups evaluated within the peginterferon beta-1a every-2-week arm or every-4-week arm over 2 years. Although for both doses some differences in the point estimates for ARR were noted among the subgroups, considerable overlap in the confidence intervals suggested that the efficacy of peginterferon beta-1a is similar in all patients irrespective of gender, age, body weight, geographical region, and disease activity at initiation of treatment. Within each peginterferon beta-1a dosing group, ARR was generally similar across most subgroups.

Management Strategies for Flu-Like Symptoms and Injection-Site Reactions Associated with Peginterferon Beta-1a: Obtaining Recommendations Using the Delphi Technique.

BACKGROUND: Flu-like symptoms (FLSs) and injection-site reactions (ISRs) have been reported with interferon beta treatments for multiple sclerosis (MS). We sought to obtain consensus on the characteristics/management of FLSs/ISRs in patients with relapsing-remitting MS based on experiences from the randomized, placebo-controlled ADVANCE study of peginterferon beta-1a. METHODS: ADVANCE investigators with a predefined number of enrolled patients were eligible to participate in a consensus-generating exercise using a modified Delphi method. An independent steering committee oversaw the development of two sequential Delphi questionnaires. An average rating (AR) of 2.7 or more was defined as consensus a priori. RESULTS: Thirty and 29 investigators (ie, responders) completed questionnaires 1 and 2, respectively, representing 374 patients from ADVANCE. Responders reported that the incidence/duration of FLSs/ISRs in their typical patient generally declined after 3 months of treatment. Responders reached consensus that FLSs typically last up to 24 hours (AR = 3.17) and have mild/moderate effects on activities of daily living (AR = 3.34). Patients should initiate acetaminophen/nonsteroidal anti-inflammatory drug treatment on a scheduled basis (AR = 3.31) and change the timing of injection (AR = 3.28) to manage FLSs. Injection-site rotation/cooling and drug administration at room temperature (all AR ≥ 3.10) were recommended for managing ISRs. Patient education on FLSs/ISRs was advocated before treatment initiation. CONCLUSIONS: Delphi responders agreed on the management strategies for FLSs/ISRs and agreed that patient education is critical to set treatment expectations and promote adherence.

Computerized morphometry of the cirrhotic liver: comparative analysis in primary biliary cirrhosis, alcoholic cirrhosis, and posthepatitic cirrhosis.

Fibrosis and nodular regeneration are the hallmarks of liver cirrhosis. To assess the degree of fibrosis and the severity of the structural changes affecting parenchymal and extraparenchymal components in liver cirrhosis, a computerized morphometric model has been applied to liver specimens from patients undergoing liver transplantation for primary biliary cirrhosis, posthepatitic and alcoholic cirrhosis. Fifty-eight hepatectomy specimens from patients undergoing liver transplantation for cirrhosis were analyzed: 17 alcoholic, 28 posthepatitic (HBV-related and HCV-related cirrhosis), and 13 primary biliary cirrhoses. Liver specimens were fixed in 10% neutral-buffered formalin and embedded in paraffin. Sections were stained with chromotrope-aniline blue method and monoclonal antibodies against cytokeratin 7 and CD31. Volume fractions of parenchymal compartment and fibrosis were stereologically determined on the specimens stained with chromotrope-aniline blue method. Volume fractions of portal bile ducts, proliferated bile ductules, and hepatocytes with biliary metaplasia were measured on cytokeratin 7 stains, while volume fractions of capillary units have been evaluated on CD31 staining. Volume fraction of fibrosis was higher in primary biliary cirrhosis than in the other disease-induced cirrhosis. The main differences were related to immunohistochemical staining. Volume fraction of hepatocytes with biliary metaplasia was higher in HCV-related cirrhosis, whereas volume fractions of biliary structures were more prominent in HBV-related cirrhosis. Primary biliary cirrhosis was characterized by a reduced number of bile ducts and by a wider expression of cytokeratin 7 into periportal hepatocytes. Capillary units were more prominent in primary biliary cirrhosis than alcoholic and posthepatitic cirrhosis. Our computerized morphometric model well describes and quantifies the morphological alterations of the liver and it could represent an adjunctive tool to evaluate the degree of dysplastic phenomena involving parenchymal and extraparenchymal compartments.

Analysis of histological and immunohistochemical patterns of the liver in posthepatitic and alcoholic cirrhosis by computerized morphometry.

To assess the degree of fibrosis and the structural changes affecting parenchymal and extraparenchymal components in liver cirrhosis, a computerized morphometric model has been applied to liver specimens from patients with posthepatitic and alcoholic cirrhosis. All specimens have been stained with chromotrope-aniline blue method and monoclonal antibodies against cytokeratin 7, CD31, and VIII factor. Volume fractions of parenchymal compartment and fibrosis have been determined stereologically on CAB slices; moreover, volume fractions of portal bile ducts and proliferated bile ductules, hepatocytes with biliary metaplasia, capillary units, and vascular structures have been measured. Volume fraction of fibrosis was higher in alcoholic cirrhosis when compared with the case of posthepatitic cirrhosis. Volume fractions describing parenchymal compartment showed a similar trend in both viral groups. The main differences were related to immunohistochemical stainings. Volume fraction of hepatocytes with biliary metaplasia was higher in hepatitis C virus-related cirrhosis, whereas volume fractions of biliary structures were more prominent in hepatitis B virus-related cirrhosis. Capillary units were more prominent in posthepatitic cirrhosis than in alcoholic cirrhosis. Interestingly, both forms of posthepatitic cirrhosis show similar features when compared with alcoholic cirrhosis. Our computerized morphometric model well describes and quantifies the morphological alterations of the liver, and it could represent an adjunctive tool to evaluate the degree of dysplastic phenomena involving parenchymal and extraparenchymal components.