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
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 β 1a in Participants With Relapsing-Remitting Multiple Sclerosis (DECIDE)): https://clinicaltrials.gov/ct2/show/NCT01064401.
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 threedimensional 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 translocationprone gene loci may favor gene rearrangements.
A dherence to multiple sclerosis (MS) diseasemodifying therapies, such as interferons, has been linked to improved treatment outcomes and reduced health-care costs. 1,2 Reasons for poor patient adherence to prescribed MS therapies include frequency of administration and adverse events, such as flu-like symptoms (FLSs) and injection-site reactions (ISRs), associated with interferon beta treatments. [3][4][5][6][7][8] Peginterferon beta-1a is a pegylated form of interferon beta-1a approved for the treatment of relapsing forms of MS. The safety and efficacy of peginterferon beta-1a 125 μg administered subcutaneously every 2 or 4 weeks
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