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Background: Heterozygous mutations in the gene encoding progranulin (GRN) that lead to haploinsufficiency of the progranulin protein (PGRN) cause the fatal neurodegenerative disease frontotemporal dementia (FTD‐GRN). A promising treatment approach for FTD‐GRN is to restore PGRN to levels detected in healthy individuals. In pursuit of this objective, Arkuda Therapeutics is developing brain‐penetrant, orally bioavailable small molecules that increase PGRN levels within the central nervous system (CNS). Method: A functional cell‐based assay was utilized to identify novel compounds that stimulate PGRN secretion from a murine microglial cell line. Compounds with good in vitro potency were further optimized through an iterative series of selectivity, ADME, pharmacokinetic (PK), safety and pharmacology assessments. Result: When applied to cells, ARKD‐104 increased PGRN and PSAP secretion and engaged lysosomal pathways as evidenced by intracellular changes in granulins, saposins, and lysosomal lipids including bis(monoacylglycero)phosphate (BMP). Oral administration of ARKD‐104 to cynomolgus monkeys resulted in a dose and exposure‐dependent increase in PGRN measured in cerebrospinal fluid (CSF). The exposure‐response relationship demonstrated that a systemic exposure of 8 nM ARKD‐104 in plasma (unbound) doubled the amount PGRN in CSF. PGRN levels were further increased to more than 4‐times pre‐dose levels at the highest tested dose. Elevation of PGRN levels was sustained with repeat dosing of ARKD‐104. ARKD‐104 was characterized for CNS drug‐like properties including PK, metabolism, brain penetration, selectivity, and safety. In these assessments, ARKD‐104 demonstrated a profile suggesting that beneficial increases in PGRN can be achieved with once daily oral dosing in human. Conclusion: ARKD‐104 has excellent CNS drug‐like properties, increases PGRN in the CNS of non‐human primates and increases important cofactors of lysosomal enzymes,. ARKD‐104 is therefore a promising candidate for continued development as a treatment for FTD‐GRN, Parkinson's disease and other neurodegenerative disorders exhibiting lysosomal dysfunction. [ABSTRACT FROM AUTHOR]

Modeling of the random movement of fine sediment particles in open‐channel turbulent flow is mostly built upon the memoryless Brownian motion process. Such a process describes the chaotic behavior of small particles without considering temporal correlations in terms of the particle moving velocity and direction (i.e., memory). However, when particles are transported in time‐persistent turbulent flow, the movements of the suspended particles may exhibit persistency that depends on the various temporal durations of turbulent flow structures—such persistence results in direction and magnitude variations in the velocity of the fine moving particles. The diffusion property of the particles may then deviate from normal diffusion. The conventional memoryless random walk models may not provide a comprehensive description of the particle diffusion process for the duration of turbulence structures when the particles are subject to memory effects. In this study, a novel random walk model is proposed to present the temporal correlation of the suspended sediment particle velocity caused by turbulence structures in open channel flow. The probabilistic properties of the proposed model are discussed. In particular, enhanced physical insights are obtained regarding the particle diffusion behavior in turbulent flows. Numerical simulations are conducted to demonstrate that, similar to the conventional memoryless random walk models, the proposed model shows normal diffusion for long‐term observations, despite its local superdiffusion behavior. The effective diffusion coefficient of the proposed stochastic process on a long‐term time scale is formulated. Key Points: The temporal scale of turbulence structures is mathematically represented by considering the memory effect in a random walk modelThe diffusive particle behavior has a transition from superdiffusion to normal diffusion with an increase in the observation time scaleThe effective diffusion coefficient of the proposed stochastic process on a long‐term time scale is formulated [ABSTRACT FROM AUTHOR]

Background: Pathological and genetic evidence implicates toxic effects of aggregated α-synuclein in the pathophysiology of neuronal dysfunction and degeneration in Parkinson's disease. Immunotherapy targeting aggregated α-synuclein is a promising strategy for delaying disease progression.Objective: This study (NCT02459886) evaluated the safety, tolerability, and pharmacokinetics of BIIB054, a human-derived monoclonal antibody that preferentially binds to aggregated α-synuclein, in healthy volunteers and participants with Parkinson's disease.Methods: A total of 48 healthy volunteers (age 40-65, 19 women) and 18 Parkinson's disease participants (age 47-75, 5 women, Hoehn and Yahr stage ≤2.5) were in the study. Volunteers were enrolled into 6 single-dose cohorts of BIIB054 (range 1-135 mg/kg) or placebo, administered intravenously; Parkinson's disease participants received a single dose of BIIB054 (15 or 45 mg/kg) or placebo. All participants were evaluated for 16 weeks with clinical, neuroimaging, electrocardiogram, and laboratory assessments. Serum and cerebrospinal fluid BIIB054 concentrations were measured. BIIB054/α-synuclein complexes were measured in plasma.Results: Most adverse events were mild and assessed by investigators as unrelated to the study drug. Pharmacokinetic parameters for volunteers and the Parkinson's disease participants were similar. BIIB054 serum exposure and maximum concentrations were dose proportional during the dose range studied. In volunteers and the Parkinson's disease participants, the serum half-life of BIIB054 was 28 to 35 days; the cerebrospinal fluid-to-serum ratio ranged from 0.13% to 0.56%. The presence of BIIB054/α-synuclein complexes in plasma was confirmed; all Parkinson's disease participants showed almost complete saturation of the BIIB054/α-synuclein complex formation.Conclusions: BIIB054 has favorable safety, tolerability, and pharmacokinetic profiles in volunteers and Parkinson's disease participants, supporting further clinical development. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: In familial frontotemporal lobar degeneration (f‐FTLD), plasma levels of neurofilament light (NfL) are elevated at least two years prior to symptom onset and predict future clinical status. The Neurofilament Surveillance Project (NSP), an actively recruiting observational study, seeks to obtain higher resolution data of temporal changes in plasma NfL to better understand its clinical utility in f‐FTLD interventional trials. The NSP is a pre‐competitive collaboration sponsored by the Bluefield Project to Cure FTD and funded by biotechnology and pharmaceutical companies and nonprofit organizations. Method: Participants must be members of families with disease‐causing mutations in C9orf72, MAPT or GRN and enrolled in the ALLFTD natural history study. Up to 335 participants, with roughly equal representation across mutation type, provide plasma quarterly for 3 years (4355 samples total) to enable the observation of peripheral NfL levels longitudinally during disease onset and progression. Plasma is collected by certified mobile research nurses during remote visits, and NfL is measured in batch at least every 6 months. NfL measurements from one plasma aliquot per draw will be correlated with annual assessments obtained in the ALLFTD study, including measures of disease severity (CDRÒ+NACC‐FTLD, CGI, etc.), cognitive function from the UDS Neuropsychology Battery, and volumetric MRI data. Additional plasma aliquots are reserved for future analyses of other biomarkers during the course of the study; another subset of aliquots is reserved to share with interested investigators after the study ends. Result: As of 1/19/22, the NSP had enrolled 161 participants, including 62 from C9orf72 kindreds, 60 from MAPT kindreds, and 28 from GRN kindreds. One‐hundred forty‐five participants had completed their initial visit, and 109 had completed more than 3, and up to 5, quarterly blood draws. Enrollment and study visits are ongoing despite COVID‐related limitations. Conclusion: The quarterly blood sampling from this study, combined with annual comprehensive clinical assessments through the ALLFTD natural history study, will enable a more detailed understanding of when and how NfL levels change during phenoconversion and/or disease progression in f‐FTLD mutation carriers. These data will be especially informative in the context of the targeted investigational therapeutics for f‐FTLD now entering clinical trials. [ABSTRACT FROM AUTHOR]

Background: Subcutaneous peginterferon beta-1a has previously been shown to reduce the number of T2-hyperintense and gadolinium-enhancing (Gd+) lesions over 2 years in patients with relapsing-remitting multiple sclerosis (RRMS), and to reduce T1-hypointense lesion formation and the proportion of patients showing evidence of disease activity, based on both clinical and radiological measures, compared with placebo over 1 year of treatment. The objectives of the current analyses were to evaluate T1 lesions and other magnetic resonance imaging (MRI) measures, including whole brain volume and magnetization transfer ratio (MTR) of normal appearing brain tissue (NABT), and the proportions of patients with no evidence of disease activity (NEDA), over 2 years.Methods: Patients enrolled in the ADVANCE study received continuous peginterferon beta-1a every 2 or 4 weeks for 2 years, or delayed treatment (placebo in Year 1; peginterferon beta-1a every 2 or 4 weeks in Year 2). MRI scans were performed at baseline and Weeks 24, 48, and 96. Proportions of patients with NEDA were calculated based on radiological criteria (absence of Gd + and new/newly-enlarging T2 lesions) and clinical criteria (no relapse or confirmed disability progression) separately and overall.Results: Peginterferon beta-1a every 2 weeks significantly reduced the number and volume of T1-hypointense lesions compared with delayed treatment over 2 years. Changes in whole brain volume and MTR of NABT were suggestive of pseudoatrophy during the first 6 months of peginterferon beta-1a treatment, which subsequently began to resolve. Significantly more patients in the peginterferon beta-1a every 2 weeks group compared with the delayed treatment group met MRI-NEDA criteria (41% vs 21%; odds ratio [OR] 2.56; p < 0.0001), clinical-NEDA criteria (71% vs 57%; OR 1.90; p < 0.0001) and achieved overall-NEDA (37% vs 16%; OR 3.09; p < 0.0001).Conclusion: Peginterferon beta-1a provides significant improvements in MRI measures and offers patients a good chance of remaining free from evidence of MRI, clinical and overall disease activity over a sustained 2-year period.Trial Registration: ClinicalTrials.gov: NCT00906399 ; Registered on: May 20, 2009. [ABSTRACT FROM AUTHOR]

Background: Efficacy of interferon beta in multiple sclerosis (MS) can be dampened in patients who develop neutralizing antidrug antibodies (NAbs). Peginterferon beta1a is an interferon conjugated with a polyethylene glycol (PEG) moiety. Pegylation increases a drug’s half life and exposure, and may also reduce immunogenicity. Objective: The objective of this study was to characterize the incidence and impact of immunogenicity to peginterferon beta1a over 2 years in patients with MS. Methods: Patients with relapsing–remitting MS (N = 1512) were randomized to subcutaneous peginterferon beta1a 125 μg every 2 or 4 weeks, or placebo, for 1 year; patients in the placebo group were rerandomized to active treatment in year 2. The incidence and titers of binding antibodies (BAbs) and NAbs to interferon and antibodies to PEG (anti-PEG) were assessed in analytically validated assays. The clinical impact of immunogenicity on relapse and magnetic resonance imaging endpoints was evaluated. Results: Over 2 years, 6%, less than 1%, and 7% of patients developed anti-interferon BAbs, NAbs, and anti-PEG antibodies, respectively. There was no discernible clinically meaningful effect of antibody status on the pharmacodynamic, efficacy, or safety parameters evaluated, although these analyses were limited by the low incidence of treatment-emergent antibodies. Conclusion: The treatment effect of peginterferon beta1a in patients with relapsing–remitting MS is not expected to be attenuated by immunogenicity. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy and safety of subcutaneous peginterferon beta-1a over 2 years in patients with relapsing-remitting multiple sclerosis in the ADVANCE study. Methods: Patients were randomized to placebo or 125 μg peginterferon beta-1a every 2 or 4 weeks. For Year 2 (Y2), patients originally randomized to placebo were re-randomized to peginterferon beta-1a every 2 weeks or every 4 weeks. Patients randomized to peginterferon beta-1a in Year 1 (Y1) remained on the same dosing regimen in Y2. Results: Compared with Y1, annualized relapse rate (ARR) was further reduced in Y2 with every 2 week dosing (Y1: 0.230 [95% CI 0.183-0.291], Y2: 0.178 [0.136-0.233]) and maintained with every 4 week dosing (Y1: 0.286 [0.231-0.355], Y2: 0.291 [0.231-0.368]). Patients starting peginterferon beta-1a from Y1 displayed improved efficacy versus patients initially assigned placebo, with reductions in ARR (every 2 weeks: 37%, p<0.0001; every 4 weeks: 17%, p=0.0906), risk of relapse (every 2 weeks: 39%, p<0.0001; every 4 weeks: 19%, p=0.0465), 12-week disability progression (every 2 weeks: 33%, p=0.0257; every 4 weeks: 25%, p=0.0960), and 24-week disability progression (every 2 weeks: 41%, p=0.0137; every 4 weeks: 9%, p=0.6243). Over 2 years, greater reductions were observed with every 2 week versus every 4 week dosing for all endpoints and peginterferon beta-1a was well tolerated. Conclusions: Peginterferon beta-1a efficacy is maintained beyond 1 year, with greater effects observed with every 2 week versus every 4 week dosing, and a similar safety profile to Y1. Clinicaltrials.gov Registration Number: NCT00906399. [ABSTRACT FROM AUTHOR]

Objective: Painful legs and moving toes (PLMT) is a syndrome consisting of pain in the lower legs with involuntary movements of the toes or feet. Its incidence and prevalence remain largely unknown since it is still a relatively rare disorder. We are reporting a case of PLMT along with the first review ofliterature on all previously reported cases and a discussion on its clinical management. Methods: A review of published literature on PLMT was done using MEDLINE and PubMed databases. Searches were conducted to find articles from 1971 – 2010. Medical subject headings used to search the databases included PLMT with subheadings of painful legs/moving toes, electromyography, polysomnography, as well as keyword search using "PLMT". Single author reviewed titles and abstracts of potentially relevant articles. Results: We reviewed approximately 19 PLMT articles that have been published to date, with a total of 72 patients: 30.5% males and 69.5% females (median age 55 & 64 yrs, respectively). The most common predisposing conditions were neuropathy and radiculopathy. Numerous treatments including antiepileptics, benzodiazepines, antispasmodic agents, and antidepressants have been tried with little success. GABAergic agents such as gabapentin and pregabalin were the most effective in attenuating the pain and the movements, possibly via both central and peripheral mechanisms. Conclusion: Physicians should be aware of this rare debilitating condition. Though much progress has been made in elucidating its etiology, the exact mechanism still remains a mystery. It is important to consider PLMT in a patient with painful legs and/or restless leg syndrome without any significant history of neurological disease or trauma. Diagnosis is essentially clinical and treatment is complex, which includes different combinations of medications and invasive techniques that generally produce a poor outcome. [ABSTRACT FROM AUTHOR]

The article offers information on the palliative care for patients with Huntington's disease (HD). It says that HD's symptoms include progressive dementia, inability to talk and care for themselves that may result to complications including chronic infections, falls, and cardiovascular disease. It also states the supportive care services for HD patients such as motor manifestations and cognitive deficits. Moreover, it suggests hospice services for advanced disease patients.

Background: Subcutaneous peginterferon beta-1a provided clinical benefits at Year 1 (placebo-controlled period) of the 2-Year Phase 3 ADVANCE study in relapsing-remitting multiple sclerosis (RRMS). Here we report the effect of peginterferon beta-1a on brain magnetic resonance imaging (MRI) lesions, and no evidence of disease activity (NEDA; absence of clinical [relapses and 12-week confirmed disability progression] and MRI [gadolinium-enhancing, and new or newly-enlarging T2 hyperintense lesions] disease activity) during Year 1.Methods: RRMS patients (18-65 years; Expanded Disability Status Scale score ≤5) were randomized to double-blind placebo or peginterferon beta-1a 125 μg every 2 or 4 weeks. Sensitivity analyses of last observation carried forward and composite disease activity (using minimal MRI allowance definitions) were conducted.Results: 1512 patients were randomized and dosed (placebo n = 500; peginterferon beta-1a every 2 [n = 512] or 4 [n = 500] weeks). Every 2 week dosing significantly reduced, versus placebo and every 4 week dosing, the number of new or newly-enlarging T2 hyperintense lesions at Weeks 24 (by 61% and 51%, respectively) and 48 (secondary endpoint; by 67% and 54%, respectively); all p < 0.0001. Every 2 week dosing also provided significant reductions versus placebo and every 4 week dosing in the number of new T1 hypointense, gadolinium-enhancing, and new active (gadolinium-enhancing plus non-enhancing new T2) lesions (all p < 0.0001), as well as the volume of T2 and T1 lesions (p < 0.05) at Weeks 24 and 48. Significantly more patients dosed every 2 weeks had NEDA versus placebo and every 4 weeks (all p < 0.01) from baseline to Week 48 (33.9% versus 15.1% and 21.5%, respectively [odds ratios, ORs: 2.89 and 1.87]), from baseline to Week 24 (41.0% versus 21.9% and 30.7%, [ORs: 2.47 and 1.57]) and from Week 24 to Week 48 (60.2% versus 28.9% and 36.6%, [ORs: 3.71 and 2.62]). Consistent results were seen when allowing for minimal MRI activity.Conclusion: During Year 1 of ADVANCE, significantly more RRMS patients receiving peginterferon beta-1a every 2 weeks had NEDA, and early and sustained improvements in all MRI endpoints, versus placebo and every 4 week dosing. NEDA sensitivity analyses align with switch strategies in clinical practice settings and provide insight into future responders/non-responders.Trial Registration: ClinicalTrials.gov: NCT00906399. [ABSTRACT FROM AUTHOR]

Background: The huntingtin gene ( HTT ) pathogenic cytosine-adenine-guanine (CAG) repeat expansion responsible for Huntington disease (HD) is phased with single nucleotide polymorphisms (SNPs), providing targets for allele-selective treatments., Objective: This prospective observational study defined the frequency at which rs362307 (SNP1) or rs362331 (SNP2) was found on the same allele with pathogenic CAG expansions., Methods: Across 7 US sites, 202 individuals with HD provided blood samples that were processed centrally to determine the number and size of CAG repeats, presence and heterozygosity of SNPs, and whether SNPs were present on the mutant HTT allele using long-read sequencing and phasing., Results: Heterozygosity of SNP1 and/or SNP2 was identified in 146 (72%) individuals. The 2 polymorphisms were associated only with the m HTT allele in 61% (95% high density interval: 55%, 67%) of individuals., Conclusions: These results are consistent with previous reports and demonstrate the feasibility of genotyping, phasing, and targeting of HTT SNPs for personalized treatment of HD., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: ADVANCE was a phase III trial of the efficacy and safety of subcutaneous peginterferon beta-1a 125 µg every 2 or 4 weeks in patients with relapsing-remitting multiple sclerosis (RRMS). ATTAIN was a 2-year extension study of ADVANCE. The aim was to evaluate the long-term safety, tolerability, and efficacy of peginterferon beta-1a 125 µg every 2 or 4 weeks in ATTAIN., Methods: ADVANCE dosing schedules were maintained in ATTAIN, except that every-4-weeks dosing patients were switched to every-2-weeks dosing after conversion of the study to an open-label protocol. ATTAIN was considered complete when the last patient completed the 96-week extension study. Primary endpoints included adverse event (AE) and serious AE (SAE) incidence. Secondary endpoints included relapse, magnetic resonance imaging, and disability outcomes., Results: Of the 1512 patients randomized in ADVANCE, 1076 (71%) continued treatment in ATTAIN; of these, 842 (78%) completed the open-label extension study. During ATTAIN, 478 patients (87%) in the every-2-weeks group and 471 patients (89%) in the every-4-weeks group experienced an AE; SAEs were reported in 90 patients (16%) in the every-2-weeks group and 113 patients (21%) in the every-4-weeks group. The most frequent AEs reported were injection site reactions and flu-like symptoms, both of which numerically decreased over time. Peginterferon beta-1a every 2 weeks versus every 4 weeks significantly reduced the adjusted annualized relapse rate over 6 years (0.188 versus 0.263, p = 0.0052) and the risk of relapse over 5 years (36% versus 49%, p = 0.0018). Fewer new T1, new/newly enlarging T2, and gadolinium-enhancing magnetic resonance imaging lesions were observed with every-2-weeks dosing than every-4-weeks dosing over 4 years., Conclusions: Results from the ADVANCE extension study, ATTAIN, confirm the favorable long-term safety and tolerability profile of peginterferon beta-1a in patients with RRMS and provide additional evidence for the clinical and radiological benefits associated with this therapy., Competing Interests: Conflict of interest statement: SDN has received research support (paid directly to institution) from Biogen, Genentech, the National MS Society, and Novartis, and has participated in scientific advisory boards for Biogen and Genentech. TFS has received research support from Biogen and Novartis and has received honoraria for participation in scientific advisory boards and speaking from Acorda Therapeutics, Biogen, Genentech, Genzyme, Novartis, and Teva Neurosciences. DLA reports an equity interest in NeuroRx during the conduct of the study and personal fees from Acorda, Biogen, EMD Serono, Genentech, Genzyme, Hoffman-La Roche, Innate Immunotherapy, MedImmune, Mitsubishi, Novartis, Receptos, Sanofi-Aventis, and Teva outside the submitted work, as well as grants from Biogen and Novartis. GN has participated in scientific advisory boards for Bayer HealthCare, Biogen, Genzyme, and Merck, and received personal compensation for speaking activities from Bayer HealthCare, Biogen, Genzyme, Merck, Novartis, and Teva. SH, YC, and SS were full-time employees of Biogen and holders of Biogen stock and/or stock options at the time of the analysis. MLN is a full-time employee of Biogen and holder of Biogen stock and/or stock options. MK has received research grants, research support, and personal compensation for consulting or speaking activities from Biogen, the Canadian Institute of Health Research, Genzyme, the MS Society of Canada, Novartis, Sanofi, Teva, and Wellesley Therapeutics. MK’s institution has received research grants from Biogen and the Canadian Institute of Health Research and research support from the Chapman Chair in MS Clinical Research at London Health Sciences Centre.

Background: In the pivotal phase III 2-year ADVANCE study, subcutaneous peginterferon beta-1a 125 mcg every 2 weeks demonstrated significant improvements in clinical outcomes, including disability endpoints, in patients with relapsing-remitting multiple sclerosis (RRMS). Here, we aim to further evaluate disability data from ADVANCE, and explore associations between confirmed disability progression (CDP), functional status, and health-related quality of life (HRQoL)., Methods: In total, 1512 patients were randomized to placebo or peginterferon beta-1a 125 mcg every 2 or 4 weeks. After 1 year, patients on placebo were re-randomized to peginterferon beta-1a every 2 or 4 weeks. CDP was defined as ⩾1.0 point increase from a baseline Expanded Disability Status Scale (EDSS) score ⩾ 1.0, or ⩾1.5-point increase from baseline 0, confirmed 12 or 24 weeks after onset., Results: Peginterferon beta-1a every 2 weeks significantly reduced risk of 12- and 24-week CDP at 1 year compared with placebo (12-week CDP: 6.8% versus 10.5%, p = 0.038; 24-week CDP: 4% versus 8.4%, p = 0.0069, peginterferon beta-1a every 2 weeks versus placebo, respectively). Benefits were maintained over 2 years (11.2% and 7.7%, peginterferon beta-1a every 2 weeks in 12- and 24-week CDP, respectively). Approximately 90% of patients with 24-week CDP had simultaneous worsening by ⩾1 point in at least one functional system score, most commonly pyramidal. Displaying a 24-week CDP was associated with worse scores on the Multiple Sclerosis Functional Composite (MSFC) scale and several HRQoL instruments; the impact of CDP was attenuated by treatment with peginterferon beta-1a every 2 weeks., Conclusions: Peginterferon beta-1a has the potential to prevent/delay worsening of disability in patients with relapsing-remitting multiple sclerosis. Furthermore, improved benefits in disability status with peginterferon beta-1a were also associated with improved functional status and HRQoL [ClinicalTrials.gov identifier: NCT00906399]., Competing Interests: Conflict of interest statement: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: SDN has participated in scientific advisory boards for Biogen, Genzyme, and Novartis, and has received research support from Biogen, Novartis, and the National MS Society. BCK was not affiliated to Biogen at the time of study conduct and data analysis, but is now an employee and stock holder of Biogen. SL, XY, EK, SH, and BS are employees and stockholders of Biogen.

Background: Subcutaneous peginterferon beta-1a every 2 weeks significantly affects clinical outcomes in patients with relapsing-remitting multiple sclerosis (RRMS)., Objectives: To explore relationships between relapses and worsening of disability in patients with RRMS, and assess the treatment effect of peginterferon beta-1a on relapse recovery., Methods: Post-hoc analysis of the 2-year, randomized, double-blind, parallel-group, Phase 3 ADVANCE study. The severity of relapses, proportion of patients with relapses associated with residual disability (onset of 24-week confirmed disability progression (CDP) within 90 days following a relapse), and persistence of changes in Functional Systems Scores, were compared between treatment groups., Results: Subcutaneous peginterferon beta-1a every 2 weeks significantly reduced the proportion of patients experiencing relapse associated with CDP over 2 years (6.6%, compared with 15.1% of patients who received placebo in Year 1; p  = 0.02). Reduction in relapses associated with residual disability was greater than the treatment effect on overall relapse rate, and occurred despite similar relapse severity across treatment groups., Conclusions: The beneficial effect of peginterferon beta-1a on risk of CDP may be attributable to the combination of an overall reduction in the risk of relapses and improvement in recovery from relapses, thus limiting further disability progression., Trial Registration: ClinicalTrials.gov identifier: NCT00906399.

Objective: To evaluate the efficacy and safety of subcutaneous peginterferon beta-1a over 2 years in patients with relapsing-remitting multiple sclerosis in the ADVANCE study., Methods: Patients were randomized to placebo or 125 µg peginterferon beta-1a every 2 or 4 weeks. For Year 2 (Y2), patients originally randomized to placebo were re-randomized to peginterferon beta-1a every 2 weeks or every 4 weeks. Patients randomized to peginterferon beta-1a in Year 1 (Y1) remained on the same dosing regimen in Y2., Results: Compared with Y1, annualized relapse rate (ARR) was further reduced in Y2 with every 2 week dosing (Y1: 0.230 [95% CI 0.183-0.291], Y2: 0.178 [0.136-0.233]) and maintained with every 4 week dosing (Y1: 0.286 [0.231-0.355], Y2: 0.291 [0.231-0.368]). Patients starting peginterferon beta-1a from Y1 displayed improved efficacy versus patients initially assigned placebo, with reductions in ARR (every 2 weeks: 37%, p<0.0001; every 4 weeks: 17%, p=0.0906), risk of relapse (every 2 weeks: 39%, p<0.0001; every 4 weeks: 19%, p=0.0465), 12-week disability progression (every 2 weeks: 33%, p=0.0257; every 4 weeks: 25%, p=0.0960), and 24-week disability progression (every 2 weeks: 41%, p=0.0137; every 4 weeks: 9%, p=0.6243). Over 2 years, greater reductions were observed with every 2 week versus every 4 week dosing for all endpoints and peginterferon beta-1a was well tolerated., Conclusions: Peginterferon beta-1a efficacy is maintained beyond 1 year, with greater effects observed with every 2 week versus every 4 week dosing, and a similar safety profile to Y1.Clinicaltrials.gov, Registration Number: NCT00906399., (© The Author(s), 2015.)

Objectives: A sub-study to evaluate safety, tolerability, ease-of-use and patient satisfaction with a single-use autoinjector administering subcutaneous peginterferon-β1a (a pegylated interferon-β1a in clinical development) in a subset of relapsing-remitting multiple sclerosis (MS) patients participating in ATTAIN, a long-term dose-frequency blinded extension of the Phase III randomized ADVANCE study., Methods: Over 8 weeks, patients self-administered peginterferon-β1a 125 µg or placebo every 2 weeks (two injections via manual pre-filled syringe [PFS]; two injections via single-use autoinjector). Primary end points were incidence of adverse events (AEs), patient assessment of injection pain score (10-point Visual Analog Scale), and clinician assessment of injection site reactions (ISRs). Secondary objectives included patient assessment of ease-of-use and satisfaction with the autoinjector and evaluation of autoinjector training materials., Results: In 39 patients, the safety profile of peginterferon-β1a was similar when delivered via autoinjector or PFS; AEs were mostly mild or moderate in severity. Clinicians and patients reported a similar tolerability profile using both PFS and autoinjector, and pain scores were low (< 1), with no reports of clinician-assessed ISRs after administration with the autoinjector. Patients perceived the single-use autoinjector to be easy to use and convenient; overall patient satisfaction with the autoinjector and accompanying training materials was high., Conclusion: The safety and tolerability profile of peginterferon-β1a delivered via autoinjector was similar to delivery via PFS. Patients found the autoinjector easy to use and convenient; this device may simplify the injection process for MS patients who require long-term therapy, thereby potentially improving patient's quality of life and adherence.