Biogen Research Articles

Updated Follow-up of the Alta Study, a Phase 1/2 Study of Giroctocogene Fitelparvovec (SB-525) Gene Therapy in Adults with Severe Hemophilia a

Updated Follow-up of the Alta Study, a Phase 1/2 Study of Giroctocogene Fitelparvovec (SB-525) Gene Therapy in Adults with Severe Hemophilia a

Associations of DMT Therapies with COVID-19 Severity in Multiple Sclerosis: An International Cohort Study

Associations of DMT Therapies with COVID-19 Severity in Multiple Sclerosis: An International Cohort Study

Parkinson's Disease Symptoms Have a Distinct Impact on Caregivers' and Patients' Stress: A Study Assessing the Consequences of the COVID-19 Lockdown.

Parkinson's Disease Symptoms Have a Distinct Impact on Caregivers' and Patients' Stress: A Study Assessing the Consequences of the COVID-19 Lockdown.

Biogen licenses Denali’s LRRK2 inhibitors

Biogen is committing over $1 billion—$560 million in cash and $465 million in equity—to Denali Therapeutics as part of a Parkinson’s disease partnership. The deal, meant to reduce Biogen’s reliance...

Disease Modifying Therapies and COVID-19 Severity in Multiple Sclerosis

Background: Immunosuppressive and immunomodulatory therapies are a major issue during the current coronavirus disease 2019 (Covid-19) pandemic, and in anticipation of possible next waves. Methods: In a nationwide study we retrospectively collected data of persons with Multiple Sclerosis (PwMS) with suspected or confirmed Covid-19. We assessed the association of therapies for MS with Covid-19 by comparing their observed frequency with the one expected in non-pandemic conditions (expressing the association by Odds Ratios [OR]). We evaluated baseline characteristics and MS therapies associated to a severe Covid-19 course by multivariate logistic models. Findings: Of 784 PwMS with suspected (n=593) or confirmed (n=191) Covid-19 and a median follow-up of 84 days (range=30-135), 13 (1·66%) died: 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-three (4·2%) were admitted to an Intensive Care Unit; 90 (11·5%) had a radiologically documented pneumonia; 88 (11·2%) were hospitalized. We found an excess of patients treated with Ocrelizumab (OR=1·84,95%CI=1·31-2·56, pInterpretation: This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, the study detected elements of risk and protection with respect to Covid-19 in MS. These will need to be considered in countries where the pandemic is persisting and in preparation for post-pandemic scenarios. Funding: Roche donated the web-Platform and funded a fellowship to the University of Genoa.Declaration of Interests: MP. Sormani reports grants from Roche, during the conduct of the study; personal fees from Biogen, Merck, Roche, Sanofi, Novartis, Medday, Geneuro, Celgene, Mylan outside the submitted work. N. DeRossi received speaker honoraria from Biogen Idec, Genzyme, Novartis, Sanofi-Aventis; received funding for participation in advisory board to Novartis, Biogen and Genzyme-Sanofi and for travel to scientific meetings from Biogen Idec, Teva, Sanofi-Genzyme, Roche, Almirall and Novartis. L. Moiola has received speaker’s honoraria from the following companies: Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, and TEVA. M. Radaelli received speaker honoraria from Biogen Idec, Sanofi-Genzyme ,Novartis and Merck Serono and funding for travel to scientific meetings from Biogen Idec, Sanofi-Genzyme, Novartis, Merck Serono, Teva and Roche. P. Immovilli reports personal fees from Roche, personal fees from Biogen, personal fees from Merck, outside the submitted work. M. Capobianco reports personal fees and non-financial support from Biogen, personal fees and non-financial support from Merck Serono, personal fees and non-financial support from Roche, personal fees and non-financial support from Novartis, personal fees and non-financial support from Sanofi, personal fees from Almirall, outside the submitted work. M. Trojano reports grants and personal fees from Biogen, grants and personal fees from Novartis, grants and personal fees from Roche, grants and personal fees from Merck, personal fees from Sanofi, personal fees from TEVA, from null, outside the submitted work. G. Comi reports personal fees from Novartis, Teva Pharmaceutical Industries Ltd, Teva Italia Srl, Sanofi Genzyme, Genzyme Corporation, Genzyme Europe, Merck KGgA, Merck Serono SpA, Celgene Group, Biogen Idec, Biogen Italia Srl, F. Hoffman-La Roche, Roche SpA, Almirall SpA, Forward Pharma, Medday, Excemed, outside the submitted work. F. Patti reports grants from Biogen, grants from Merck, grants from FISM, grants from Onlus association, grants from University of Catania, personal fees from Almirall, personal fees from Bayer, personal fees from Biogen, personal fees from Merck, personal fees from Roche, personal fees from Sanofi, personal fees from TEVA, outside the submitted work. M. Salvetti reports grants and personal fees from Biogen, grants and personal fees from Merck, grants and personal fees from Novartis, grants and personal fees from Roche, grants and personal fees from Sanofi, grants and personal fees from Teva, grants from Italian Multiple Sclerosis Foundation, grants from Sapienza University of Rome, outside the submitted work. IS, LC, CC, PZ, GT, MAB have nothing to disclose.Ethics Approval Statement: The study was approved by the Regional Ethics Committee of Liguria (University of Genoa) (n 130/2020 – DB id 10433) and at a national level by Agenzia Italiana del Farmaco (AIFA).

THU0192 UPADACITINIB TREATMENT AND THE ROUTINE ASSESSMENT OF PATIENT INDEX DATA 3 (RAPID3) AMONG PATIENTS WITH RHEUMATOID ARTHRITIS

Background: Upadacitinib (UPA) is an oral reversible JAK inhibitor engineered for greater selectivity for JAK1 vs JAK2, JAK3, and TYK2, and is currently being assessed for the treatment of RA. RAPID3 is a pooled index of the three key patient-reported measures: patient global assessment, pain, and physical function. Objectives: In this analysis we assessed the effect of UPA treatment on RAPID3 in the SELECT-BEYOND, SELECT-COMPARE, and SELECT-MONOTHERAPY trials. Methods: In SELECT-BEYOND1, bDMARD-IR pts received UPA 15 mg or 30 mg once daily (QD), or PBO for 12 wks while continuing stable csDMARD therapy. In SELECT-COMPARE2, MTX-IR pts received UPA 15 mg QD, PBO, or ADA 40 mg every 2 wks for 12 wks while continuing MTX. In SELECT-MONOTHERAPY3, pts received UPA monotherapy 15 mg or 30 mg QD, or continued MTX monotherapy (cMTX) for 14 wks. We assessed the least squares mean changes from baseline (BL) in RAPID3 and the proportion of pts reporting RAPID3 remission (≤3), low (LDA, >3 to ≤6), moderate (MDA, >6 to ≤12), and high disease activity (HDA, >12). Correlations between RAPID3 remission and remissions defined by CDAI, SDAI, and DAS28(CRP) were also assessed using Pearson correlation coefficients. Non-responder imputation was used for categorical endpoints, and last observation carried forward for continuous endpoints in pts who received rescue therapy in SELECT-COMPARE. Other continuous data are as observed. Data were analyzed descriptively. Results: 498, 648, and 1629 pts were randomized in SELECT-BEYOND, -MONOTHERAPY, and -COMPARE, respectively. Numerically higher improvements from BL in RAPID3 were reported with UPA 15 mg and 30 mg treatment vs PBO in SELECT-BEYOND, and vs cMTX in SELECT-MONOTHERAPY (Table). UPA 15 mg QD was also associated with greater reductions from baseline in RAPID3 vs PBO and ADA in SELECT-COMPARE (Table). Of note, the improvements in RAPID3 with UPA and ADA exceeded the minimal clinically important difference (MCID = 3.84). The proportions of pts achieving RAPID3 remission were numerically higher in the UPA 15 mg and 30 mg groups vs PBO and cMTX in SELECT-BEYOND and SELECT-MONOTHERAPY, respectively (Figure). In addition, the proportions of pts in RAPID3 HDA were lower with UPA vs PBO and cMTX in these trials. In SELECT-COMPARE, higher rates of RAPID3 remission, with fewer pts in HDA, were evident with UPA 15 mg treatment vs PBO and ADA (Figure). Correlations between RAPID3 and other remission endpoints were significant (p Conclusion: UPA was associated with improvements in RAPID3, both as monotherapy and in combination, in MTX-IR (SELECT-COMPARE and SELECT-MONOTHERAPY) or bDMARD-IR (SELECT-BEYOND) pts. UPA treatment can result in improved patient-reported disease activity, pain, and physical function in RA. Disclosure of Interests: Martin Bergman Shareholder of: Johnson & Johnson – stockholder, Consultant of: AbbVie, BMS, Celgene Corporation, Genentech, Janssen, Merck, Novartis, Pfizer, Sanofi – consultant, Speakers bureau: AbbVie, Celgene Corporation, Novartis, Pfizer, Sanofi – speakers bureau, Yoshiya Tanaka Grant/research support from: Asahi-kasei, Astellas, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, Pfizer, and Ono, Consultant of: Abbvie, Astellas, Bristol-Myers Squibb, Eli Lilly, Pfizer, Speakers bureau: Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Sanofi, UCB, and Teijin, Gustavo Citera Grant/research support from: AbbVie, Amgen, Eli Lilly, Gema, Genzyme, Novartis and Pfizer Inc, Consultant of: AbbVie, Amgen, Eli Lilly, Gema, Genzyme, Novartis and Pfizer Inc, Sami Bahlas: None declared, Mira Ali Shareholder of: AbbVie, Employee of: AbbVie, Sebastian Meerwein Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Yanna Song Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Vibeke Strand Consultant of: AbbVie, Amgen, Biogen, Celltrion, Consortium of Rheumatology Researchers of North America, Crescendo Bioscience, Eli Lilly, Genentech/Roche, GlaxoSmithKline, Hospira, Janssen, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi, UCB

THU0165 PROSARA - A PROSPECTIVE, MULTICENTER, NON-INTERVENTIONAL STUDY TO EVALUATE THE SAFETY AND EFFECTIVENESS OF SARILUMAB FOR THE TREATMENT OF ACTIVE RHEUMATOID ARTHRITIS IN REGULAR CARE IN GERMANY

Background: Blockade of IL-6 signaling by sarilumab has been demonstrated to be an effective treatment approach for rheumatoid arthritis. Due to strict inclusion and exclusion criteria, randomized controlled trials may not represent the heterogeneous RA patient population encountered in regular care. Objectives: The current study investigated the safety and effectiveness of sarilumab in the treatment of RA in regular care in Germany. Methods: The prospective, observational, single-arm 24-months PROSARA study (SARILL08661) is currently running in Germany at 79 sites, aiming to include up to 750 RA patients treated with sarilumab. RA patients are selected at physician discretion and treated according to the label. Study objectives include the documentation of safety and various effectiveness outcomes. This interim analysis included patients with data available up to 12 weeks. All analyses are descriptive only. Results: To date 348 patients were included in the study; of which 265 patients had post-baseline data. The mean age of the patients analyzed was 58.6 years (24-83); 76.3% are female. The mean disease duration was 10.3 years; comorbidities were present in 80.7% of patients. At baseline, 32.5% were biologic naive. Most common pretreatment with b/ts DMARDs included TNF-inhibitors (TNFi, 56.2%), non-TNFi biologics (29.1%) or JAK-inhibitors (JAKi, 17.4%). At baseline, 49% received sarilumab as monotherapy and 29% in combination with conventional DMARDs (not specified for 22%). After 12 weeks of treatment with sarilumab, the mean DAS28-ESR decreased from 5.0±1.46 to 3.0±1.44 and CDAI from 26.7±13.79 to 13.6±11.4, respectively. DAS28-ESR remission/ low disease activity was achieved in 42.8% [n=77/180 patients with valid data on this parameter]/ 59.4% [n=107/180] of patients; 13.6% [n=28/206] and 49% [n=101/206] of patients reached CDAI remission and low disease activity. Boolean remission was observed in 9.5% [n=19/201] of patients at week 12. HAQ-DI improved from 1.3 at baseline to 1.1 at week 12 (n=195). The mean CDAI improvement was similar for autoantibody-positive (RF and/or ACPA; CDAI -12.5 at week 12) compared to -negative patients (CDAI -15.4 at week 12). Patients switching from JAKi to sarilumab (n=32), were more severely affected, had longer disease duration and received more prior treatments than patients switched from another compound. Of note, similar efficacy was observed among patients that switched from JAKi to sarilumab vs patients switched from other DMARDs; disease activity outcome measures including DAS28, CDAI, TJC, SJC and global assessments improved consistently (Figure 1). Safety was consistent with the anticipated profile of IL-6-R-inhibition and no new safety signals occurred. Adverse events and serious adverse events were described in 33.9% and 6.3% of patients, respectively. Conclusion: Sarilumab administered in regular care demonstrated rapid and clinically meaningful improvement in a general RA patient population including patients switching from JAKi. The safety profile was consistent with data reported from controlled clinical trials. Disclosure of Interests: Eugen Feist Consultant of: Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Sanofi, Speakers bureau: Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Sanofi, Peer-Malte Aries Consultant of: Sanofi, Speakers bureau: Sanofi, Silke Zinke: None declared, Harald Burkhardt Grant/research support from: Pfizer, Roche, Abbvie, Consultant of: Sanofi, Pfizer, Roche, Abbvie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scripps, Janssen, and Novartis, Speakers bureau: Sanofi, Pfizer, Roche, Abbvie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scripps, Janssen, and Novartis, Inka Albrecht Employee of: Sanofi, Oliver Bley Employee of: Sanofi, Michael Obermeier: None declared, Patrizia Sternad: None declared, Martin Welcker Grant/research support from: Abbvie, Novartis, UCB, Hexal, BMS, Lilly, Roche, Celgene, Sanofi, Consultant of: Abbvie, Actelion, Aescu, Amgen, Celgene, Hexal, Janssen, Medac, Novartis, Pfizer, Sanofi, UCB, Speakers bureau: Abbvie, Aescu, Amgen, Biogen, Berlin Chemie, Celgene, GSK, Hexal, Mylan, Novartis, Pfizer, UCB, Cornelia Kuhne Grant/research support from: Novartis, Amgen, Roche/Chugai, Pfizer, Celgene, AbbVie, Sanofi, Ann-Dorthe Holst: None declared, Niklas Thomas Baerlecken: None declared, Hans-Peter Tony Consultant of: AbbVie, Astra-Zeneca, BMS, Chugai, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi

THU0135 PATIENT GLOBAL ASSESSMENT LEVELS PRECLUDE THE MAJORITY OF RHEUMATOID ARTHRITIS PATIENTS OTHERWISE IN REMISSION, FROM REACHING THIS STATUS: SYSTEMATIC LITERATURE REVIEW AND META-ANALYSES INCLUDING 23,297 PATIENTS

Background: Based on the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean-based remission definition for rheumatoid arthritis (RA), the main reason for near-misses (failing Boolean remission solely due to one criterion >1) is a patient global assessment (PGA) >1/10.1-3 The frequency of this PGA-near-remission status has not been well established. Objectives: To synthesize the overall prevalence of ACR/EULAR Boolean-based remission and PGA-near-remission cross-sectionally in published studies, and to explore association with disease duration. Methods: We systematically searched PubMed database (from 1/jan/2011 till 15/jan/2020) for “Rheumatoid arthritis” AND Boolean [OR synonyms] AND PGA [OR synonyms], and carried out a hand search of the references of the included studies. Two reviewers independently assessed the study inclusion and extracted the data (n (%) of patients in each remission status, mean (SD) disease duration, and country/city). Studies were excluded if any of the four Boolean criterion was not considered (e.g. C-Reactive Protein not assessed), or if only patients with low disease activity or remission were selected. If different time assessments were provided, we selected the 1y follow-up, as the most common. Random effects meta-analyses of proportions with double arcsine transformation were performed (also by disease duration subgroups) using MEDCALC®. Heterogeneity was assessed by I2. Results: From 41 studies identified, 8 studies concerning 12 subsamples were analysed (n=23,297 patients; of which 22% had ≤2 years mean disease duration). The overall prevalence of Boolean remission was 12% (95%CI: 10-15%, p Conclusion: The overall prevalence of PGA-near-remission in patients with RA followed in clinical practice was 1/3 more prevalent than Boolean remission, a difference more pronounced in patients with established disease. Overall, over 61% of all RA patients otherwise in remission failed to satisfy the Boolean definition of remission solely due to a PGA>1. The use of PGA in the definition of treatment target exposes a substantial proportion of patients to the risk of overtreatment with immunosuppressive agents, while being deprived of the adjunctive therapy they probably need.

1122 Sleep Architecture and Leg Movement Activity During Sleep in Patients with Multiple Sclerosis

Abstract Introduction Although sleep in patients with Multiple Sclerosis (MS) has been investigated in several studies using subjective measures, objective sleep data collected using polysomnography (PSG) are still scanty and often divergent. We herein present the largest study to date evaluating sleep architecture and total leg movement activity during sleep (LMS) in patients with MS. Methods We collected PSG recordings from 80 patients affected by multiple sclerosis (MS, 48.1±10.61yo 67.5% females), and 60 age and gender matched healthy control subjects (HC, 48.5±17.20 yo, 56% females). Group differences were computed using non-parametric statistics for all traditional sleep architecture parameters, LMS, short-interval (SILMS), periodic (PLMS), isolated LMS (ISOLMS) indices and duration, inter-movement interval (IMI) graphs and time-of-night distribution of LMS. Results Patients with MS showed a significantly decreased total sleep period, an increased number of awakenings and stages shifts per hour of sleep, and an increased representation of stage 1 (min and %) compared to the HC group; 26 (32.5%) MS patients had PLMS ≥15/hour versus 8 (13.3%) HC subjects. On average, the comparison between MS and HC groups yielded significant results in terms of an increase in LMS, PLMS, SILMS and ISOLMS indices but not durations. Moreover, MS patients displayed a higher periodicity index, an increased PLMS activity at all inter-movement intervals considered and their PLMS time-of-night distribution revealed that the PLMS increase was stable over the course of the night. Conclusion Sleep continuity is significantly impaired in patients with MS. Moreover, MS patients also an increased total LMS activity, including PLMS, which may contribute to disrupt sleep continuity. A disinhibition of lower spinal network due to cervical or supraspinal MS lesions might be implicated in the mechanisms underlying this latter finding. Support The Employer Department of Neurology, Regional Hospital Lugano (EOC), Lugano, Switzerland receives financial support from Teva, Merck Serono, Biogen Idec, Bayer Schering, Genzyme, Roche and Novartis. The submitted work is not related to these agreements.

Neurogenetic Traits Conferring Vulnerability to Cortical Progression of Parkinson's Disease

Background: The genetic traits that underlie vulnerability to neuronal damage across specific brain circuits in Parkinson’s disease (PD) remain to be elucidated. In this study, we characterized the brain topological intersection between propagating connectivity networks in healthy controls (HC) and PD participants and gene expression patterns across the human cortex – such as the SNCA gene (encoding alpha-synuclein protein, a hallmark of PD pathology). Methods: To characterize the functional scaffolding of connections emanating from PD-related pathology epicenters in the brainstem, we first performed Stepwise Functional Connectivity (SFC) analysis using intrinsic connectivity as revealed by neuroimaging. We then leveraged the Allen Human Brain Atlas (AHBA) to examine the spatial intersection of the observed SFC patterns with genetic transcription profiles. Findings: A rich set of genes were transcriptionally associated to PD-related biologic processes, including dopamine secretion, neuropeptide transmission, and axonal and synaptic assemblies, for which the gene SNCA played a central role. As hypothesized, we further confirmed that brain connectivity originated from PD-related pathology epicenters in the brainstem largely recapitulated the anatomical distribution of alpha-synuclein histopathology in postmortem data. Finally, we discovered that the gene set most related to cortical propagation patterns of PD-related pathology was primarily involved in microtubule cellular components. Interpretation: This study sheds light on exciting new avenues for enhancing detection of PD neuronal vulnerability via an evaluation of in vivo connectivity trajectories across the human brain and successful integration of neuroimaging-genetic strategies. Funding Statement: This research was supported by grants from the National Institutes of Health (NIH; R01AG061811, and R01AG061445 to J.S.), the Ministry of Education, Science, and Technological Development of the Republic of Serbia (grant number 175090), the Italian Ministry of Health (grant number RF-2018-12366746) and Carlos III Institute of Health (PI11/02109) Spain, the Basque Government through the BERC 2018-2021 program and by the Spanish State Research Agency through BCBL Severo Ochoa excellence accreditation SEV-2015-0490 and the Spanish Ministry of Economy and Competitiveness (RYC-2017- 21845 and PID2019-105520GB-100 to C.C-G.). Declaration of Interests: S.B. reports no disclosures. F.A. is Section Editor of NeuroImage: Clinical; has received speaker honoraria from Philips, Novartis and Biogen Idec; and receives or has received research supports from the Italian Ministry of Health, AriSLA (Fondazione Italiana di Ricerca per la SLA), and the European Research Council. I.D. reports no disclosures. E.B. reports no disclosures. F.d.O.U. reports no disclosures. M.D-A. report honoraria for lectures, travel, and accommodation to attend scientific meetings from Alter, Bial, Merk, Novartis, Sanofi Genzyme, UCB, and Zambon. C.C-G. reports no disclosures. M.R-O. reports honoraria for lectures, travel and accommodation to attend scientific meetings from Boston Scientific and Bial. T. Stojkovic has received speaker honoraria from Actavis and Alzheimer's Association International Research Grant. V.S. Kostic has received speaker honoraria from Actavis and Solveo. M. Filippi is Editor-in-Chief of the Journal of Neurology; received compensation for consulting services and/or speaking activities from Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). J. Sepulcre reports no disclosures. Ethics Approval Statement: Both studies were approved by the local ethics committees at University of Belgrade and Gipuzkoa Clinical Research Ethics Committee respectively and written informed consent to participate in the study was obtained from all participants.

Optimum design of hybrid renewable energy system through load forecasting and different operating strategies for rural electrification

This paper demonstrates the optimum design and techno-economic assessment of hybrid renewable energy system (HRES) for rural electrification in the remote district of Korkadu, India. The renewable energy resources namely solar photovoltaic, wind turbine and bio generators are considered as the main sources because of its high potential in Korkadu district. This paper estimates the load forecasting for the selected district, which is a mixture of different load patterns namely residential, commercial, institutional and agricultural demands. The desired HRES has to meet the forecasted load demand for reliable electrification. The optimum design and techno-economic analysis of proposed HRES system is carried using powerful tool HOMER. This study also compares HRES’s operational behavior with different operational strategies such as load following strategy, cycle charging strategy and combined strategy of the system. The outcome of the proposed dispatched strategy expressed the contribution of solar power as 86.8%, wind as 12.7% and bio gen power as 0.5% to meet out developed rural load pattern with 6.8% of battery bank losses and 1.78% of converter losses. This research work also illustrate the HRES based power generation can be a cost effective sustainable power alternative to the conventional grid extension system.

Diagnostic Accuracy of Amyloid versus FDG PET in Patients with Cognitive Impairment and Autopsy

Background: β-Amyloid and Flurodeoxyglucose (FDG) PET are clinically available diagnostic tools in the assessment of neurodegenerative disorders. We compared the diagnostic accuracy of [11C]Pittsburgh Compound B (PIB) and [18F]FDG PET in a large sample of patients with cognitive decline and neuropathology. Methods: 101 individuals underwent PIB and FDG during life and post-mortem neuropathological assessment. PET scans were visually interpreted by three raters blinded to clinical information. PIB scans were rated as positive or negative for cortical retention while FDG scans were read as showing an Alzheimer’s disease (AD) or non-AD metabolic pattern. AD neuropathological changes (ADNC) were measured at autopsy. Majority visual reads were compared to intermediate-high ADNC as the gold standard. Findings: 60 males and 41 females were included (average age: 67·2Y, mean MMSE: 21·9, mean PET-to-autopsy interval: 4·4Y). At autopsy, 32 patients showed pure AD pathology, 13 mixed AD and non-AD and 56 non-AD neuropathology. Compared to FDG, PIB showed higher sensitivity for detecting intermediate-high ADNC (96% [95% confidence interval: 89-100%] vs 80% [68-92%] for FDG, p=0·02) and higher negative predictive value (96% [91-100%] vs 84% [74-93%], p=0·01), but equivalent specificity (86% [76-95%] vs 84% [74-93%], p=0·80) and positive predictive value (84% [74-94%] vs 80% [68-92%], p=0·53). In patients with congruent PIB and FDG reads (77/101), combined sensitivity was 97% [92-100%] and specificity 98% [93-100%]. Nine of 24 patients with incongruent reads were found to have co-occurrence of AD and non-AD pathologies. Interpretation: PIB had higher sensitivity to detect intermediate-high ADNC compared to FDG, particularly at early clinical stages, with similar specificity. When both modalities are congruent, sensitivity and specificity approach 100%, while mixed pathology should be considered when PIB and FDG are incongruent. Funding Statement: National Institute of Health (R01-AG045611, P01-AG1972403, P50-AG023501, P30-AG010129, R01-AG032306, K24-AG053435, R01-AG038791, K08-AG052648, P30-AG010129, K23-AG045289), the Alzheimer’s Association (AARF-16-443577), Bluefield Project to Cure FTD, Tau Consortium. Declaration of Interests: Orit H Lesman-Segev – none, Renaud La Joie – none, Iryna Lobach - none, Howard J Rosen - Dr Rosen has received research support from Biogen Pharmaceuticals, has consulting agreements with Wave Neuroscience and Ionis Pharmaceuticals, and receives research support from NIH. Sang Won Seo - none, Mustafa Janabi - none, Suzanne L Baker - consult for Genentech, Lauren Edwards - none, Julie Pham - none, John Olichney - has received grant funding from Roche/Genentech, Adam Boxer - Dr. Boxer receives research support from NIH, the Tau Research Consortium, the Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, Corticobasal Degeneration Solutions, the Alzheimer’s Drug Discovery Foundation and the Alzheimer's Association. He has served as a consultant for Aeton, Abbvie, Alector, Amgen, Arkuda, Arvinas, Asceneuron, Ionis, Lundbeck, Novartis, Passage BIO, Sangamo, Samumed, Third Rock, Toyama and UCB, and received research support from Avid, Biogen, BMS, C2N, Cortice, Eli Lilly, Forum, Genentech, Janssen, Novartis, Pfizer, Roche and TauRx. Eric Huang - none, Marilu Gorno-Tempini – none, Ji-Hye L. Hwang - none, Charles DeCarli - none, Mackenzie Hepker - none, Salvatore Spina - none, Bruce L Miller – Dr. Miller receives grants in support of the Memory and Aging Center from the NIH/NIA, the Quest Diagnostics Dementia Pathway Collaboration, Cornell University and The Bluefield Project to Cure Frontotemporal Dementia. He serves as Medical Director for the John Douglas French Foundation; Scientific Director for the Tau Consortium; Director/Medical Advisory Board of the Larry L. Hillblom Foundation; and Past President of the International Society of Frontotemporal Dementia (ISFTD). Lea T Grinberg - Dr. Grinberg receives research support from Avid Radiopharmaceuticals, Eli Lilly. She has received consulting fees from Simon Foundation and Cura Sen Inc. She serves as associate editor for Frontiers in Aging Neurosciences, Frontiers in Dementia and Journal of Alzheimer Disease William W. Seeley - Dr. Seeley has received consulting fees from Biogen Idec, Third Rock Ventures, and Guidepoint Global Advisors. He serves on the editorial board of Acta Neuropathologica and Neuroimage Clinical. William J Jagust - Dr. Jagust has received honoraria as a consultant to Novartis, Genentech, and Curasen Gil D Rabinovici – Dr. Rabinovici receives research support from Avid Radiopharmaceuticals, Eli Lilly, GE Healthcare and Life Molecular Imaging. He has received honoraria as a consultant for Axon Neurosciences, Eisai and Merck, and speaking honoraria from GE Healthcare. Dr. Rabinovici serves as Associate Editor for JAMA Neurology. Ethics Approval Statement: Informed consent was obtained from all subjects or their surrogate decision makers, and the UCSF, UCD, University of California Berkeley (UCB) and/or Lawrence Berkeley National Laboratory (LBNL) Institutional Review Boards for human research approved the study.

Tossing and Turning in Bed: A Wearable Sensor Documents Abnormal Nocturnal Movements in Parkinson's Disease

Background: Sleep interruptions and nocturnal hypokinesia are common in Parkinson's disease (PD). Pilot work using wearable technologies showed fewer nocturnal movements in patients with advanced PD compared to controls. However, the prevalence of these impairments in early stage of the disease and the influence of non-motor symptoms, and dopaminergic medication are unknown. Methods: This study evaluated wearable sensor data collected in 305 patients with PD at different Hohen and Yahr disease stages (HY HY H&Y3=77) and 205 healthy controls (HC). Subjects wore a tri-axial accelerometer continuously (24/7) on the lower back for at least 2 days. Percent upright-time and nighttime walking were defined based on the vertical axis of the acceleration signal and were classified as sleep interruptions. The number, velocity, time, side, and degree of rotations in bed during the night evaluated nocturnal movements. Findings: Nocturnal lying-time was similar between PD and controls (p=0.501), however, the number of turns and the turn velocity significantly decreased (p<0.001) with H&Y stage. Advanced patients (H&Y3) had more upright periods during the night while the number and velocity of their turns were reduced (p<=0.021). Recently diagnosed patients (<1 year from diagnosis) were similar to controls in number of nocturnal turns (p=0.148) but showed longer turning time (p=0.001) and reduced turn magnitude (p=0.002). Nocturnal movements were significantly correlated with non-motor symptoms, cognition, and dopaminergic medication. Interpretation: Reduced nocturnal movements are already detectable in recently diagnosed patients and are associated with increased PD motor severity and dysautonomia. Using wearable sensors for continuous monitoring at night may offer an unbiased, objective measure of disease severity that could enhance optimal nighttime dopaminergic treatment and utilization of turning strategies. Funding Statement: European Commission (FP7 project V-TIME-278169), The Michael J Fox Foundation for Parkinson's research, a grant from Biogen Inc and by the NIHR/Wellcome Trust Clinical Research Facility (CRF). Declaration of Interests: Anat Mirelman, Jeff Hausdorff and Nir Giladi report having submitted a patent for assessment of mobility using wearable sensors in Parkinson's disease. The intellectual property rights are held by the Tel Aviv Medical Center. Prof. Mirelman and Hausdorff also serve as consultants for the Michael J Fox Foundation, Biogen, Sanofi (JH) and Neuroderm (AM) in areas relating to the use of wearable sensors to assess mobility in PD. JMH and AM have received grant funding from the European Commission and MJFF. Lynn Rochester reports no conflict of interests pertaining to the manuscript. She receives grants from the Medical Research Council, European Commission, NIHR, Wellcome Trust, EPSRC, Parkinson's UK, and the Stroke Association. Alice Nieuwboer reports no conflict of interest pertaining to the manuscript. She has received grant funding from the European Commission. Bastiaan R Bloem currently serves on the editorial of Practical Neurology and Digital Biomarkers, has received honoraria from serving on the scientific advisory board for Abbvie, Biogen, UCB and Walk with Path, has received fees for speaking at conferences from AbbVie, Zambon, Roche, GE Healthcare and Bial, and has received research support from the Netherlands Organization for Scientific Research, the Michael J Fox Foundation, UCB, Abbvie, the Stichting Parkinson Fonds, the Hersenstichting Nederland, the Parkinson’s Foundation, Verily Life Sciences, Horizon 2020, the Topsector Life Sciences and Health, and the Parkinson Vereniging. Jesse Cederbaum and Mirek Brys are shareholders in Biogen, Inc. Nir Giladi reports reports counseling for: Neuroderm, Intec Pharma, Teva, Genzyme-Sanofi, Biogen, Lysosomal Therapeutics, Denali, Cellanis, GaitBetter, Vibrant and Sionara; that he holds shares or options in Lysosomal Therapeutics, Cellanis, GaitBetter and Vibrant; that he has received royalties from Lysosomal Therapeutics; that he received honorarium from UCB, Teva, Novartis, Abbvie, Genzyme-Sanofie, Neuroderm, Bial, Shire, MDS; that he has chaired the DSMBs for Teva and Pharma2B; that he is a PI on a Center Grant given by Biogen to TLVMC. Inbar Hillel, Silvia Sel Din, Laura Avanzino, Inbal Maidan, Talia Herman, Meir Kestenbaum, Avner Thaler, Tanya Gurevich and Avi Orr Urtreger report no disclosures pertaining to the manuscript. Ethics Approval Statement: The studies were approved by local ethical committees and were performed according to the principles of the Declaration of Helsinki. All participants gave their informed written consent prior to participation.

Delayed Diagnosis of Hidradenitis Suppurativa and Its Effect on Patients and Healthcare System

Background: Hidradenitis suppurativa (HS) is a neglected chronic inflammatory disease affecting the skin of axillary, inguinal, gluteal, and perianal body areas. Besides pain, purulent discharge, and destruction of skin architecture, HS patients experience metabolic, musculoskeletal, and psychological disorders. This study determined the delay in HS diagnosis and its consequences. Methods: A prospective, multi-center, epidemiologic, non-interventional clinical trial based on real-world data in Germany. Self-explanatory questionnaires and medical examinations performed by dermatologists of 394 patients with HS, regardless of therapy, were considered. Findings: The average duration from manifestation of first symptoms until HS diagnosis was 10·0±9·6 (mean±SD) years. During this time, HS patients consulted on average more than three different physicians - most frequently general practitioners, dermatologists, surgeons, gynecologists - and faced more than three misdiagnoses. Diagnosis delay was longer in younger and non-smoking patients. In most cases, HS was correctly diagnosed by dermatologists. The longer the delay of diagnosis, the greater the disease severity at diagnosis. Delayed HS diagnosis was also associated with an increased number of surgical interventions, concomitant diseases, and days of work missed. Interpretation: This study demonstrates an enormous delay in the diagnosis of HS, which results in more severe disease. It also shows for the first time that a delay in diagnosis of a chronic inflammatory disease leads to a higher number of concomitant systemic disorders. In addition to the impaired health status, delayed diagnosis of HS impairs the professional life of affected people. Trial Registration: German Clinical Trials Register (DRKS-ID: DRKS00013778). Funding Statement: AbbVie Deutschland GmbH & Co. KG. Declaration of Interests: G.K. has received honoraria for participation in advisory boards, in clinical trials and/or as speaker from AbbVie Deutschland GmbH & Co. KG, Abbott GmbH, Actelion Pharmaceuticals Ltd., Basilea Pharmaceutica Ltd., Bayer AG, Biogen IDEC GmbH, Celgene GmbH, JanssenCilag GmbH, LEO Pharma GmbH, Lilly Deutschland GmbH, MSD Sharp & Dohme GmbH, Novartis Pharma GmbH, Parexel International GmbH, Pfizer Deutschland GmbH, and UCB Pharma GmbH. K.W. has received research grants, travel grants, consulting honoraria and/or lecturer honoraria from AbbVie Inc., AbbVie Deutschland GmbH & Co. KG, Bayer Schering Pharma AG, Celgene GmbH, Flexopharm GmbH & Co. KG, Generon Corporation Ltd., Janssen Pharmaceutica NV, Johnson & Johnson Pharmaceutical Services LLC, Novartis Pharma GmbH, Pfizer Deutschland GmbH, and UCB Pharma GmbH. S.S.-B. has received honoraria for participation in advisory boards, in clinical trials and/or as speaker from AbbVie Inc., AbbVie Deutschland GmbH & Co. KG, Novartis Pharma GmbH, and Pfizer Deutschland GmbH. S.K. has no conflicts of interest to declare. S.G.-K. and S.B. are employees of Abbvie Deutschland GmbH & Co. KG and my own AbbVie stocks. R.S. has received research grants, scientific awards or honoraria for participation in advisory boards, clinical trials or as speaker for one or more of the following: AbbVie Inc., AbbVie Deutschland GmbH & Co. KG, Bayer Schering Pharma AG, Biogen IDEC GmbH, Boehringer Ingelheim Pharma GmbH & Co. KG, Celgene GmbH, Celgene International II Sarl, Charite Research Organisation GmbH, Dr. Willmar Schwabe GmbH & Co. KG, Flexopharm GmbH & Co. KG, Generon Corporation ltd., JanssenCilag GmbH, La Roche-Posay Laboratoire Dermatologique Deutschland, Novartis Pharma GmbH, Parexel International GmbH, Pfizer Deutschland GmbH, Sanofi -Aventis Deutschland GmbH, TFS Trial Form Support GmbH, UCB Pharma GmbH. Ethics Approval Statement: The Ethics Committee of Charite-Universitatsmedizin Berlin approved the study protocol. All patients provided written informed consent. The study was conducted in accordance with the Declaration of Helsinki on Ethical Principles for Medical Research.

Evidence-Based Prevention of Alzheimer's Disease: Systematic Review and Meta-Analysis of 243 Observational Prospective Studies and 153 Randomized Controlled Trials

Background: Evidence on preventing Alzheimer's disease (AD) is challenging to interpret due to varying study designs with heterogeneous endpoints and credibility. We completed a systematic review and meta-analysis of current evidence with prospective designs to propose clinical recommendations on AD prevention. Methods: Electronic databases and relevant websites were searched from inception to March 1, 2019. Both observational prospective studies (OPSs) and randomized controlled trials (RCTs) were included. The multivariable-adjusted effect estimates were pooled by random-effects models, with credibility assessment according to its risk of bias, inconsistency, and imprecision. Levels of evidence and classes of recommendations were summarized. Findings: A total of 44,676 reports were identified, and 243 OPSs and 153 RCTs were eligible for analysis after exclusion based on pre-decided criteria, among which 104 modifiable factors and 11 interventions were included for the meta-analyses. In the OPSs, 26 risk factors and 8 protective factors were found to significantly modify AD risk by an effect size of over 25%, amongst which eight factors were rated at a moderate-to-high level of evidence. Among the interventions tested in RCTs, physical exercise and the homocysteine lowering treatment were the most promising interventions to reduce AD risk. Finally, 21 recommendations are proposed based on the consolidated evidence, with 'Class I' recommendations targeting 19 factors: ten are with 'Level A' strong evidence (cognitive activity, hyperhomocysteinemia, high BMI in late-life, depression, stress, diabetes, head trauma, hypertension in midlife, orthostatic hypotension, and education) and nine with 'Level B' weaker evidence (obesity in midlife, weight loss in late-life, physical exercise, smoking, sleep, CVD, frailty, atrial fibrillation, and Vitamin C). In contrast, two interventions are not recommended: estrogen replacement therapy (Level A2) and acetylcholinesterase inhibitors (Level B). Interpretation: Our study mapped the current evidence profile and assessed the findings in order to guide future research directions for AD prevention. Evidence-based recommendations are proposed, offering clinicians and stakeholders current guidance for the prevention of AD. Funding Statement: The authors stated: There was no direct funding source for this study. Declaration of Interest: JTY serves as an associate editor-in-chief for Annals of Translational Medicine, is senior editor for Journal of Alzheimer's Disease. SA has received grants from Europe, Ipsen, and France Alzheimer, served as a consultant for Ipsen, Pierre Fabre, Lilly, Nestle, Sanof, and Servier, and received non-financial support from Biogen, Nutrition Sante, Pfzer, and Icon, and other support from the AMPA Association. SG has received clinical trial support from Lilly and Roche in DIAN-TU, TauRx Therapeutics (TauRx), and Lundbeck; has been a data safety monitoring board (DSMB) member of ADCS, ATRI, API, and Eisai; and has been a scientific adviser to Affiris, BoehringerIngelheim, Lilly, Roche, Servier, Sanofi, Schwabe, Takeda, and TauRx. PSA has received grants from the US Alzheimer’s Association, Janssen, Lilly, the US National Institute on Aging, and Toyama; and consulting fees from Abbott, Abbvie, Amgen, Anavex, AstraZeneca, Biogen Idec, Biotie, Bristol-Myers Squibb, Cardeus, Cohbar, Eisai, Elan, Eli Lilly, Genentech, Ichor, iPerian, Janssen, Lundbeck, Medivation, Merck, NeuroPhage, Novartis, Pfizer, Probiodrug, Roche, Somaxon, and Toyama, outside the submitted work. BV reports grants from Pierre Fabre, Avid, Exonhit, AbbVie, Lilly, Lundbeck, MSD, Otsuka, Regenron, Sanof, Roche, AstraZeneca, LPG Systems, Nestle, and Alzheon, and personal fees from Lilly, Lundbeck, MSD, Otsuka, Roche, Sanof, Biogen, Nestle, Transition Therapeutics, and Takeda. All other authors declare no competing interests. Ethics Approval Statement: The authors followed the recommendations by the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2009 guidelines.

The potential impact of azithromycin in idiopathic pulmonary fibrosis

There is growing evidence of the role of infection in the pathogenesis and progression of idiopathic pulmonary fibrosis (IPF) [1–4]. Over a third of patients with IPF will be hospitalised, at least once, during the course of their disease [5]. These events not only carry a significant morbidity and mortality, but also a health care cost and burden [6]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Macaluso has nothing to disclose. Conflict of interest: Dr. Alzaher has nothing to disclose. Conflict of interest: Dr. Chaube has nothing to disclose. Conflict of interest: Dr. Chua has nothing to disclose. Conflict of interest: Dr. Wells reports speakers and consultancy fees from Intermune Roche, Boehringer ingelheim and Bayer Conflict of interest: TMM has, via his institution, received industry-academic funding from GlaxoSmithKline R&D and UCB and has received consultancy or speakers fees from Apellis, Astra Zeneca, aTyr Pharma, Bayer, Biogen Idec, Boehringer Ingelheim, Galapagos, GlaxoSmithKline R&D, ProMetic, Roche, Sanumed and UCB. Conflict of interest: Dr. George reports personal fees from Roche Pharmaceuticals, personal fees from Boehringer Ingelheim, outside the submitted work. Conflict of interest: Dr. Renzoni has recieved speakers fees from BI, Roche and Mundipharma Conflict of interest: Dr. Molyneaux has nothing to disclose. Conflict of interest: Dr. Maritano Furcada has nothing to disclose.

Utilization Patterns of Oral Disease-Modifying Drugs in Commercially Insured Patients with Multiple Sclerosis.

The approval of new oral disease-modifying drugs (DMDs), such as fingolimod, dimethyl fumarate (DMF), and teriflunamide, has considerably expanded treatment options for relapsing forms of multiple sclerosis (MS). However, data describing the use of these agents in routine clinical practice are limited. To describe time trends and identify factors associated with oral DMD treatment initiation and switching among individuals with MS. Using data from a large sample of commercially insured patients, we evaluated changes over time in the proportion of MS patients who initiated treatment with an oral DMD and who switched from an injectable DMD to an oral DMD between 2009 and 2014 in the United States. We evaluated predictors of oral DMD use using conditional logistic regression in 2 groups matched on calendar time: oral DMD initiators matched to injectable DMDs initiators and oral DMD switchers matched to those who switched to a second injectable DMD. Our cohort included 7,576 individuals who initiated a DMD and 1,342 who switched DMDs, of which oral DMDs accounted for 6% and 39%, respectively. Oral DMD initiation and switching steadily increased from 5% to 16% and 35% to 84%, respectively, between 2011 and 2014, with DMF being the most commonly used agent. Of the potential predictors with clinical significance, a recent neurologist consultation (OR = 1.60; 95% CI = 1.20-2.15) and emergency department visit (OR = 1.43; 95% CI = 1.01-2.01) were significantly associated with oral DMD initiation. History of depression was noted to be a potential predictor of oral DMD initiation; however, the estimate for this predictor did not reach statistical significance (OR = 1.35; 95% CI = 0.99-1.84). No clinically relevant factors measured in our data were associated with switching to an oral DMD. Oral DMDs were found to be routinely used as second-line treatment. However, we identified few factors predictive of oral DMD initiation or switching, which implies that their selection is driven by patient and/or physician preferences. This study was funded by CVS Caremark through an unrestricted research grant to Brigham and Women's Hospital. Shrank and Matlin were employees of, and shareholders in, CVS Health at the time of the study; they report no financial interests in products or services that are related to the subject of this study. Spettell is an employee of, and shareholder in, Aetna. Chitnis serves on clinical trial advisory boards for Novartis and Genzyme-Sanofi; has consulted for Bayer, Biogen Idec, Celgene, Novartis, Merck-Serono, and Genentech-Roche; and has received research support from NIH, National Multiple Sclerosis Society, Peabody Foundation, Consortium for MS Centers, Guthy Jackson Charitable Foundation, EMD-Serono, Novartis Biogen, and Verily. Desai reports receiving a research grant from Merck for unrelated work. Gagne is principal investigator of a research grant from Novartis Pharmaceuticals Corporation to the Brigham and Women's Hospital and has received grant support from Eli Lilly, all for unrelated work. He is also a consultant to Aetion and Optum. Minden reports grants from Biogen and other fees from Genentech, EMD Serano, Avanir, and Novartis, unrelated to this study. The other authors have no conflicts to report. This study was presented as a poster at the International Society for Pharmacoepidemiology 32nd Annual Meeting; August 25-28, 2016; Dublin, Ireland.

Clustering of Bleeding Symptoms in Patients Previously Diagnosed As Type 3 Von Willebrand Disease: Results from a Large Cohort of Type 3 Von Willebrand Disease (the 3Winters-Ips Project)

Clustering of Bleeding Symptoms in Patients Previously Diagnosed As Type 3 Von Willebrand Disease: Results from a Large Cohort of Type 3 Von Willebrand Disease (the 3Winters-Ips Project)

Preference for Emicizumab over Prior Factor Treatments: Results from the HAVEN 3 and HAVEN 4 Studies

Preference for Emicizumab over Prior Factor Treatments: Results from the HAVEN 3 and HAVEN 4 Studies

Efficacy of an Extended Half-Life GlycoPEGylated rFVIII (N8-GP): Pooled Analysis of ABR (Results from Two Clinical Trials)

IntroductionThe short half-life of standard factor VIII (FVIII) products means that frequent injections (3 to 4 times/week) are needed for effective prophylaxis in patients with hemophilia A. N8-GP (turoctocog alfa pegol), an extended half-life glycoPEGylated recombinant FVIII developed for the prophylaxis and treatment of bleeds in patients with hemophilia A, allows for less frequent dosing. Bleed frequency is an important outcome measure in hemophilia, particularly when choosing a dosing regimen that best suits a broad range of patients.ObjectivesTo summarize annualized bleeding rate (ABR) data from 2 clinical trials of N8-GP in patients with severe hemophilia A.MethodsPatients with severe hemophilia A (FVIII <1%) were enrolled into the pathfinder comprehensive clinical trial program:•pathfinder 2 main phase•Adults/adolescents ≥12 years, N8-GP 50 IU/kg every 4 days (Q4D) or 20-75 IU/kg on demandpathfinder 2 extension phase•Adults/adolescents ≥12 years, randomized to receive N8-GP 50 IU/kg Q4D or 75 IU/kg once weekly (Q7D)•Patients with ≤2 bleeds in the last 6 months were eligible for randomizationpathfinder 5 main phase•Children <12 years, N8-GP 60 IU/kg (50-75 IU/kg) twice weekly.ABR was analyzed using a Poisson-regression model on the number of bleeds per patient, allowing for over-dispersion and using log-planned observation duration as an offset to allow for different treatment durations, with age cohort as a factor for pathfinder 5. Median and estimated Poisson mean ABR data from the 2 trials were summarized for overall, spontaneous, traumatic, joint, and muscle bleeds.ResultsFor adults/adolescents receiving N8-GP 50 IU/kg Q4D (pathfinder 2 main phase) and those randomized to receive 50 IU/kg Q4D or 75 IU/kg Q7D (pathfinder 2 extension), median overall ABRs were 1.18, 0.00, and 0.00, respectively (Table). Corresponding median ABRs were:•For spontaneous bleeds 0.00, 0.00, and 0.00•For traumatic bleeds 0.00, 0.00, and 0.00•For joint bleeds 0.85, 0.00, and 0.00•For muscle bleeds 0.00, 0.00, and 0.00.For children (aged 0-11 years) receiving 60 IU/kg twice weekly (pathfinder 5), median overall, spontaneous, traumatic, joint, and muscle ABRs were 1.95, 0.00, 0.00, 0.00, and 0.00, respectively. Poisson estimated mean ABR data for all bleed types are also shown in the Table.ConclusionN8-GP provides effective prophylactic protection in adult/adolescent and pediatric patients with severe hemophilia A, as demonstrated by low ABRs in phase 3 clinical trials. For patients of all ages, N8-GP enables simplicity in the choice of prophylaxis dose and dosing frequency with no need for pharmacokinetic-tailored dosing. [Display omitted] DisclosuresChowdary:Bayer, CSL Behring, Novo Nordisk, Pfizer, and SOBI (publ): Research Funding; Baxalta (Shire), Baxter, Biogen Idec, CSL Behring, Freeline, Novo Nordisk, Pfizer, Roche, Shire, and SOBI: Consultancy. Hvitfeldt Poulsen:Lecturer on Nordic meeting on EHL FVIII (SOBI): Other: Lecturer ; Primary investigator and national coordinator on clinical trials from Bayer Health Care: Other: Primary Investigator and national coordinator; Nordic advisory boards (Bayer Health Care, Roche): Membership on an entity's Board of Directors or advisory committees; Chaired an educational haemophilia symposium for nurses: Other: Chair. Escobar:Bayer, CSL Behring, Genentech, Hemabiologics, Kedrion, Novo Nordisk, Octapharma, Pfizer and Shire: Consultancy; Pfizer: Research Funding. Kearney:Bayer, Bioverativ, Daiichi Sankyo, Grifols and Novo Nordisk: Research Funding; Bayer, Bioverativ and Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Chitlur:Novo Nordisk Inc: Consultancy; Baxter, Bayer, Biogen Idec, and Pfizer: Honoraria. Klamroth:Baxalta (Shire), Bayer, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Shire, and SOBI: Research Funding; Baxalta (Shire), Bayer, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Shire, and SOBI: Consultancy. Negrier:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta/Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Research Funding; LFB: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi/Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Clausen:Novo Nordisk: Employment. Driessler:Novo Nordisk: Employment. Landorph:Novo Nordisk: Employment. Santagostino:Kedrion: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Grifols: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees.