Late Breaking News Session , 08:30-09:30, Auditorium II

Transcription

1 Late Breaking News Session , 08:30-09:30, Auditorium II O424 Long-term efficacy and safety of everolimus as adjuctive therapy in patients with tuberous sclerosis complex (TSC)-associated treatment -refractory seizures: Final analysis of the EXIST-3 study D. N. Franz 1, J. Lawson 2, Z. Yapıcı 3, H. Ikeda 4, T. Polster 5, R. Nabbout 6, P. Curatolo 7, P. de Vries 8, D. Dlugos 9, J. Fan 10, B. Mookerjee 11, S. Peyrard 12, D. Pelov 10, J. French 13 1 Cincinnati Children s Hospital Medical Center, Department of Neurology, Ohio, USA, 2 Sydney Children s Hospital, The Tuberous Sclerosis Multidisciplinary Management Clinic, Randwick, Australia, 3 Istanbul, Turkey, 4 Shizuoka Institute of Epilepsy and Neurological Disorders, NHO Epilepsy Center, Shizuoka, Japan, 5 Bethel Epilepsy Center, Department of Presurgical Evaluation, Germany, Germany, 6 Paris, France, 7 6Tor Vergata University Hospital, Rome, Italy, 8 Cape Town, South Africa, 9 The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Departments of Neurology and Pediatrics, Philadelphia, USA, 10 Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA, 11 Novartis Pharma AG, Basel, Switzerland, 12 Novartis Pharmaceuticals S.A.S, Rueil-Malmaison, France, 13 NYU Comprehensive Epilepsy Center, Epilepsy, New York, India Background and aims: We assessed long-term efficacy and safety of adjunctive everolimus in patients with TSC-associated refractory seizures in the phase 3 EXIST-3 study (NCT ). Methods: Patients completing the extension phase continued receiving everolimus in the post-extension phase (PEP. Efficacy endpoints included response rate (RR, 50% reduction in average weekly seizure frequency [SF] from baseline) and median percent reduction (PR) in SF until end of extension phase. Questionnaires on changes in seizure presentation (frequency, intensity, and/or development of new seizure types) were analyzed at 12-week intervals throughout the PEP. Safety was assessed from start of everolimus in all patients who received 1 dose. Results: Among 361 everolimus-treated patients from the core phase, 343(95%) entered extension and 249(69%) the PEP. Median duration of everolimus exposure was 30.4 months. Efficacy persisted over time with slightly greater effects in younger patients (Figure 1). Among 244 patients evaluated in the PEP, 18.9% were seizure-free since last visit; 64.8% had stable or improved seizure status for the first 3 months of the PEP. This trend continued in subsequent 3-month intervals: 18.2% and 64.5% from 3-6 months, 17.1% and 70.1% from 6-9 months, and 20% and 61.8% from 9-12 months (Table 1). Most common adverse events (AEs, >30%) were pyrexia, stomatitis, and diarrhoea; incidence decreased over time (Table 2). Four deaths occurred during the study due to sudden unexplained death in epilepsy (n=2), pneumonia, and septic shock (n=1 each).

2 A) Median Percentage Reduction in Seizure Frequency from the start of everolimus in Overall Population and by Age Category B) Seizure frequency by 12-week interval from randomization and by treatment group Full analysis set Conclusion: Long-term exposure to everolimus achieved sustained reductions in TSCassociated treatment-refractory seizures over time with a tolerable safety profile.

3 Table 1. Questionnaires on changes in Seizure Presentation during the Post-extension Phase Table 2 Disclosure: Nothing to disclose O425 Neurological outcome of post-anoxic refractory status epilepticus after aggressive treatment S. Beretta 1, A. Coppo 2, E. Bianchi 3, C. Zanchi 1, D. Carone 1, A. Stabile 1, G. Padovano 1, E. Sulmina 2, A. Grassi 2, G. Bogliun 1, G. Foti 2, C. Ferrarese 4, A. Pesenti 5, E. Beghi 4, L. Avalli 2 1 Epilepsy Center, Department of Neurology, Milan, Italy, 2 University of Milano Bicocca, Department of Intensive Care, Monza, Italy, 3 IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Neuroscience, Milan, Italy, 4 Monza, Italy, 5 IRCCS Mario Negri Institute for Pharmacological Research, Department of Anesthesia, Critical Care and Emergency, Milan, Italy

4 Background and aims: To investigate neurological outcome of cardiac arrest patients with refractory status epilepticus (RSE) treated with a standardized aggressive protocol with antiepileptic drugs and anesthetics, compared to patients with other EEG patterns. Methods: Prospective cohort study of 166 consecutive patients with cardiac arrest in coma, stratified according to four independent EEG patterns (benign; non-periodic RSE; generalized periodic discharges, GPDs; malignant non-epileptiform) and multi-modal prognostic indicators. Primary outcomes were survival and cerebral performance category (CPC) at 6 months. Results: Non-periodic RSE occurred in 36 patients (21.7%) and was treated with an aggressive standardized protocol as long as multi-modal prognostic indicators were not unfavorable. RSE started after 3 +/- 2.3 days after cardiac arrest and lasted 4.7 +/- 4.3 days. A benign EEG pattern was recorded in 76 patients (45.8%), a periodic pattern (GPDs) in 13 patients (7.8%) and a malignant non-epileptiform EEG pattern in 41 patients (24.7%). The four EEG patterns were highly associated to different prognostic indicators (low flow time, clinical motor seizures, N20 responses, NSE, neuroimaging). Survival and good neurological outcome (CPC 1 or 2) at 6 months were 72.4% and 71.1% for benign EEG pattern, 54.3% and 44.4% for non-periodic RSE, 15.4% and 0% for GPDs and 2.4% and 0% for malignant nonepileptiform EEG pattern, respectively. Conclusion: Aggressive and prolonged treatment of non-periodic RSE is justified in a substantial proportion of cardiac arrest patients. Discontinuous/unreactive EEG background activity and periodic discharges heralds a much worse prognosis than RSE after cardiac arrest. Disclosure: Nothing to disclose. O426 Being a morning person increases the risk of Parkinson disease: a Mendelian randomisation study A. Noyce 1, D. Kia 1, K. Heilbron 2, J. Jepson 3, G. Hemani 4, T. I. P. D. G. C. The 23andMe Research Team 5, D. Hinds 2, D. Lawlor 4, G. Davey Smith 4, J. Hardy 1, A. Singleton 6, M. Nalls 6, N. W. Wood 1 1 UCL Institute of Neurology, Department of Molecular Neuroscience, London, United Kingdom, 2 23andMe, Inc., 899 W Evelyn Avenue, Mountain View, USA, 3 UCL Institute of Neurology, Department of Clinical & Experimental Epilepsy, London, United Kingdom, 4 MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom, 5 The International Parkinson's Disease Genomics Consortium, Bristol, United Kingdom, 6 National Institutes for Health, Laboratory for Neurogenetics, Bethesda, USA Background and aims: Circadian rhythm may play a role in neurodegenerative diseases such as Parkinson s disease (PD). Chronotype is the behavioural manifestation of circadian rhythm and Mendelian randomisation (MR) involves the use of genetic variants to explore causal effects of exposures on outcomes. This study aimed to explore a causal relationship between chronotype and risk of PD. Methods: Two-sample MR was undertaken using publicly available GWAS data. Associations between genetic instrumental variables and morning person (one extreme of chronotype) were obtained from 23andMe, Inc., and UK Biobank, and consisted of the perallele odds ratio of being a morning person for 15 independent variants. The per-allele difference in log-odds of PD for each variant was estimated from a recent meta-analysis. The inverse variance weighted (IVW) method was used to estimate an odds ratio (OR) for the effect of being a morning person on PD. Additional MR methods were used to check for bias in the IVW estimate, arising through violation of MR assumptions. Results: Being a morning person was causally linked with risk of PD (OR 1.27; 95% CI ; p=0.012). Sensitivity analyses did not suggest that invalid instruments were biasing

5 the effect estimate and there was no evidence for a reverse causal relationship between liability for PD and chronotype. Conclusion: We observed causal evidence to support the notion that being a morning person, a phenotype driven by the circadian clock, was associated with a higher risk of PD. Further work on the mechanisms are warranted and may lead to novel therapeutic targets. Disclosure: Nothing to disclose. O427 Efficacy and safety of Erenumab in episodic migraine patients with 2-4 prior preventive treatment failures : results from the phase 3b LIBERTY study U. Reuter 1, P. J. Goadsby 2, M. Lanteri-Minet 3, M. Ferrari 4, S. Wen 5, P. Hours-Zesiger 6, J. Klatt 7 1 Berlin, Germany, 2 London, United Kingdom, 3 Nice, France, 4 LUMC, Neurology, Leiden, Netherlands, 5 Novartis Pharmaceuticals Corporation, 6Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, 6 Novartis Pharma AG, Basel, Switzerland, 7 Basel, Switzerland Background and aims: Erenumab is a fully human anti-cgrp receptor antibody being evaluated as preventive treatment for migraine. Current oral preventive therapies are associated with low adherence rates due to lack of efficacy and/or poor tolerability. A 12- week, double-blind, Phase 3b LIBERTY study (NCT ) was designed to assess efficacy and safety of erenumab in episodic migraine patients with 2 4 prior preventive migraine treatment (PMT) failures. Methods: Patients (N=246) were randomised (1:1) to erenumab 140 mg or placebo. The primary endpoint was proportion of patients achieving >=50% reduction from baseline in monthly migraine days (MMDs) during Weeks Secondary endpoints included change from baseline in MMDs, monthly acute migraine-specific medication days (MSMDs) at Week 12; and safety/tolerability. Results: At baseline, proportion of patients who failed 2, 3, and 4 prior PMTs were 38.6%, 37.8%, and 22.8%, respectively. The mean (SD) MMDs were 9.3 (2.64) and MSMDs were 4.6 (2.89). At Week 12, the proportion of patients achieving >=50% reduction in MMD was higher in erenumab 140 mg group vs placebo (30.3% vs 13.7%; OR [95%CI]: 2.73 [1.43, 5.19]; p=0.002). There were greater reductions in MMDs and MSMDs with erenumab 140 mg vs placebo (mean difference [95%CI] in MMD: 1.61 [ 2.70, 0.52]; p=0.004; mean difference (95%CI) in MSMD: 1.73 [ 2.46, 1.01]; p<0.001). Safety and tolerability of erenumab were comparable to placebo. No patients in the erenumab group discontinued due to adverse events. Conclusion: These results confirm efficacy and safety of erenumab in this first dedicated study of a difficult-to-treat population with 2 4 prior PMT failures. Disclosure: This study was supported by Novartis Pharma AG, Basel, Switzerland.