77 results on '"Gheuens S"'
Search Results
2. P1545: DURABILITY OF HEMOGLOBIN RESPONSE AND REDUCTION IN TRANSFUSION BURDEN IS MAINTAINED OVER TIME IN PATIENTS WITH PYRUVATE KINASE DEFICIENCY TREATED WITH MITAPIVAT IN A LONG-TERM EXTENSION STUDY
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Grace, R. F., primary, Glenthøj, A., additional, Barcellini, W., additional, Verhovsek, M., additional, Rothman, J. A., additional, Morado Arias, M., additional, Layton, D. M., additional, Andres, O., additional, Galactéros, F., additional, van Beers, E. J., additional, Onodera, K., additional, Viprakasit, V., additional, Chonat, S., additional, Porter, J. B., additional, Judge, M. P., additional, Kosinski, P. A., additional, Hawkins, P., additional, Gheuens, S., additional, Xu, R., additional, McGee, B., additional, Beynon, V., additional, and Al-Samkari, H., additional
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- 2022
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3. P112: ENERGIZE AND ENERGIZE-T: TWO PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDIES OF MITAPIVAT IN ADULTS WITH NON--TRANSFUSION-DEPENDENT OR TRANSFUSION-DEPENDENT ALPHA- OR BETA-THALASSEMIA
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Kuo, K, primary, Layton, D, additional, Al-Samkari, H, additional, Kattamis, A, additional, Sheth, S, additional, Taher, A, additional, Viprakasit, V, additional, Chamberlain, C, additional, Czapla, L, additional, Gheuens, S, additional, Lynch, M, additional, Tong, B, additional, Uhlig, K, additional, and Cappellini, M, additional
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- 2022
- Full Text
- View/download PDF
4. ENERGIZE AND ENERGIZE-T: TWO PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDIES OF MITAPIVAT IN ADULTS WITH NON–TRANSFUSION-DEPENDENT OR TRANSFUSION-DEPENDENT ALPHA- OR BETA-THALASSEMIA
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Kuo, KH, primary, Layton, DM, additional, Al-Samkari, H, additional, Kattamis, A, additional, Sheth, S, additional, Taher, A, additional, Viprakasit, V, additional, Chamberlain, CX, additional, Czapla, L, additional, Gheuens, S, additional, Jiang, L, additional, Lynch, M, additional, Tong, B, additional, Uhlig, K, additional, and Cappellini, MD, additional
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- 2021
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5. Patterning Chronic Active Demyelination in Slowly Expanding/Evolving White Matter MS Lesions
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Elliott, C., primary, Arnold, D.L., additional, Chen, H., additional, Ke, C., additional, Zhu, L., additional, Chang, I., additional, Cahir-McFarland, E., additional, Fisher, E., additional, Zhu, B., additional, Gheuens, S., additional, Scaramozza, M., additional, Beynon, V., additional, Franchimont, N., additional, Bradley, D.P., additional, and Belachew, S., additional
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- 2020
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6. Nusinersen versus sham control in later-onset spinal muscular atrophy
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Vogt, Sibylle, Krueger, Marcus, Pechmann, Astrid, Rippberger, Bianca, Eckenweiler, Matthias, Schara, Ulrike, Koelbel, Heike, Andres, Barbara, Rupprich, Katrin, Gangfuss, Andrea, Jachertz, Philipp, Della Marina, Adela, Sponemann, Nina, Pane, Markia, Palermo, Concetta, Piastra, Marco, Fanelli, Lavinia, de Sanctis, Roberto, Genovese, Orazio, Antonaci, Laura, Pera, Maria Carmela, Lamendola, Priscilla, Messina, Sonia, Vita, Gianluca, Di Bella, Vincenzo, Sframeli, Maria, Rosa, Matteo, Barcellona, Costanza, Distefano, Maria Grazia, Cavallaro, Filippo, Versaci, Antonio, de Luca, Francesco, Vita, Giuseppe, Nacimento Osorio, Andres, Tizzano, Eduardo, Ortez Gonzalez, Carlos Ignacio, Ortigoza Escobar, Juan Dario, Colomer Oferil, Juame, Medina Cantillo, Julita, Febrer Rotger, Anna, Vigo Morancho, Meritxell, Eldblom, Johanneh, Darin, Niklas, Kroksmark, Anna Karin, Lindstedt, Asa, Michael, Eva, Kimber, Eva, Wahlgren, Lisa, Chan, Sophelia Hoi-Shan, Chim, Stella, Chiu, Joseph, Ho, Alvin Chi Chung, Ip, Jing Kun Janice, Lam, Wendy Wai Man, Ng, Maggie Chui-San, Wan, Connie, Wong, Virginia Chun Nei, Yue, Yvonne, Arakawa, Reiko, Yamauchi, Akemi, Nagata, Satoru, Ito, Yasushi, Nakatsukasa, Hidetsugu, Takeshita, Akiko, Hirasawa, Kyoko, Ikai, Tetsuo, Eto, Kaoru, Otamni, Yui, Takeshima, Yasuhiro, Fukuda, Noroki, Tanaka, Yasuhiro, Shimomura, Hideki, Lee, Tomoko, Shibano, Takayuki, Mercuri, E., Tachikawa, Tomohiro, Darras, B. T., Chae, Jong-Hee, Chiriboga, C. A., Lim, Byung Chan, Day, J. W., Shin, Hyung-Ik, Campbell, C., Kim, Soo Yeon, Connolly, A. M., Choi, Sun Ah, Iannaccone, S. T., Son, Woo Sung, Kirschner, J., Jo, Hyemi, Kuntz, N. L., Chun, Seong Min, Saito, K., Kim, Hyuna, Shieh, P. B., Tulinius, M., Mazzone, E. S., Montes, J., Bishop, K. M., Yang, Q., Foster, R., Gheuens, S., Bennett, C. F., Farwell, W., Schneider, E., de Vivo, D. C., Finkel, R. S., Bradley, Walter G., Kaufmann, Petra, Dickson, Patricia I., Reingold, Stephen C., Davis, Charles S., Arredondo, Kristen, Castro, Diana, Cowie, Margaret, Farrow-Gillespie, Alan, Hebert, Andrew, Kauk, Melissa, Miller, Nancy, Nelson, Leslie, Spain, Thomas, Cappell, Joshua, Constantinescu, Andrei, Cruz, Rosangel, Dastgir, Jahannaz, de Vivo, Darryl, Dunaway, Sally, Engelstad, Kristin, Khandji, Alexander G., Kramer, Samantha, Marra, Jonathan, Popolizio, Molly, Salazar, Rachel, Weimer, Louis H., Aziz-Zaman, Sonya, Lamarca, Nicole, Ghosh, Partha, Al-Ghamdi, Fouad, Liew, Wendy, Graham, Robert, Berde, Charles, Sethna, Navil, Koka, Anjali, Wang, Luke, Laine, Regina, Souris, Michelle, Ordonez, Grace, Harrington, Timothy, Szelag, Heather, Pasternak, Amy, Mirek, Elizabeth, Quigley, Janet, Finkel, Richard, Berry, Debbie, Civitello, Matthew, Endsley, Julie Duke, Eden, Candace, Leon, Wendy, O'Reardon, Kathleen, Sigurdardottir, Laufey, Johnson, Craig, Turner, Jenna, Vega, Melisa, Weber-Guzman, Fabiola, Zinn, Matthias, Rocha, Ana Carolina Tesi, Watson, Karolina, d'Souza, Genevieve, Ramamurthi, R. J., Gee, Richard, Kitsuwa-Lowe, Janis, Hagerman, Katharine, Crasta, Sheela, Welsh, Lesly, Paulose, Shirley, Mcfall, Danielle, Perez, Jennifer, Patnaik, Swetapadma, Sanjanwala, Bharati, Sakamuri, Sarada, Proud, Crystal, Purse, Bona Park, Duong, Trinh Tina, Sampson, Jacinda, Tennekoon, Gihan, Brandsema, John, Glanzman, Allan, Flickinger, Jean, Toms, Michele, Adang, Laura, Stanford, Delores, Mayer, Oscar, Zigmont, Joshua, Chadehumbe, Madeline, Kichula, Elizabeth, Finanger, Erika, Russman, Barry, Roberts, Colin, Frank, Andrea, Benjamin, Danielle, Zilke, Kirsten, Golumbek, Paul T., Zaidman, Craig M., Anand, Pallavi, Gadeken, Rebecca, Siener, Catherine, Kuntz, Nancy, Epstein, Leon, Krueger, Jena, Goldman, Stewart, Krosschell, Kristin, Blomgren, Colleen, Choi, Hyoung Won, Kurz, Jonathan, Parsons, Julie, Janas, Joanne, Yang, Michele, Ballard, Alison, Carry, Terri, Shea, Stephanie, Bielsky, Alan, Booker, Kaylee, Camuto, Alicia, Lord-Halvorson, Sierra, Gibbons, Melissa, Zimmerman, Carl, Allen, Victoria, Fuhr, Peter, Johnson, Hannah, Tran, Vi, Vanderveen, Gina, Shieh, Perry, Fowler, Eileen, Parziale, Nicholas, Rao, Lekha, Skura, Christy, Kelley, Carolyn, Shu, Francy, Oskoui, Maryam, Zielinski, David, Poulin, Chantal, Ingelmo, Pablo Mauricio, Desilets, Sarah Turgeon, Dinunzio, Pamela, Rivera, Gonzalo, Srour, Myriam, Arpin, Stephanie, Goobie, Sharan, Gibson, Paul, Scholtes, Cheryl, Mcdonald, Wendy, Zapata, Eugenio, Nguyen, Cam-Tu Emilie, Servais, Laurent, Gargaun, Elena, Le Moing, Anne-Gaelle, Gidaro, Teresa, Vialle, Raphael, Guye, Marie-Laurence, Lilien, Charlotte, Olliver, Gwenn, Gilabert, Stephanie, Borell, Sabine, Wider, Sabine, Stein, Sabine, Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Department of Paediatrics, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Vall d'Hebron University Hospital [Barcelona], CIBER de Enfermedades Raras (CIBERER), Handicaps génétiques de l'enfant (Inserm U393), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Seoul National University Hospital, Max-Planck-Institut für Mikrostrukturphysik (MPI-HALLE), Max-Planck-Gesellschaft, The University of Tokyo (UTokyo), Institut de Chimie Organique et Analytique (ICOA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institute of Plasma Physics, Chinese Academy of Sciences (ASIPP), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire de mécanique des solides (LMS), École polytechnique (X)-Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), CureSMA [Elk Grove Village, IL, USA], Harvard Medical School [Boston] (HMS), Institute for Marine and Antarctic Studies [Hobart] (IMAS), University of Tasmania [Hobart, Australia] (UTAS), The Hospital for sick children [Toronto] (SickKids), University of Toronto, The Open University [Milton Keynes] (OU), Department of Pediatrics, Feinberg School of Medicine, Northwestern University [Evanston]-Northwestern University [Evanston]-Northwestern University, University Hospital Basel [Basel], McGill University Health Center [Montreal] (MUHC), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Service of Clinical Trials and Databases, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Amiens-Picardie, Groupe de Recherche sur l'Analyse Multimodale de la Fonction Cérébrale - UMR INSERM_S 1105 (GRAMFC), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Oxford, Schara, Ulrike (Beitragende*r), Koelbel, Heike (Beitragende*r), Rupprich, Katrin (Beitragende*r), Gangfuss, Andrea (Beitragende*r), Della Marina, Adela (Beitragende*r), and Sponemann, Nina (Beitragende*r)
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0301 basic medicine ,Male ,[SDV]Life Sciences [q-bio] ,spinal ,Medizin ,Oligonucleotides ,Spinal Muscular Atrophies of Childhood ,Pediatrics ,law.invention ,Age of Onset ,Child ,Child, Preschool ,Double-Blind Method ,Female ,Humans ,Infant ,Injections, Spinal ,Least-Squares Analysis ,Motor Skills ,Oligonucleotides, Antisense ,Medicine (all) ,0302 clinical medicine ,age of onset ,Randomized controlled trial ,law ,Clinical endpoint ,inglese ,injections ,Motor skill ,motor skills ,General Medicine ,SMA ,Settore MED/26 - NEUROLOGIA ,medicine.anatomical_structure ,female ,Anesthesia ,Nusinersen ,Spinal ,antisense ,preschool ,Injections ,03 medical and health sciences ,least-squares analysis ,Settore MED/39 - NEUROPSICHIATRIA INFANTILE ,Settore MED/41 - ANESTESIOLOGIA ,medicine ,Antisense ,Preschool ,business.industry ,Spinal muscular atrophy ,Motor neuron ,medicine.disease ,030104 developmental biology ,Age of onset ,business ,030217 neurology & neurosurgery - Abstract
Background: Nusinersen is an antisense oligonucleotide drug that modulates pre–messenger RNA splicing of the survival motor neuron 2 (SMN2) gene. It has been developed for the treatment of spinal muscular atrophy (SMA). Methods: We conducted a multicenter, double-blind, sham-controlled, phase 3 trial of nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2:1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274. The primary end point was the least-squares mean change from baseline in the Hammersmith Functional Motor Scale–Expanded (HFMSE) score at 15 months of treatment; HFMSE scores range from 0 to 66, with higher scores indicating better motor function. Secondary end points included the percentage of children with a clinically meaningful increase from baseline in the HFMSE score (≥3 points), an outcome that indicates improvement in at least two motor skills. Results: In the prespecified interim analysis, there was a least-squares mean increase from baseline to month 15 in the HFMSE score in the nusinersen group (by 4.0 points) and a least-squares mean decrease in the control group (by –1.9 points), with a significant between-group difference favoring nusinersen (least-squares mean difference in change, 5.9 points; 95% confidence interval, 3.7 to 8.1; P Conclusions: Among children with later-onset SMA, those who received nusinersen had significant and clinically meaningful improvement in motor function as compared with those in the control group. (Funded by Biogen and Ionis Pharmaceuticals; CHERISH ClinicalTrials.gov number, NCT02292537. opens in new tab.)
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- 2018
7. 24-MONTH ANALYSIS FROM PRIME, A PHASE 1B STUDY IN PATIENTS WITH PRODROMAL/MILD ALZHEIMER’S DISEASE
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von Rosenstiel, P, primary, Gheuens, S, additional, O’Gorman, J, additional, Chiao, P, additional, Hock, C, additional, Nitsch, R, additional, Budd Haeberlein, S, additional, and Sandrock, A, additional
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- 2018
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8. B.05 Nusinersen in infants who initiate treatment in a presymptomatic stage of spinal muscular atrophy (SMA): interim results from the Phase 2 NURTURE study
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De Vivo, DC, primary, Bertini, E, additional, Hwu, W, additional, Foster, R, additional, Bhan, I, additional, Gheuens, S, additional, Farwell, W, additional, Reyna, SP, additional, and Vajsar, J, additional
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- 2018
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9. B.06 Safety and efficacy of nusinersen in infants/children with spinal muscular atrophy (SMA): part 1 of the phase 2 EMBRACE study
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Shieh, PB, primary, Acsadi, G, additional, Mueller-Felber, W, additional, Crawford, TO, additional, Richardson, R, additional, Natarajan, N, additional, Castro, D, additional, Gheuens, S, additional, Bhan, I, additional, Gambino, G, additional, Sun, P, additional, Farwell, W, additional, Reyna, SP, additional, and Vajsar, J, additional
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- 2018
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10. Outcomes after 1-year in presymptomatic infants with genetically diagnosed spinal muscular atrophy (SMA) treated with nusinersen: interim results from the NURTURE study
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Hwu, W., primary, De, D., additional, Bertini, E., additional, Foster, R., additional, Gheuens, S., additional, Farwell, W., additional, and Reyna, S., additional
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- 2017
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11. Nusinersen demonstrates greater efficacy in infants with shorter disease duration: End of study results from the ENDEAR study in infants with spinal muscular atrophy (SMA)
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Servais, L., primary, Farrar, M., additional, Finkel, R., additional, Kirschner, J., additional, Muntoni, F., additional, Sun, P., additional, Gheuens, S., additional, Schneider, E., additional, and Farwell, W., additional
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- 2017
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12. Infants and children with SMA treated with nusinersen in clinical trials: experience of risk for respiratory or other events with repeat anesthesia/sedation for intrathecal administration
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Finkel, R., primary, Mercuri, E., additional, Chiriboga, C., additional, Kuntz, N., additional, Richman, S., additional, Bhan, I., additional, Hughes, S., additional, Foster, R., additional, Farwell, W., additional, and Gheuens, S., additional
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- 2017
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13. Infants and children with SMA treated with nusinersen in clinical trials: an integrated safety analysis
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Mercuri, E., primary, Finkel, R., additional, Farrar, M., additional, Richman, S., additional, Foster, R., additional, Hughes, S., additional, Farwell, W., additional, and Gheuens, S., additional
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- 2017
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14. Safety and efficacy of nusinersen in infants/children with spinal muscular atrophy (SMA): part 1 of the phase 2 EMBRACE study
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Acsadi, G., primary, Shieh, P., additional, Crawford, T., additional, Richardson, R., additional, Natarajan, N., additional, Castro, D., additional, Gheuens, S., additional, Gambino, G., additional, Sun, P., additional, Reyna, S., additional, Farwell, W., additional, and Mueller-Felber, W., additional
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- 2017
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15. Efficacy and safety of nusinersen in children with later-onset spinal muscular atrophy (SMA): end of study results from the phase 3 CHERISH study
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Mercuri, E., primary, Finkel, R., additional, Kirschner, J., additional, Chiriboga, C., additional, Kuntz, N., additional, Sun, P., additional, Gheuens, S., additional, Bennett, C., additional, Schneider, E., additional, and Farwell, W., additional
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- 2017
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16. Efficacy and safety of nusinersen in infants with presymptomatic spinal muscular atrophy (SMA): Interim results from the NURTURE study
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Bertini, E., primary, Hwu, W.-L., additional, Reyna, S.P., additional, Farwell, W., additional, Gheuens, S., additional, Sun, P., additional, Zhong, Z.J., additional, and De Vivo, D.C., additional
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- 2017
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17. Efficacy and safety of nusinersen in infants with spinal muscular atrophy (SMA): Final results from the phase 3 ENDEAR study
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Finkel, R., primary, Kuntz, N., additional, Mercuri, E., additional, Chiriboga, C.A., additional, Darras, B., additional, Topaloglu, H., additional, Montes, J., additional, Su, J., additional, Zhong, Z.J., additional, Gheuens, S., additional, Bennett, C.F., additional, Schneider, E., additional, and Farwell, W., additional
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- 2017
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18. Interim analysis of the phase 3 CHERISH study evaluating nusinersen in patients with later-onset spinal muscular atrophy (SMA): Primary and descriptive secondary endpoints
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Mercuri, E., primary, Finkel, R., additional, Kirschner, J., additional, Chiriboga, C.A., additional, Kuntz, N., additional, Darras, B., additional, Shieh, P.B., additional, Saito, K., additional, De Vivo, D.C., additional, Mazzone, E.S., additional, Montes, J., additional, Yang, Q., additional, Zhong, Z.J., additional, Gheuens, S., additional, Bennett, C.F., additional, Schneider, E., additional, and Farwell, W., additional
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- 2017
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19. Interim Efficacy and Safety Results from the Phase 3 ENDEAR Study of Nusinersen in Infants Diagnosed with Spinal Muscular Atrophy (SMA)
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Finkel, R., additional, Kuntz, N., additional, Mercuri, E., additional, Muntoni, F., additional, Chiriboga, C., additional, Darras, B., additional, Topaloglu, H., additional, Montes, J., additional, Su, J., additional, Zhong, Z., additional, Gheuens, S., additional, Bennett, C., additional, Schneider, E., additional, and Farwell, W., additional
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- 2017
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20. Simultaneous PML-IRIS after discontinuation of natalizumab in a patient with MS.
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Gheuens S, Smith DR, Wang X, Alsop DC, Lenkinski RE, Koralnik IJ, Gheuens, S, Smith, D R, Wang, X, Alsop, D C, Lenkinski, R E, and Koralnik, I J
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- 2012
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21. Simultaneous Pml-Iris After Discontinuation of Natalizumab in A Patient With MS
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Marousi, S., primary, Travasarou, M., additional, Karageorgiou, C. E., additional, Gheuens, S., additional, and Koralnik, I. J., additional
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- 2012
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22. Metabolic profile of PML lesions in patients with and without IRIS: An observational study
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Gheuens, S., primary, Ngo, L., additional, Wang, X., additional, Alsop, D. C., additional, Lenkinski, R. E., additional, and Koralnik, I. J., additional
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- 2012
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23. Progressive multifocal leukoencephalopathy in individuals with minimal or occult immunosuppression
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Gheuens, S., primary, Pierone, G., additional, Peeters, P., additional, and Koralnik, I. J, additional
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- 2009
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24. Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy.
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Mercuri, E., Darras, B. T., Chiriboga, C. A., Day, J. W., Campbell, C., Connolly, A. M., Iannaccone, S. T., Kirschner, J., Kuntz, N. L., Saito, K., Shieh, P. B., Tulinius, M., Mazzone, E. S., Montes, J., Bishop, K. M., Yang, Q., Foster, R., Gheuens, S., Bennett, C. F., and Farwell, W.
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TREATMENT of spinal muscular atrophy , *ANTISENSE drugs , *OLIGONUCLEOTIDES , *MESSENGER RNA , *ADVERSE health care events , *AGE factors in disease , *COMPARATIVE studies , *SPINAL injections , *RESEARCH methodology , *MEDICAL cooperation , *MOTOR ability , *MUSCULAR atrophy , *NUCLEOTIDES , *REGRESSION analysis , *RESEARCH , *EVALUATION research , *RANDOMIZED controlled trials , *BLIND experiment , *THERAPEUTICS - Abstract
Background: Nusinersen is an antisense oligonucleotide drug that modulates pre-messenger RNA splicing of the survival motor neuron 2 ( SMN2) gene. It has been developed for the treatment of spinal muscular atrophy (SMA).Methods: We conducted a multicenter, double-blind, sham-controlled, phase 3 trial of nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2:1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274. The primary end point was the least-squares mean change from baseline in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score at 15 months of treatment; HFMSE scores range from 0 to 66, with higher scores indicating better motor function. Secondary end points included the percentage of children with a clinically meaningful increase from baseline in the HFMSE score (≥3 points), an outcome that indicates improvement in at least two motor skills.Results: In the prespecified interim analysis, there was a least-squares mean increase from baseline to month 15 in the HFMSE score in the nusinersen group (by 4.0 points) and a least-squares mean decrease in the control group (by -1.9 points), with a significant between-group difference favoring nusinersen (least-squares mean difference in change, 5.9 points; 95% confidence interval, 3.7 to 8.1; P<0.001). This result prompted early termination of the trial. Results of the final analysis were consistent with results of the interim analysis. In the final analysis, 57% of the children in the nusinersen group as compared with 26% in the control group had an increase from baseline to month 15 in the HFMSE score of at least 3 points (P<0.001), and the overall incidence of adverse events was similar in the nusinersen group and the control group (93% and 100%, respectively).Conclusions: Among children with later-onset SMA, those who received nusinersen had significant and clinically meaningful improvement in motor function as compared with those in the control group. (Funded by Biogen and Ionis Pharmaceuticals; CHERISH ClinicalTrials.gov number, NCT02292537 .). [ABSTRACT FROM AUTHOR]- Published
- 2018
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25. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy.
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Finkel, R. S., Tizzano, E., Topaloglu, H., Tulinius, M., Glanzman, A. M., Bishop, K., Bennett, C. F., Schneider, E., Zhong, Z. J., Gheuens, S., Farwell, W., De Vivo, D. C., Mercuri, E., Darras, B. T., Connolly, A. M., Kuntz, N. L., Kirschner, J., Chiriboga, C. A., Montes, J., and Saito, K.
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SPINAL muscular atrophy , *MOTOR neurons , *RNA splicing , *NEUROMUSCULAR diseases , *HUMAN deletion mutation , *RNA metabolism , *AGE factors in disease , *ARTIFICIAL respiration , *CARRIER proteins , *COMPARATIVE studies , *SPINAL injections , *RESEARCH methodology , *MEDICAL cooperation , *MOTOR ability , *MUSCULAR atrophy , *NUCLEOTIDES , *PROGNOSIS , *RESEARCH , *RNA , *STATISTICAL sampling , *SURVIVAL analysis (Biometry) , *EVALUATION research , *RANDOMIZED controlled trials , *BLIND experiment , *THERAPEUTICS - Abstract
Background: Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein.Methods: We conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis.Results: In the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41%] vs. 0 of 27 [0%], P<0.001), and this result prompted early termination of the trial. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants [51%] vs. 0 of 37 [0%]), and the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; P=0.005). The likelihood of overall survival was higher in the nusinersen group than in the control group (hazard ratio for death, 0.37; P=0.004), and infants with a shorter disease duration at screening were more likely than those with a longer disease duration to benefit from nusinersen. The incidence and severity of adverse events were similar in the two groups.Conclusions: Among infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug. (Funded by Biogen and Ionis Pharmaceuticals; ENDEAR ClinicalTrials.gov number, NCT02193074 .). [ABSTRACT FROM AUTHOR]- Published
- 2017
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26. P.380 - Safety and efficacy of nusinersen in infants/children with spinal muscular atrophy (SMA): part 1 of the phase 2 EMBRACE study.
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Acsadi, G., Shieh, P., Crawford, T., Richardson, R., Natarajan, N., Castro, D., Gheuens, S., Gambino, G., Sun, P., Reyna, S., Farwell, W., and Mueller-Felber, W.
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TREATMENT of spinal muscular atrophy , *THERAPEUTIC use of oligonucleotides , *THERAPEUTICS ,INFANTS' injuries - Published
- 2017
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27. P.384 - Outcomes after 1-year in presymptomatic infants with genetically diagnosed spinal muscular atrophy (SMA) treated with nusinersen: interim results from the NURTURE study.
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Hwu, W., De, D., Bertini, E., Foster, R., Gheuens, S., Farwell, W., and Reyna, S.
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SPINAL muscular atrophy , *INFANT health , *GENETICS - Published
- 2017
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28. P.385 - Infants and children with SMA treated with nusinersen in clinical trials: experience of risk for respiratory or other events with repeat anesthesia/sedation for intrathecal administration.
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Finkel, R., Mercuri, E., Chiriboga, C., Kuntz, N., Richman, S., Bhan, I., Hughes, S., Foster, R., Farwell, W., and Gheuens, S.
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SPINAL muscular atrophy , *CLINICAL trials , *PATIENTS - Published
- 2017
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29. P.381 - Nusinersen demonstrates greater efficacy in infants with shorter disease duration: End of study results from the ENDEAR study in infants with spinal muscular atrophy (SMA).
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Servais, L., Farrar, M., Finkel, R., Kirschner, J., Muntoni, F., Sun, P., Gheuens, S., Schneider, E., and Farwell, W.
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SPINAL muscular atrophy , *INFANT diseases , *BLIND experiment , *PATIENTS - Published
- 2017
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30. P.378 - Efficacy and safety of nusinersen in children with later-onset spinal muscular atrophy (SMA): end of study results from the phase 3 CHERISH study.
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Mercuri, E., Finkel, R., Kirschner, J., Chiriboga, C., Kuntz, N., Sun, P., Gheuens, S., Bennett, C., Schneider, E., and Farwell, W.
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SPINAL muscular atrophy , *OLIGONUCLEOTIDES , *PATIENTS - Published
- 2017
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31. P.379 - Infants and children with SMA treated with nusinersen in clinical trials: an integrated safety analysis.
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Mercuri, E., Finkel, R., Farrar, M., Richman, S., Foster, R., Hughes, S., Farwell, W., and Gheuens, S.
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SPINAL muscular atrophy , *NEUROMUSCULAR diseases in infants , *TREATMENT of spinal muscular atrophy - Published
- 2017
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32. Early-onset reduced bone mineral density in patients with pyruvate kinase deficiency.
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Al-Samkari H, Grace RF, Glenthøj A, Andres O, Barcellini W, Galactéros F, Kuo KHM, Layton DM, Morado Arias M, Viprakasit V, Dong Y, Tai F, Hawkins P, Gheuens S, Morales-Arias J, Gilroy KS, Porter JB, and van Beers EJ
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- Humans, Bone Density, Pyruvate Kinase, Anemia, Hemolytic, Congenital Nonspherocytic genetics, Pyruvate Metabolism, Inborn Errors
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- 2023
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33. Mitapivat in adult patients with pyruvate kinase deficiency receiving regular transfusions (ACTIVATE-T): a multicentre, open-label, single-arm, phase 3 trial.
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Glenthøj A, van Beers EJ, Al-Samkari H, Viprakasit V, Kuo KHM, Galactéros F, Chonat S, Porter J, Zagadailov E, Xu R, Oluyadi A, Hawkins P, Gheuens S, Beynon V, and Barcellini W
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- Adolescent, Adult, Alanine Transaminase, Anemia, Hemolytic, Congenital Nonspherocytic, Aspartate Aminotransferases, Female, Humans, Male, Pharmaceutical Preparations, Piperazines, Pyruvate Metabolism, Inborn Errors, Quinolines, Treatment Outcome, Triglycerides, Hemoglobins, Pyruvate Kinase deficiency
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Background: Mitapivat, an oral activator of pyruvate kinase (PK) in red blood cells (RBCs), has shown significant improvements in haemoglobin and haemolysis among patients with pyruvate kinase deficiency who were not receiving regular transfusions. We aimed to evaluate the efficacy and safety of mitapivat in adults with pyruvate kinase deficiency receiving regular transfusions., Methods: ACTIVATE-T was an open-label, single-arm, phase 3 trial conducted in 20 centres across Europe, North America, and Asia. Eligible participants were adults (aged ≥18 years) with a clinical laboratory confirmation of pyruvate kinase deficiency receiving regular transfusions (at least six episodes in the previous year). Participants received oral mitapivat during a 16-week dose-optimisation period (5 mg, 20 mg, 50 mg twice daily) and 24-week fixed-dose period. The primary endpoint was a reduction in transfusion burden (≥33% reduction in number of RBC units transfused during the fixed-dose period, compared with the participant's individual historical transfusion burden, standardised to 24 weeks). Efficacy and safety were assessed in all participants who received at least one dose of mitapivat. This trial is registered with ClinicalTrials.gov, NCT03559699, and is complete., Findings: Between June 26, 2018, and Feb 4, 2020, 27 participants (20 [74%] female and seven [26%] male; 20 [74%] White, three [11%] Asian, and four [15%] not reported) were enrolled and received at least one dose of mitapivat. Median duration of exposure to mitapivat was 40·3 weeks (IQR 40·0-41·3). A reduction in transfusion burden by at least 33% was found in ten (37%) participants (95% CI 19-58; p=0·0002). The most common treatment-emergent adverse events were increase in alanine aminotransferase (ten [37%] participants), headache (ten [37%]), increase in aspartate aminotransferase (five [19%]), fatigue (five [19%]), and nausea (five [19%]). Two grade 3 treatment-emergent adverse events were related to study treatment: joint swelling (one participant [4%]) and an increase in aspartate aminotransferase (one participant [4%]). Three participants had serious treatment-emergent adverse events, none related to the study treatment: increased blood triglycerides, ovarian cyst, and renal colic (each in one participant [4%]). No treatment-related deaths were observed., Interpretation: Mitapivat represents a novel therapy that can reduce transfusion burden in some adults with pyruvate kinase deficiency receiving regular transfusions, and is the first disease-modifying agent approved in this disease., Funding: Agios Pharmaceuticals., Competing Interests: Declaration of interests EZ, RX, AO, PH, SG, and VB are employees and shareholders of Agios Pharmaceuticals. AG has received fees for consultancy work and as a member of advisory boards from Agios Pharmaceuticals, bluebird bio, Celgene, Novartis, and Novo Nordisk; and research grants from Alexion, Saniona, and Sanofi. EJvB has received fees as a member of advisory board from Agios Pharmaceuticals; and research funding from Agios Pharmaceuticals, Novartis, Pfizer, and RR Mechatronics. HA-S has received fees for consultancy work from Agios Pharmaceuticals, argenx, Dova–Sobi, Novartis, Rigel, Forma Therapeutics, and Moderna; and research funding from Agios Pharmaceuticals, Dova, and Amgen. VV has received fees for consultancy work, honoraria, research funding, and speakers bureau from Bristol-Myers Squibb; and fees for consultancy work and research funding from Agios Pharmaceuticals, Ionis, La Jolla Pharmaceuticals, Protagonist Therapeutics, and Vifor Pharma. KHMK has received fees for consultancy work from Agios Pharmaceuticals, Alexion, Apellis, bluebird bio, Celgene, Pfizer, and Novartis; honoraria from Alexion and Novartis; research funding from Pfizer; and membership on an entity's Board of Directors or advisory committees from Bioverativ. FG has been on board membership or advisory committee for Addmedica. SC has received fees for consultancy work from Agios Pharmaceuticals, Alexion, Daiichi Sankyo, Novartis, and Takeda; and research funding from Agios Pharmaceuticals, Alexion, Apellis, Global Blood Therapeutics, Novartis, and Takeda. WB has received honoraria from Agios Pharmaceuticals, Alexion, and Novartis; and been on board membership or advisory committee for Bioverativ and Incyte. JP declares no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
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- 2022
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34. Mitapivat versus Placebo for Pyruvate Kinase Deficiency.
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Al-Samkari H, Galactéros F, Glenthøj A, Rothman JA, Andres O, Grace RF, Morado-Arias M, Layton DM, Onodera K, Verhovsek M, Barcellini W, Chonat S, Judge MP, Zagadailov E, Xu R, Hawkins P, Beynon V, Gheuens S, and van Beers EJ
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- Adult, Anemia, Hemolytic, Congenital Nonspherocytic drug therapy, Double-Blind Method, Hemoglobins analysis, Hemoglobins drug effects, Hemolysis drug effects, Humans, Pyruvate Metabolism, Inborn Errors drug therapy, Piperazines pharmacology, Piperazines therapeutic use, Pyruvate Kinase deficiency, Quinolines pharmacology, Quinolines therapeutic use
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Background: Pyruvate kinase deficiency is a rare, hereditary, chronic condition that is associated with hemolytic anemia. In a phase 2 study, mitapivat, an oral, first-in-class activator of erythrocyte pyruvate kinase, increased the hemoglobin level in patients with pyruvate kinase deficiency., Methods: In this global, phase 3, randomized, placebo-controlled trial, we evaluated the efficacy and safety of mitapivat in adults with pyruvate kinase deficiency who were not receiving regular red-cell transfusions. The patients were assigned to receive either mitapivat (5 mg twice daily, with potential escalation to 20 or 50 mg twice daily) or placebo for 24 weeks. The primary end point was a hemoglobin response (an increase from baseline of ≥1.5 g per deciliter in the hemoglobin level) that was sustained at two or more scheduled assessments at weeks 16, 20, and 24. Secondary efficacy end points were the average change from baseline in the hemoglobin level, markers of hemolysis and hematopoiesis, and the change from baseline at week 24 in two pyruvate kinase deficiency-specific patient-reported outcome measures., Results: Sixteen of the 40 patients (40%) in the mitapivat group had a hemoglobin response, as compared with none of the 40 patients in the placebo group (adjusted difference, 39.3 percentage points; 95% confidence interval, 24.1 to 54.6; two-sided P<0.001). Patients who received mitapivat had a greater response than those who received placebo with respect to each secondary end point, including the average change from baseline in the hemoglobin level. The most common adverse events were nausea (in 7 patients [18%] in the mitapivat group and 9 patients [23%] in the placebo group) and headache (in 6 patients [15%] and 13 patients [33%], respectively). Adverse events of grade 3 or higher occurred in 10 patients (25%) who received mitapivat and 5 patients (13%) who received placebo., Conclusions: In patients with pyruvate kinase deficiency, mitapivat significantly increased the hemoglobin level, decreased hemolysis, and improved patient-reported outcomes. No new safety signals were identified in the patients who received mitapivat. (Funded by Agios Pharmaceuticals; ACTIVATE ClinicalTrials.gov number, NCT03548220.)., (Copyright © 2022 Massachusetts Medical Society.)
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- 2022
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35. Patterning Chronic Active Demyelination in Slowly Expanding/Evolving White Matter MS Lesions.
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Elliott C, Arnold DL, Chen H, Ke C, Zhu L, Chang I, Cahir-McFarland E, Fisher E, Zhu B, Gheuens S, Scaramozza M, Beynon V, Franchimont N, Bradley DP, and Belachew S
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- Adult, Brain diagnostic imaging, Brain drug effects, Brain pathology, Demyelinating Diseases drug therapy, Demyelinating Diseases pathology, Diffusion Magnetic Resonance Imaging, Double-Blind Method, Female, Humans, Male, Middle Aged, Multiple Sclerosis pathology, White Matter drug effects, White Matter pathology, Antibodies, Monoclonal therapeutic use, Demyelinating Diseases diagnostic imaging, Multiple Sclerosis diagnostic imaging, Multiple Sclerosis drug therapy, White Matter diagnostic imaging
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Background and Purpose: Slowly expanding/evolving lesions measured by conventional T1-weighted/T2-weighted brain MR imaging may contribute to progressive disability accumulation in MS. We evaluated the longitudinal change in myelin and axonal tissue integrity in white matter slowly expanding/evolving lesions by means of the magnetization transfer ratio and DTI radial diffusivity., Materials and Methods: Slowly expanding/evolving lesions were detected within the Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of BIIB033 in Participants With Relapsing Forms of Multiple Sclerosis When Used Concurrently With Avonex (SYNERGY) Phase 2 clinical trial dataset (NCT01864148), comprising patients with relapsing-remitting and secondary-progressive MS ( n = 299) with T1-weighted/T2-weighted MR imaging at all trial time points (baseline to week 72)., Results: Compared with non-slowly expanding/evolving lesions (areas not classified as slowly expanding/evolving lesion) of baseline nonenhancing T2 lesions, slowly expanding/evolving lesions had a lower normalized magnetization transfer ratio and greater DTI radial diffusivity, both in patients with relapsing-remitting MS ( n = 242) and secondary-progressive MS ( n = 57, P < .001 for all). Although the changes with time in both the normalized magnetization transfer ratio and DTI radial diffusivity between slowly expanding/evolving lesions and non-slowly expanding/evolving lesions were positively correlated ( P < .001), a decrease in the normalized magnetization transfer ratio and a greater increase in DTI radial diffusivity were observed in slowly expanding/evolving lesions versus non-slowly expanding/evolving lesions from baseline to week 72 in relapsing-remitting MS and secondary-progressive MS ( P < .001 for all)., Conclusions: Patterns of longitudinal change in the normalized magnetization transfer ratio and DTI radial diffusivity in slowly expanding/evolving lesions were consistent with progressive demyelination and tissue loss, as seen in smoldering white matter MS plaques., (© 2020 by American Journal of Neuroradiology.)
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- 2020
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36. Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study.
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De Vivo DC, Bertini E, Swoboda KJ, Hwu WL, Crawford TO, Finkel RS, Kirschner J, Kuntz NL, Parsons JA, Ryan MM, Butterfield RJ, Topaloglu H, Ben-Omran T, Sansone VA, Jong YJ, Shu F, Staropoli JF, Kerr D, Sandrock AW, Stebbins C, Petrillo M, Braley G, Johnson K, Foster R, Gheuens S, Bhan I, Reyna SP, Fradette S, and Farwell W
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- Child, Preschool, Female, Follow-Up Studies, Humans, Infant, Infant, Newborn, Male, Motor Activity, Muscular Atrophy, Spinal genetics, Muscular Atrophy, Spinal physiopathology, Oligonucleotides adverse effects, Survival of Motor Neuron 2 Protein genetics, Time Factors, Treatment Outcome, Muscular Atrophy, Spinal therapy, Oligonucleotides administration & dosage
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Spinal muscular atrophy (SMA) is a neurodegenerative disease associated with severe muscle atrophy and weakness in the limbs and trunk. We report interim efficacy and safety outcomes as of March 29, 2019 in 25 children with genetically diagnosed SMA who first received nusinersen in infancy while presymptomatic in the ongoing Phase 2, multisite, open-label, single-arm NURTURE trial. Fifteen children have two SMN2 copies and 10 have three SMN2 copies. At last visit, children were median (range) 34.8 [25.7-45.4] months of age and past the expected age of symptom onset for SMA Types I or II; all were alive and none required tracheostomy or permanent ventilation. Four (16%) participants with two SMN2 copies utilized respiratory support for ≥6 h/day for ≥7 consecutive days that was initiated during acute, reversible illnesses. All 25 participants achieved the ability to sit without support, 23/25 (92%) achieved walking with assistance, and 22/25 (88%) achieved walking independently. Eight infants had adverse events considered possibly related to nusinersen by the study investigators. These results, representing a median 2.9 years of follow up, emphasize the importance of proactive treatment with nusinersen immediately after establishing the genetic diagnosis of SMA in presymptomatic infants and emerging newborn screening efforts., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2019
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37. Neuroimaging and pediatric HIV.
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Bearden DR and Gheuens S
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- 2019
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38. An Integrated Safety Analysis of Infants and Children with Symptomatic Spinal Muscular Atrophy (SMA) Treated with Nusinersen in Seven Clinical Trials.
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Darras BT, Farrar MA, Mercuri E, Finkel RS, Foster R, Hughes SG, Bhan I, Farwell W, and Gheuens S
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- Child, Preschool, Clinical Trials as Topic, Female, Humans, Infant, Infant, Newborn, Injections, Spinal methods, Male, Oligonucleotides adverse effects, Muscular Atrophy, Spinal drug therapy, Oligonucleotides therapeutic use
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Background: Treatment with nusinersen has demonstrated significant and clinically meaningful benefits in clinical trials in infants and children with spinal muscular atrophy (SMA)., Objective: The objective of this analysis was to characterize the safety of nusinersen across the clinical trial program in infants and children with symptomatic SMA., Methods: An integrated safety analysis evaluated end of study data from seven completed clinical trials that enrolled infants and children with symptomatic SMA who were treated with intrathecal nusinersen or underwent sham procedures. Two of the studies were conducted in symptomatic infants with infantile-onset SMA (most likely to develop SMA type I or II) and the remaining five in symptomatic children and adolescents with later-onset SMA (have or are most likely to develop SMA type II or III). Safety assessments included incidence of adverse events (AEs), physical and neurological examinations, vital signs, clinical laboratory tests (serum chemistry, hematology, and urinalysis), and electrocardiograms., Results: Data were analyzed from 323 infants and children, including 240 treated with nusinersen (100 with infantile-onset SMA and 140 with later-onset SMA) and 83 who underwent sham procedures (41 infantile-onset, 42 later-onset). Median (range) exposure to nusinersen was 449.0 (6-1538) days (375.9 participant-years). The most common AEs with nusinersen were pyrexia, upper respiratory tract infection, nasopharyngitis, vomiting, headache, and constipation. The incidence of serious AEs was lower with nusinersen than with the sham procedure (41% vs. 61%). The overall incidence of respiratory, thoracic, and mediastinal AEs was higher in participants with symptomatic infantile-onset SMA than those with symptomatic later-onset SMA and similar in nusinersen- versus sham procedure-treated participants. Rates of post-lumbar puncture syndrome and related events were higher with nusinersen versus sham procedure in later-onset SMA participants. No abnormal patterns or trends in laboratory test results were observed., Conclusions: Nusinersen demonstrated a favorable safety profile in children with symptomatic infantile- and later-onset SMA. Most reported AEs and serious AEs were consistent with the nature and frequency of events typically seen with SMA or in the context of lumbar puncture procedures., Registration: NCT01494701, NCT01703988, NCT01839656, NCT02193074, NCT02292537, NCT01780246, NCT02052791.
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- 2019
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39. Nusinersen in later-onset spinal muscular atrophy: Long-term results from the phase 1/2 studies.
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Darras BT, Chiriboga CA, Iannaccone ST, Swoboda KJ, Montes J, Mignon L, Xia S, Bennett CF, Bishop KM, Shefner JM, Green AM, Sun P, Bhan I, Gheuens S, Schneider E, Farwell W, and De Vivo DC
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- Adolescent, Child, Child, Preschool, Female, Humans, Male, Treatment Outcome, Oligonucleotides therapeutic use, Spinal Muscular Atrophies of Childhood drug therapy
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Objective: To report results of intrathecal nusinersen in children with later-onset spinal muscular atrophy (SMA)., Methods: Analyses included children from a phase 1b/2a study (ISIS-396443-CS2; NCT01703988) who first received nusinersen during that study and were eligible to continue treatment in the extension study (ISIS-396443-CS12; NCT02052791). The phase 1b/2a study was a 253-day, ascending dose (3, 6, 9, 12 mg), multiple-dose, open-label, multicenter study that enrolled children with SMA aged 2-15 years. The extension study was a 715-day, single-dose level (12 mg) study. Time between studies varied by participant (196-413 days). Assessments included the Hammersmith Functional Motor Scale-Expanded (HFMSE), Upper Limb Module (ULM), 6-Minute Walk Test (6MWT), compound muscle action potential (CMAP), and quantitative multipoint incremental motor unit number estimation. Safety also was assessed., Results: Twenty-eight children were included (SMA type II, n = 11; SMA type III, n = 17). Mean HFMSE scores, ULM scores, and 6MWT distances improved by the day 1,150 visit (HFMSE: SMA type II, +10.8 points; SMA type III, +1.8 points; ULM: SMA type II, +4.0 points; 6MWT: SMA type III, +92.0 meters). Mean CMAP values remained relatively stable. No children discontinued treatment due to adverse events., Conclusions: Nusinersen treatment over ∼3 years resulted in motor function improvements and disease activity stabilization not observed in natural history cohorts. These results document the long-term benefit of nusinersen in later-onset SMA, including SMA type III., Clinicaltrialsgov Identifier: NCT01703988 (ISIS-396443-CS2); NCT02052791 (ISIS-396443-CS12)., Classification of Evidence: This study provides Class IV evidence that nusinersen improves motor function in children with later-onset SMA., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
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- 2019
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40. Safety and efficacy of natalizumab in patients with acute ischaemic stroke (ACTION): a randomised, placebo-controlled, double-blind phase 2 trial.
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Elkins J, Veltkamp R, Montaner J, Johnston SC, Singhal AB, Becker K, Lansberg MG, Tang W, Chang I, Muralidharan K, Gheuens S, Mehta L, and Elkind MSV
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- Adolescent, Adult, Aged, Aged, 80 and over, Brain Ischemia drug therapy, Double-Blind Method, Female, Humans, International Cooperation, Male, Middle Aged, PubMed, Retrospective Studies, Young Adult, Brain Ischemia complications, Immunologic Factors metabolism, Natalizumab therapeutic use, Stroke drug therapy, Stroke etiology, Treatment Outcome
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Background: In animal models of acute ischaemic stroke, blocking of the leukocyte-endothelium adhesion by antagonism of α4 integrin reduces infarct volumes and improves outcomes. We assessed the effect of one dose of natalizumab, an antibody against the leukocyte adhesion molecule α4 integrin, in patients with acute ischaemic stroke., Methods: In this double-blind, phase 2 study, patients with acute ischaemic stroke (aged 18-85 years) from 30 US and European clinical sites were randomly assigned (1:1) to 300 mg intravenous natalizumab or placebo with stratification by treatment window and baseline infarct size. Patients, investigators, and study staff were masked to treatment assignments. The primary endpoint was the change in infarct volume from baseline to day 5 and was assessed in the modified intention-to-treat population. Secondary endpoints were the change in infarct volume from baseline to day 30, and from 24 h to days 5 and 30; the National Institute of Health Stroke Scale (NIHSS) at baseline, 24 h, and at days 5 (or discharge), 30, and 90; and modified Rankin Scale (mRS) and Barthel Index (BI) at days 5 (or discharge), 30, and 90. This trial is registered with ClinicalTrials.gov, number NCT01955707., Findings: Between Dec 16, 2013, and April 9, 2015, 161 patients were randomly assigned to natalizumab (n=79) or placebo (n=82). Natalizumab did not reduce infarct volume growth from baseline to day 5 compared with placebo (median absolute growth 28 mL [range -8 to 303] vs 22 mL [-11 to 328]; relative growth ratio 1·09 [90% CI 0·91-1·30], p=0·78) or to day 30 (4 mL [-43 to 121] vs 4 mL [-28 to 180]; 1·05 [0·88-1·27], p=0·68), from 24 h to day 5 (8 mL [-30 to 177] vs 7 mL [-13 to 204]; 1·00 [0·89-1·12], p=0·49), and from 24 h to day 30 (-5 mL [-93 to 81] vs -5 mL [-48 to 48]; 0·98 [0·87-1·11], p=0·40). No difference was noted between the natalizumab and placebo groups in the NIHSS (score ≤1 or ≥8 point improvement) from baseline at 24 h, day 5 (or discharge), day 30 (27 [35%] vs 36 [44%]; odds ratio 0·69 [90% CI 0·39-1·21], p=0·86), and day 90 (36 [47%] vs 37 [46%]; 1·10 [0·63-1·93], p=0·39). More patients in the natalizumab group than in the placebo group had mRS scores of 0 or 1 at day 30 (13 [18%] vs seven [9%]; odds ratio 2·88 [90% CI 1·20-6·93], p=0·024) and day 90 (18 [25%] vs 16 [21%]; 1·48 [0·74-2·98], p=0·18); and BI (score ≥95) at day 90 (34 [44%] vs 26 [33%]; 1·91 [1·07-3·41], p=0·033) but not significantly at day 5 or day 30 (26 [34%] vs 26 [32%]; 1·13 [0·63-2·00], p=0·37). Natalizumab and placebo groups had similar incidences of adverse events (77 [99%] of 78 patients vs 81 [99%] of 82 patients), serious adverse events (36 [46%] vs 38 [46%]), and deaths (14 [18%] vs 13 [16%]). Two patients in the natalizumab group died because of adverse events assessed as related to treatment by the investigator (pneumonia, and septic shock and multiorgan failure)., Interpretation: Natalizumab administered up to 9 h after stroke onset did not reduce infarct growth. Treatment-associated benefits on functional outcomes might warrant further investigation., Funding: Biogen., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
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- 2017
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41. Clinical Development of Aducanumab, an Anti-Aβ Human Monoclonal Antibody Being Investigated for the Treatment of Early Alzheimer's Disease.
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Budd Haeberlein S, O'Gorman J, Chiao P, Bussière T, von Rosenstiel P, Tian Y, Zhu Y, von Hehn C, Gheuens S, Skordos L, Chen T, and Sandrock A
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- Antibodies, Monoclonal, Humanized adverse effects, Clinical Trials as Topic, Humans, Immunologic Factors adverse effects, Alzheimer Disease therapy, Antibodies, Monoclonal, Humanized therapeutic use, Immunologic Factors therapeutic use
- Abstract
The amyloid hypothesis has been the dominant framework for Alzheimer's disease (AD) research, including the development of anti-AD therapies. However, none of the phase III clinical trials conducted to date that targeted amyloid β (Aβ) production, aggregation, or clearance demonstrated a statistically significant treatment effect in patients with AD. This includes the approach of using monoclonal antibodies that recognize various Aβ epitopes and display different binding selectivity. While some monoclonal antibodies have failed in phase III trials, several are still in development. Aducanumab (BIIB037) is a human antibody that selectively targets aggregated forms of Aβ, including soluble oligomers and insoluble fibrils. In PRIME (NCT01677572), an ongoing phase Ib trial (N=196 patients dosed), aducanumab was shown to reduce Aβ plaques and slow decline in clinical measures in patients with prodromal or mild AD, with acceptable safety and tolerability. The main safety finding was amyloid-related imaging abnormalities (ARIA), a side effect associated with removal of Aβ, which was dose-dependent and occurred more often in ApoE ε4 carriers than non-carriers. ENGAGE (NCT02477800) and EMERGE (NCT02484547), the ongoing phase III trials of aducanumab in early AD, have been designed based on the outcomes of PRIME and on lessons from past clinical trials in patients with AD. Those study design features include patient selection with confirmed Aβ pathology, ensuring sufficient target engagement, and conducting clinical trials in patients at earlier symptomatic stages of AD., Competing Interests: SBH, JO, PC, PvR YT, YZ, CvH, SG, LS, TC, and AS: employee and stock ownership, Biogen; TB: employee and stock ownership, patent holder, Biogen.
- Published
- 2017
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42. Brief Report: Role of Thymic Reconstitution in the Outcome of AIDS-Related PML.
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Chalkias SG, Gheuens S, Bord E, Batson S, and Koralnik IJ
- Subjects
- Acquired Immunodeficiency Syndrome drug therapy, Adult, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Female, Humans, Longitudinal Studies, Male, Middle Aged, Treatment Outcome, Young Adult, AIDS-Related Opportunistic Infections immunology, Acquired Immunodeficiency Syndrome complications, Acquired Immunodeficiency Syndrome immunology, Anti-Retroviral Agents therapeutic use, Leukoencephalopathy, Progressive Multifocal immunology, Thymus Gland physiology
- Abstract
Implications of thymopoiesis in AIDS-related opportunistic infections remain unexplored. We used progressive multifocal leukoencephalopathy (PML), caused by JC virus (JCV), as an opportunistic infection model, and we simultaneously investigated thymic output and T-cell responses against JCV in 22 patients with PML treated with combined antiretroviral therapy. Thymic output was significantly associated with JCV-specific CD4⁺ and CD8⁺ T-cell responses and improved survival. Our data suggest that patients with AIDS-related PML and impaired thymopoiesis are less likely to develop a robust JCV-specific cellular immune response and consequently are at an increased risk for a poor clinical outcome.
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- 2015
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43. Predictors of survival and functional outcomes in natalizumab-associated progressive multifocal leukoencephalopathy.
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Dong-Si T, Gheuens S, Gangadharan A, Wenten M, Philip J, McIninch J, Datta S, Richert N, Bozic C, Bloomgren G, Richman S, Weber T, and Clifford DB
- Subjects
- Adolescent, Adult, Aged, Brain pathology, Female, Humans, JC Virus, Kaplan-Meier Estimate, Leukoencephalopathy, Progressive Multifocal virology, Magnetic Resonance Imaging, Male, Middle Aged, Survivors statistics & numerical data, Viral Load, Young Adult, Immunologic Factors adverse effects, Leukoencephalopathy, Progressive Multifocal chemically induced, Leukoencephalopathy, Progressive Multifocal mortality, Natalizumab adverse effects
- Abstract
Natalizumab, a highly effective therapy for relapsing-remitting multiple sclerosis, is associated with a risk of progressive multifocal leukoencephalopathy (PML). The objective of this analysis was to examine factors predicting survival in a large natalizumab-associated PML global population. Patients with natalizumab-associated PML identified through postmarketing surveillance were followed up for up to 24 months using a structured questionnaire completed by treating physicians. Demographic and clinical characteristics, JC viral load, magnetic resonance imaging (MRI) results, and Expanded Disability Status Scale (EDSS) and Karnofsky Performance Scale (KPS) scores were compared in survivors and nonsurvivors. Kaplan-Meier analysis was used to model survival function. Among the 336 patients included in this analysis, 76 % survived, with mean follow-up time from PML diagnosis of 16.1 months for survivors; mean time from diagnosis to death was 4.7 months for nonsurvivors. Survivors were significantly younger at diagnosis, had significantly lower EDSS scores and higher KPS scores prior to PML diagnosis, and had significantly lower cerebrospinal fluid JC viral load at the time of diagnosis. Patients with less extensive disease on MRI at diagnosis had a higher survival rate than those with widespread disease. Survivors generally had less functional disability pre-PML, at PML diagnosis, and in subsequent months. In survivors, functional disability appeared to stabilize approximately 6 months post-PML diagnosis. In this analysis, younger age at diagnosis, less functional disability prior to PML diagnosis, lower JC viral load at diagnosis, and more localized brain involvement by MRI at the time of diagnosis appeared to predict improved survival in natalizumab-associated PML.
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- 2015
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44. Outcome and survival of asymptomatic PML in natalizumab-treated MS patients.
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Dong-Si T, Richman S, Wattjes MP, Wenten M, Gheuens S, Philip J, Datta S, McIninch J, Bozic C, Bloomgren G, and Richert N
- Abstract
Objective: As of 3 September 2013, 399 cases of natalizumab-associated progressive multifocal leukoencephalopathy (PML) were confirmed in multiple sclerosis (MS) patients. We evaluated outcomes of natalizumab-treated MS patients who were asymptomatic at PML diagnosis., Methods: Analyses included data available as of 5 June 2013. Asymptomatic patients diagnosed with PML by magnetic resonance imaging (MRI) findings and JC virus DNA detection in the central nervous system were compared with patients presenting with symptoms at diagnosis. Demographics, MRI, and survival over 12 months were analyzed. Expanded Disability Status Scale (EDSS) and Karnofsky Performance Scale (KPS) scores were recorded pre-PML, at diagnosis, and at 6 and 12 months post-diagnosis., Results: A total of 372 PML cases were analyzed; 30 patients were asymptomatic and 342 were symptomatic at PML diagnosis. Classifications of PML lesions on MRI in asymptomatic versus symptomatic patients were unilobar in 68% versus 37%, multilobar in 21% versus 24%, and widespread in 11% versus 40%. In both groups with unilobar lesions, frontal lobe lesions predominated. Prior to PML, mean EDSS and KPS scores were similar for asymptomatic and symptomatic patients. At diagnosis, mean EDSS score was significantly lower for asymptomatic patients (4.1; n = 11) than for symptomatic patients (5.4; n = 193; P = 0.038). Six months after PML diagnosis, asymptomatic patients had less functional disability than symptomatic patients. As of 5 June 2013, 96.7% of asymptomatic patients and 75.4% of symptomatic patients were alive., Interpretation: PML patients asymptomatic at diagnosis had better survival and less functional disability than those who were symptomatic at diagnosis.
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- 2014
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45. Immune reconstitution after allogeneic hematopoietic stem cell transplantation is associated with selective control of JC virus reactivation.
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Tan CS, Broge TA Jr, Ngo L, Gheuens S, Viscidi R, Bord E, Rosenblatt J, Wong M, Avigan D, and Koralnik IJ
- Subjects
- Adult, Case-Control Studies, Female, Hematologic Neoplasms immunology, Hematologic Neoplasms therapy, Hematologic Neoplasms virology, Humans, JC Virus immunology, Leukoencephalopathy, Progressive Multifocal immunology, Male, Transplantation Conditioning methods, Transplantation, Homologous, Virus Activation immunology, Hematopoietic Stem Cell Transplantation methods, JC Virus physiology, Leukoencephalopathy, Progressive Multifocal virology
- Abstract
JC virus (JCV) causes progressive multifocal leukoencephalopathy (PML) in immunocompromised patients. The mechanism of JCV reactivation and immunity in a transplanted immune system remains unclear. We prospectively studied 30 patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) and collected blood and urine samples before HSCT and 3, 6, and 12 to 18 months after HSCT. Before HSCT, JCV DNA was detected in 7 of 30 urine, 5 of 30 peripheral blood mononuclear cells (PBMC) and 6 of 30 plasma samples. Although JC viruria remained stable after HSCT with detection in 5 of 21 samples, viremia was detected in only 1 of 22 plasma and none of 22 PBMC samples 12 to 18 months after HSCT. Prevalence of anti-JCV IgG was 83% before HSCT and decreased to 72% at 12 to 18 months. Anti-JCV IgM was rarely detected. JCV-specific CD4(+) and CD8(+) T cell responses increased 12 to 18 months after HSCT. Although JC viruria correlated directly with detection of anti-JCV IgG, the cellular immune response to JCV measured by ELISpot was inversely correlated with anti-JCV IgG response. The diagnosis of acute myelogenous leukemia and age group were 2 independent patient factors associated with significantly reduced cellular immune responses to JCV. This prospective study in HSCT patients provides a model of interactions between the host immune response and viral activation in multiple compartments during the recovery of the immune system., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
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- 2014
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46. Hyperperfusion in progressive multifocal leukoencephalopathy is associated with disease progression and absence of immune reconstitution inflammatory syndrome.
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Khoury MN, Gheuens S, Ngo L, Wang X, Alsop DC, and Koralnik IJ
- Subjects
- Adult, Aged, Disease Progression, Female, Humans, Immune Reconstitution Inflammatory Syndrome diagnosis, Immune Reconstitution Inflammatory Syndrome physiopathology, Leukoencephalopathy, Progressive Multifocal diagnosis, Leukoencephalopathy, Progressive Multifocal physiopathology, Magnetic Resonance Imaging, Male, Middle Aged, Multimodal Imaging, Perfusion Imaging, Predictive Value of Tests, Young Adult, Immune Reconstitution Inflammatory Syndrome pathology, Leukoencephalopathy, Progressive Multifocal pathology
- Abstract
We sought to characterize perfusion patterns of progressive multifocal leukoencephalopathy lesions by arterial spin labelling perfusion magnetic resonance imaging and to analyse their association with immune reconstitution inflammatory syndrome, and survival. A total of 22 patients with progressive multifocal leukoencephalopathy underwent a clinical evaluation and magnetic resonance imaging of the brain within 190 days of symptom onset. The presence of immune reconstitution inflammatory syndrome was determined based on clinical and laboratory criteria. Perfusion within progressive multifocal leukoencephalopathy lesions was determined by arterial spin labelling magnetic resonance imaging. We observed intense hyperperfusion within and at the edge of progressive multifocal leukoencephalopathy lesions in a subset of subjects. This hyperperfusion was quantified by measuring the fraction of lesion volume showing perfusion in excess of twice normal appearing grey matter. Hyperperfused lesion fraction was significantly greater in progressive multifocal leukoencephalopathy progressors than in survivors (12.8% versus 3.4% P = 0.02) corresponding to a relative risk of progression for individuals with a hyperperfused lesion fraction ≥ 4.0% of 9.1 (95% confidence interval of 1.4-59.5). The presence of hyperperfusion was inversely related to the occurrence of immune reconstitution inflammatory syndrome at the time of scan (P = 0.03). Indeed, within 3 months after symptom onset, hyperperfusion had a positive predictive value of 88% for absence of immune reconstitution inflammatory syndrome. Arterial spin labelling magnetic resonance imaging recognized regions of elevated perfusion within lesions of progressive multifocal leukoencephalopathy. These regions might represent virologically active areas operating in the absence of an effective adaptive immune response and correspond with a worse prognosis.
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- 2013
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47. Natalizumab-associated progressive multifocal leukoencephalopathy in a patient with multiple sclerosis: a postmortem study.
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Wüthrich C, Popescu BF, Gheuens S, Marvi M, Ziman R, Denq SP, Tham M, Norton E, Parisi JE, Dang X, Lucchinetti CF, and Koralnik IJ
- Subjects
- Antibodies, Monoclonal, Humanized therapeutic use, Autopsy, Female, Humans, Leukoencephalopathy, Progressive Multifocal pathology, Middle Aged, Multiple Sclerosis pathology, Natalizumab, Antibodies, Monoclonal, Humanized adverse effects, Brain pathology, Leukoencephalopathy, Progressive Multifocal chemically induced, Multiple Sclerosis drug therapy, Spinal Cord pathology
- Abstract
Natalizumab, a monoclonal antibody directed against α4 integrins, has, to date, been associated with 399 cases of progressive multifocal leukoencephalopathy (PML) worldwide in patients receiving treatment for multiple sclerosis (MS). Because of the limited number of histologic studies, the possible interplay between MS and PML lesions has not been investigated. We report the clinical, radiologic, and histologic findings of an MS patient who developed PML after 32 months of natalizumab monotherapy. After withdrawal of natalizumab, she received plasma exchange, mefloquine, and mirtazapine but died soon thereafter. Postmortem examination was restricted to examination of the brain and spinal cord. Extensive PML lesions, characterized by the presence of JC virus DNA were found in the cerebral white matter and neocortex. Sharply demarcated areas of active PML lesions contained prominent inflammatory infiltrates composed of approximately equal numbers of CD4-positive and CD8-positive T cells, consistent with an immune reconstitution inflammatory syndrome. Conversely, all MS lesions identified were hypocellular, long-standing inactive plaques characterized by myelin loss, relative axonal preservation, and gliosis and, importantly, were devoid of JC virus DNA and active inflammation. Chronic inactive MS lesions were separate and distinct from nearby PML lesions. This case demonstrates the coexistence and apparent lack of interplay between chronic inactive MS and PML lesions, and that immune reconstitution inflammatory syndrome seems to affect the shape and appearance of PML but not MS lesions.
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- 2013
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48. A game of viral hide and seek: miliary PML masquerading as EBV encephalitis in an HIV+ patient.
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Gheuens S, Buggy BP, Tlomak W, Wüthrich C, and Koralnik IJ
- Subjects
- Adult, Electroencephalography, HIV Seropositivity complications, Humans, JC Virus, Leukoencephalopathy, Progressive Multifocal etiology, Magnetic Resonance Imaging, Male, Neurologic Examination, Polymerase Chain Reaction, Tomography, X-Ray Computed, Viral Load, Epstein-Barr Virus Infections virology, HIV Seropositivity virology, Leukoencephalopathy, Progressive Multifocal virology
- Published
- 2013
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49. Progressive multifocal leukoencephalopathy: why gray and white matter.
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Gheuens S, Wüthrich C, and Koralnik IJ
- Subjects
- Brain pathology, Brain virology, Humans, JC Virus physiology, Leukoencephalopathy, Progressive Multifocal immunology, Leukoencephalopathy, Progressive Multifocal virology, Leukoencephalopathy, Progressive Multifocal pathology
- Abstract
Since it was first described in 1958, progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the brain caused by the polyomavirus JC (JCV), has evolved tremendously. It was once considered a noninflammatory disease that affected exclusively oligodendrocytes and astrocytes in the white matter of immunosuppressed individuals and was almost always fatal. Today, we understand that PML can present during the course of an immune reconstitution inflammatory syndrome and that it affects a broader range of individuals, including patients with minimal immunosuppression and those who are treated with novel immunomodulatory medications. Furthermore, JCV-infected glial cells are frequently located at the gray matter-white matter junction or within the gray matter, causing demyelinating lesions within cortical areas. Finally, JCV variants can also infect neurons, leading to the recognition of two distinct clinical entities: JCV granule cell neuronopathy and JCV encephalopathy.
- Published
- 2013
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50. Increased program cell death-1 expression on T lymphocytes of patients with progressive multifocal leukoencephalopathy.
- Author
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Tan CS, Bord E, Broge TA Jr, Glotzbecker B, Mills H, Gheuens S, Rosenblatt J, Avigan D, and Koralnik IJ
- Subjects
- AIDS-Related Opportunistic Infections complications, AIDS-Related Opportunistic Infections immunology, AIDS-Related Opportunistic Infections virology, Adult, Aged, Aged, 80 and over, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes virology, Case-Control Studies, Female, HIV Infections complications, HIV Infections immunology, HIV Infections virology, Humans, Immunity, Cellular, JC Virus immunology, Leukoencephalopathy, Progressive Multifocal complications, Leukoencephalopathy, Progressive Multifocal virology, Male, Middle Aged, Programmed Cell Death 1 Receptor antagonists & inhibitors, Young Adult, CD8-Positive T-Lymphocytes immunology, Leukoencephalopathy, Progressive Multifocal immunology, Programmed Cell Death 1 Receptor metabolism
- Abstract
The cellullar immune response is important in the containment of progressive multifocal leukoencephalopathy (PML). We examined program cell death-1 (PD-1) expression, a marker of cellular immune exhaustion, on T lymphocytes in PML. PD-1 expression was elevated on total CD4(+) and CD8(+) T cells (medians 36% and 24%) in PML patients compared with healthy control subjects (medians 14% and 18%; P = 0.0015 and P = 0.033). In PML patients, JC virus (JCV)-specific CD8(+) cytotoxic T lymphocytes expressed PD-1 more frequently than total CD8 T lymphocytes (means 39% and 78%, P = 0.0004). Blocking the PD-1 receptor increased JCV-specific T-cell immune response in a subgroup of PML patients.
- Published
- 2012
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