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Randomized phase 2 trial of NP001, a novel immune regulator

2015; Wolters Kluwer; Volume: 2; Issue: 3 Linguagem: Inglês

10.1212/nxi.0000000000000100

2332-7812

Robert G. Miller, Gilbert Block, Jonathan Katz, Richard J. Barohn, Vidhya Gopalakrishnan, Merit Cudkowicz, Jane R. Zhang, Michael S. McGrath, Elizabeth Ludington, Stan H. Appel, Ari Azhir, Jonathan Katz, Giovanna Kushner, Cynthia Wong, Maguerite Engel, Dallas Forshew, Robert D. Osborne, Brooke Schug, Amy Akers, Bruce N. Brent, Thaïs Zayas-Bazan, Shelly McCoy, Neelam Goyal, Will Harris, Marie Gonella, Benjamin Rix Brooks, Elena Bravver, Mohammed Sanjak, Amber Ward, Amir Mehrizi, Mark Belfiore, Cynthia Lary, Joanne Nemeth, Jill Ker Conway, Ryan Bender, Scott Holsten, Jamie Shue, Hiroshi Mitsumoto, R. A. Youngman, Nicole M. Armstrong, Yei-won Lee, Louis H. Weimer, Thomas H. Brannagan, Michio Hirano, Marta Scotto, Kate Dalton, Richard Bedlack, Joel C. Morgenlander, Candace Lee Boyette, Karen Grace, Beth McLendon Arvik, Patrick Hickey, Burton Lasater Scott, Debra Lynn Heydt, Peggy Perry-Trice, Merit Cudkowicz, James Berry, Nazem Atassi, Khrista Boylan, Kathleen D. Kennelly, Pamela Desaro, Amelia Johnston, Angela Huser, Paula Fuqua, Kristin Staggs, Lorraine Babcock, Thomas B. Kryston, Mark A. Ross, E. Peter Bosch, Josephus L. Verheijde, Yvvonne Grover, Amy K. Duffy, Michael S. Lee, Roxanne R. McLaughlin, Danette J. Musil, Jennifer Early, Dana Whiteman, Joyce Wisbey, Ericka P. Simpson, Milvia Pleitez, Luis Lay, L. Halton Sharon, Thomas L. Schwartz, Linda Blanton, Eugene C. Lai, Erik P. Pioro, Rebecca Kuenzler, Nicole S. Berry, Sara Khan, Nabi Chowdhury, Julia Biernot, Kimberly Goslin, Gregory T. Carter, Patrick M. Corkrey, Miroslav Kovařík, Jeremy M. Shefner, Laura Simionescu, Megan Grosso, Mary Lou Watson, Melissa A. Reale, Anuradha Duleep, Robert Carhart, Katie Markis, Kristina Money, Travis Boevin, Neil Lava, Jonathan D. Glass, Meraida Polak, Latoya Shaw, Jane Bordeau, Susan Rogers, Susan Ferguson, Christina N. Fournier, Crystal Kelly, Tahseen Mozaffar, Annabel K. Wang, Gladys Ramsey, Patricia Tully, Michael C. Graves, Martina Wiedau‐Pazos, Rebecca Alvarez, Richard J. Barohn, April McVey, Mazen M. Dimachkie, Mamatha Pasnoor, Laura Herbelin, Maureen Walsh, Edward J. Kasarskis, William Dotson, Stephen Sitzlar, Tammy Tandy, Jeffery Carrico, Susan D. Phillips, Linda Rice, Kathryn M. Holbrook, David M. Eckmann, Lisa Chamblin, Janet M. Townsend, Janet Kaenzig, Lisa Hanley-Borgia, Kathryn E. Vanderpool, Deborah G. Taylor, Jessica M. Carpenter, Samantha Thomas, Jan Hutchinson, Jason T. King,

Neuroinflammation and Neurodegeneration Mechanisms

To assess the safety, tolerability, and preliminary efficacy of NP001, a novel immune regulator of inflammatory monocytes/macrophages, for slowing progression of amyotrophic lateral sclerosis (ALS).This was a phase 2 randomized, double-blind, placebo-controlled trial of NP001 in 136 patients with ALS of <3 years' duration and forced vital capacity ≥70%. Participants received NP001 2 mg/kg, NP001 1 mg/kg, or placebo for 6 months. Safety, tolerability, and inflammatory biomarkers were assessed throughout the study. Preliminary efficacy was evaluated using the ALS Functional Rating Scale-Revised (ALSFRS-R) slope and change from baseline, with and without matched historical placebo controls, after 6 months of treatment. A post hoc analysis of the percentage of patients ("responders") whose ALSFRS-R did not change from baseline was also conducted.NP001 was generally safe and well-tolerated, except for infusion site pain and dizziness. No significant slowing of decline in the primary or secondary measures was observed. However, slowing of progression was observed in the high-dose group in patients with greater inflammation (wide range C-reactive protein). Moreover, NP001 may have dose dependently halted symptom progression in a subset of patients. More than 2 times as many patients on high-dose NP001 (25%) did not progress during 6 months of treatment compared with those on placebo (11%). Most "responders" had an elevated biomarker of inflammation, interleukin-18, and were positive for lipopolysaccharide at baseline, which decreased after treatment with NP001.The arresting of progression of ALS symptoms by NP001 in a subset of patients with marked neuroinflammation, as observed here, will represent a novel therapeutic approach for patients with ALS, if confirmed.This study provides Class I evidence that for patients with ALS, NP001 is safe and did not significantly slow progression of the disease (difference in slope of the ALSFRS-R/month 0.12 favoring NP001, p = 0.55). The study lacks the precision to exclude an important effect of NP001.