Randomized phase 2 trial of NP001–a novel immune regulator: Safety and early efficacy in ALS. Issue 3 (June 2015)

• Record Type: Journal Article
• Authors: Miller, Robert G.; Block, Gilbert; Katz, Jonathan S.; Barohn, Richard J.; Gopalakrishnan, Vidhya; Cudkowicz, Merit; Zhang, Jane R.; McGrath, Michael S.; Ludington, Elizabeth; Appel, Stan H.; Azhir, Ari; Katz, Jonathan; Kushner, Giovanna; Wong, Cynthia; Engel, Maguerite; Forshew, Dallas; Osborne, Robert; Schug, Brooke; Akers, Amy; Brent, Bruce; Zayas-Bazan, Thais; McCoy, Shelly; Goyal, Neelam; Harris, Will; Gonella, Marie; Brooks, Benjamin R.; Bravver, Elena; Sanjak, Mohammed; Ward, Amber L.; Mehrizi, Amir; Belfiore, Mark; Lary, Cynthia; Nemeth, Joanne; Conway, Jill; Bender, Ryan; Holsten, Scott; Shue, Jamie; Mitsumoto, Hiroshi; Youngman, Regina; Armstrong, Nicole; Lee, Yei-won; Weimer, Louis H.; Brannagan, Thomas; Hirano, Michio; Scotto, Marta; Dalton, Kate; Bedlack, Richard S.; Morgenlander, Joel Charles; Boyette, Candace Lee; Grace, Karen L.; Arvik, Beth McLendon; Thomas Hickey, Patrick; Lasater Scott, Burton; Lynn Heydt, Debra; Perry-Trice, Peggy; Cudkowicz, Merit; Berry, James; Atassi, Nazem; Boylan, Kevin; Kennelly, Kathleen; DeSaro, Pamela; Johnston, Amelia; Huser, Angela; Fuqua, Paula; Staggs, Kristin; Babcock, Lorraine; Kryston, Thomas; Ross, Mark A.; Bosch, E. Peter; Verheijde, Josephus L.; Grover, Yvvonne; Duffy, Amy K.; Lee, Michael S.; McLaughlin, Roxanne R.; Musil, Danette J.; Early, Jennifer; Whiteman, Dana; Wisbey, Joyce A.; Simpson, Ericka P.; Pleitez, Milvia Y.; Lay, Luis F.; Halton, Sharon, L.; Schwartz, Thomas; Blanton, Linda; Lai, Eugene C.; Pioro, Erik P; Kuenzler, Rebecca; Berry, Nicole; Khan, Sara; Chowdhury, Nabi; Biernot, Julia; Goslin, Kimberly; Carter, Gregory T.; Corkrey, Patrick M.; Ann Kovarik, Mary; Shefner, Jeremy M.; Simionescu, Laura; Grosso, Megan; Watson, Mary Lou; Reale, Melissa A.; Duleep, Anuradha; Carhart, Robert; Markis, Katie; Money, Kristina; Boevin, Travis; Lava, Neil; Glass, Jonathan D; Polak, Meraida; Shaw, Latoya; Bordeau, Jane; Rogers, Susan; Ferguson, Susan; Fournier, Christina; Kelly, Crystal; Mozaffar, Tahseen; Wang, Annabel K; Ramsey, Gladys; Tully, Patricia A; Graves, Michael; Wiedau-Pazos, Martina; Alvarez, Rebecca; Barohn, Richard; McVey, April L.; Dimachkie, Mazen M.; Pasnoor, Mamatha; Herbelin, Laura; Walsh, Maureen; Kasarskis, Edward J.; Dotson, William F.; Sitzlar, Stephen C.; Tandy, Tammy; Carrico, Jeffery; Phillips, Susan; Rice, Linda; Holbrook, Kathryn M.; Eckmann, David; Chamblin, Lisa; Townsend, Janet; Kaenzig, Janet; Hanley-Borgia, Lisa; Vanderpool, Kathryn E.; Taylor, Deborah G.; Carpenter, Jessica; Thomas, Samantha; Hutchinson, Jan; King, Jason T.;
• Is Part Of: Neurology. Volume 2:Issue 3(2015)
• Publication Date: 2015-06
• Subjects: Neuroimmunology -- Periodicals; Neurology -- Periodicals; 616.8
• DOI: 10.1212/NXI.0000000000000100
• Languages: English
• ISSNs: 2332-7812

Abstract

Abstract : Objective: 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). Methods: 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. Results: 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. Conclusion: 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. Classification of evidence: 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.