Phase 2B randomized controlled trial of NP001 in amyotrophic lateral sclerosis: Pre-specified and post hoc analyses

Robert G. Miller, Rongzhen Zhang, Paige M. Bracci, Ari Azhir, Richard Barohn, Richard Bedlack, Michael Benatar, James D. Berry, Merit Cudkowicz, Edward J. Kasarskis, Hiroshi Mitsumoto, Georgios Manousakis, David Walk, Bjorn Oskarsson, Jeremy Shefner, Michael S. McGrath

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


Introduction/Aims: ALS is a heterogeneous disease that may be complicated or in part driven by inflammation. NP001, a regulator of macrophage activation, was associated with slowing disease progression in those with higher levels of the plasma inflammatory marker C-reactive protein (CRP) in phase 2A studies in ALS. Here, we evaluate the effects of NP001 in a phase 2B trial, and perform a post hoc analysis with combined data from the preceding phase 2A trial. Methods: The phase 2B trial enrolled 138 participants within 3 y of symptom onset and with plasma hs-CRP values >1.13 mg/L. They were randomized 1:1 to receive either placebo or NP001 for 6 mo. Change from baseline ALSFRS-R scores was the primary efficacy endpoint. Secondary endpoints included vital capacity (VC) change from baseline and percentage of participants showing no decline of ALSFRS-R score over 6 mo (non-progressor). Results: The phase 2B study did not show significant differences between placebo and active treatment with respect to change in ALSFRS-R scores, or VC. The drug was safe and well tolerated. A post hoc analysis identified a 40- to 65-y-old subset in which NP001-treated patients demonstrated slower declines in ALSFRS-R score by 36% and VC loss by 51% compared with placebo. A greater number of non-progressors were NP001-treated compared with placebo (p =.004). Discussion: Although the phase 2B trial failed to meet its primary endpoints, post hoc analyses identified a subgroup whose decline in ALSFRS-R and VC scores were significantly slower than placebo. Further studies will be required to validate these findings.

Original languageEnglish (US)
Pages (from-to)39-49
Number of pages11
JournalMuscle and Nerve
Issue number1
StatePublished - Jul 2022

Bibliographical note

Funding Information:
We thank all of the clinical sites involved in the phase 2B study, their principal investigators, study coordinators, support staff and data management center. The clinical site information and affiliated principal investigators (PIs) listed below are those identified in Neuraltus phase 2B clinical summary documents. The Participating Sites and Study Principal Investigators are listed here: Barrow Neurological Institute/PI: Shafeeq Ladha, MD. Massachusetts General Hospital/PI: James Berry, MD, MPH. Cleveland Clinic Foundation/PI: Erik Pioro, MD, PhD, FRCPC. McGill University/PI: Angela Genge, MD, FRCPC. Cedars-Sinai Medical Center/PI: Richard Lewis, MD. Ohio State University/PI: Stephen Kolb, MD, PhD. Carolinas Medical Center/PI: Benjamin Brooks, MD. Providence ALS Center/PI: Kimberly Goslin, MD, PhD. Columbia University Medical Center/PI: Jinsy Andrews, MD, MSc. University of California Irvine Medical Center/PI: Namita Goyal, MD. California Pacific Medical Center/PI: Jonathan Katz, MD. University of Kansas Medical Center/PI: Richard Barohn, MD & Mazen Dimachkie, MD. Duke Medical Center/PI: Richard Bedlack, MD. University of Kentucky Hospital/PI: Edward Kasarskis, MD, PhD. Emory University School of Medicine/PI: Christina Fournier, MD, MSc. University of Miami Miller School ofMedicine/PI: Michael Benatar, MD. Houston Methodist Hospital/PI: Ericka Simpson, MD. University of Minnesota/PI: Georgios Manousakis, MD. Mayo Clinic Arizona/PI: Mark Ross, MD. Mayo Clinic Florida/PI: Bjorn Oskarsson.

Funding Information:
R.G. Miller, the author reports no conflict of interest. R. Zhang, the author reports no conflict of interest. P.M. Bracci, the author reports no conflict of interest. A. Azhir, CEO of Neuvivo Inc. R. Barohn has received research grants from NIH and consulting support from NuFactor. R. Bedlack has received research support from ALSA, Healey Center, MediciNova. He has received consulting support from AB Science, ALSA, Alexion, Amylyx, Apellis, Biogen, Biohaven, Brainstorm, Clene, Corcept, Cytokinetics, GenieUS, Guidepoint, ITF Pharma, Mallinkrodt, Orphazyme, Shinkei, Woolsey Pharma. M. Benatar, the author reports no conflict of interest. J.D. Berry, the author reports no conflict of interest. M. Cudkowicz, the author reports no conflict of interest. E.J. Kasarskis, the author reports no conflict of interest. H. Mitsumoto has received research funding from NIH, ALS Association, SPF, MDA Wings, Tsumura & Co, Mitsubishi‐Tanabe Pharma. He has participated in advisory boards for Amylyx, PTC Bio (one time). G. Manousakis, the author reports no conflict of interest, D. Walk, the author reports no conflict of interest. B. Oskarsson the author, reports no conflict of interest. J. Shefner has received grant/research/clinical trial support from Amylyx, Biogen, Cytokinetics Incorporated, Mitsubishi Tanabe Pharma America, Sanofi, Novartis, Annexon, Jannsen. Alexion, Medicinova, Ionis, and Alector. He has received personal compensation from Amylyx, Apic Biosciences, Neurosense, Cytokinetics, Denal, GSK, Mitsubishi Tanabe Pharma America, RRD, Swanbio, Helixsmith, Novartis, Sanofi, and Sawei. M.S. McGrath, Founder and Chief scientific officer of Neuvivo Inc. Did not personally access the Neuvivo database for the primary analysis described in this manuscript.

Publisher Copyright:
© 2022 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.


  • C-reactive protein (CRP)
  • NP001
  • amyotrophic lateral sclerosis (ALS)
  • inflammation
  • respiratory function


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