Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 2 (3), e100

Randomized Phase 2 Trial of NP001-a Novel Immune Regulator: Safety and Early Efficacy in ALS

Collaborators, Affiliations

Randomized Phase 2 Trial of NP001-a Novel Immune Regulator: Safety and Early Efficacy in ALS

Robert G Miller et al. Neurol Neuroimmunol Neuroinflamm.


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.


Figure 1
Figure 1. Study design and patient flow
ALSFRS-R = Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised.
Figure 2
Figure 2. ALSFRS-R changes
(A) Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) slope after 6 months of treatment without (left) and with (right) historical controls. (B) Mean change from baseline in ALSFRS-R score at week 25 without (left) and with (right) historical controls. (C) ALSFRS-R slope after 6 months of treatment in patients with baseline wide range C-reactive protein (wr-CRP) greater than or equal to the baseline median wr-CRP. Error bars represent standard error.
Figure 3
Figure 3. Responder subset
(A) Percentage of “responders” (nonprogressing patients) at week 25 after 6 months of treatment; percentage of “responders” in historical controls was 10%. (B) Normalized mean baseline plasma concentrations of inflammatory biomarkers. (C) Mean plasma interleukin (IL)-18 in high-dose “responders” vs “nonresponders” at baseline and after the 6-month treatment period (week 25). (D) Mean plasma lipopolysaccharide (LPS) in all patients treated with 1 mg/kg or 2 mg/kg NP001 at baseline and after the 6-month treatment period (week 25). (E) Mean LPS in placebo “responders” and “nonresponders” at baseline and after the 6-month treatment period (week 25). Error bars represent standard error. Limit of detection (lod) for LPS = 0.05 EU/mL. CRP = C-reactive protein; IFN = interferon.

Similar articles

See all similar articles

Cited by 18 articles

See all "Cited by" articles


    1. Boillée S, Vande Velde C, Cleveland DW. ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 2006;52:39–59. - PubMed
    1. Henkel JS, Beers DR, Zhao W, Appel SH. Microglia in ALS: the good, the bad, and the resting. J Neuroimmune Pharmacol 2009;4:389–398. - PubMed
    1. Butovsky O, Siddiqui S, Gabriely G, et al. Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. J Clin Invest 2012;122:3063–3087. - PMC - PubMed
    1. Turner MR, Kiernan MC, Leigh PN, Talbot K. Biomarkers in amyotrophic lateral sclerosis. Lancet Neurol 2009;8:94–109. - PubMed
    1. Liu G, Fiala M, Mizwicki MT, et al. Neuronal phagocytosis by inflammatory macrophages in ALS spinal cord: inhibition of inflammation by resolvin D1. Am J Neurodegener Dis 2012;1:60–74. - PMC - PubMed