Macrophage-Targeted Sodium Chlorite (NP001) Slows Progression of Amyotrophic Lateral Sclerosis (ALS) through Regulation of Microbial Translocation

Abstract

Amyotrophic lateral sclerosis (ALS) is a heterogeneous, progressive, and universally fatal neurodegenerative disease. A subset of ALS patients has measurable plasma levels of lipopolysaccharide (LPS) and C-reactive protein (CRP) consistent with low-grade microbial translocation (MT). Unless interrupted, MT sets up a self-perpetuating loop of inflammation associated with systemic macrophage activation. To test whether MT contributed to ALS progression, blood specimens from a phase 2 study of NP001 in ALS patients were evaluated for changes in activity in treated patients as compared to controls over the 6-month study. In this post hoc analysis, plasma specimens from baseline and six-month timepoints were analyzed. Compared with baseline values, biomarkers related to MT were significantly decreased (LPS, LPS binding protein (LBP), IL-18, Hepatocyte growth factor (HGF), soluble CD163 (sCD163)) in NP001-treated patients as compared to controls, whereas wound healing and immunoregulatory factors were increased (IL-10, Epidermal growth factor (EGF), neopterin) by the end of study. These biomarker results linked to the positive clinical trial outcome confirm that regulation of macrophage activation may be an effective approach for the treatment of ALS and, potentially, other neuroinflammatory diseases related to MT.

Regulation of the Innate Immune System as a Therapeutic Approach to Supporting Respiratory Function in ALS

“…Biomarker levels for specimens collected at baseline and end of study plasma were evaluated at the same time by the commercial company AssayGate, Inc. (Ijamsville, MD, USA). An extensive biomarker analysis was recently reported using specimens from this trial and baseline values of biomarkers fell within the expected range of those reported in the literature related to patients with ALS [ 31 ].…”

“…Clearly, a larger properly powered placebo-controlled trial would need to be performed in order to test the theory that clinical VC responses to NP001 would be related to regulation of the innate immune system. The data presented in this and two previous papers analyzing clinical data from NP001 phase 2 trials [ 28 , 31 ] identified plasma CRP levels as critical to apparent clinical responsiveness to NP001. Given that CRP is an acute phase reactant, inherently variable plasma CRP levels that differ between patients can confound results tied to the selection of patients with slightly elevated CRP values.…”

“…In previous studies of ALS patients enrolled in NP001 phase 2 trials those older than 65 years of age were shown to progress at different rates than those younger than 65 and were excluded from analysis in these reports [ 28 , 31 ]. Although CRP values were not associated with age, participants in the current analysis over the age of 65 differed significantly from patients 65 or younger in the disease activity variables of: (A) the rate of ALS disease progression (positively related to baseline values of CRP, Figure 3 , R 2 = 0.25, p = 0.04, n = 17); and (B) ALS disease duration (time from ALS symptom onset to baseline) (negatively related to baseline CRP values, Figure 4 , R 2 = 0.27, p = 0.03, n = 17).…”

“…The initial phase 2A study found that patients with plasma CRP levels above a median value for all of the randomized patients, 1.13 mg/L hs-CRP units, showed more of a clinical response to NP001 than those with CRP levels lower than 1.13 mg/L [ 26 ]. A recently published evaluation of the phase 2A study with additional biomarker analysis showed that baseline CRP values defined a subset of NP001 treated patients whose plasma levels of microbial translocation (MT) associated biomarkers, had disease slowed (ALSFRS-R loss) in conjunction with MT resolution [ 31 ]. Placebo controls failed to respond clinically and didn’t resolve any of the eight biomarkers that defined the outcome in the NP001 treated group.…”

“…The pathogenesis of ALS is still poorly understood but the linkage of respiratory function with survival is clear and any therapeutic approach that positively affects VC may extend survival in patients with ALS. The data presented in the current paper were derived from a phase 2 study of NP001 that was underpowered to define a true therapeutic potential for use of NP001 except in a subset of patients defined in post hoc studies [ 28 , 31 ]. Clearly, a larger properly powered placebo-controlled trial would need to be performed in order to test the theory that clinical VC responses to NP001 would be related to regulation of the innate immune system.…”