ALS Agent NP001 Becomes First to Link Regulation of Innate Immune System With Respiratory Function

Michael McGrath, MD, PhD

New data from a previously conducted phase 2 study of NP001 (Neuvivo), an investigational regulator of innate immune function, showed that C-reactive protein (CRP) levels in patients with amyotrophic lateral sclerosis (ALS) correlated with lung function. Importantly, plasma TGFB1, a dominant regulator of inflammation, was 95% higher after 6 months in high CRP-treated patients relative to controls, suggesting the therapy may have acted in part to reset the innate immune system.^1,2

Previous research has shown that CRP plays an important role in the body clearing misfolded proteins, dying cells, and infectious agents as part of a normal innate immune system response. In accordance with FDA guidance published in 2019, the new analysis stratified and defined patients as high CRP (>1.13 mg/L; n = 75) or low CRP (<1.13 mg/L; n = 50). Following this, findings showed a 64% slower rate of vital capacity (VC) decline in patients with high CRP compared with placebo (P = .05) and those with low CRP, who showed no response.

"In terms of immune system regulation, the presence of high CRP (plasma level > 1.13 mg/kg) is a strong signal that the innate immune system, including other acute phase reactants, is engaged and trying to regulate an inflammatory process, contributing to ALS pathogenesis," lead investigator Michael McGrath, MD, PhD, chief scientific officer, Neuvivo, and Professor Emeritus of Medicine, UCSF, said in a statement.

All ALS baseline values were similar between treated and controls except for those older than 65 years who were excluded from the analysis. While those with low baseline CRP saw no change in VC over time regardless of treatment status, patients with high CRP on placebo lost an average of 2.1% VC per month. In comparison, those on NP001 with high CRP lost 0.75% VC per month. By age, there were no significant differences found between placebo and 2 mg/kg NP001 treated in both high and low CRP groups.

In patients with ALS less than 65 years, investigators found a positive linear relationship between plasma levels of the acute phase reactant serum amyloid A (SAA), a factor related to innate immune system regulation, and high CRP at baseline (R2 = 0.25; P = .004). This confirmed that the immune activation in patients with high CRP is not isolated, but a component of a generalized acute phase reaction.

"NP001 treatment acts to augment the naturally occurring immune response and supports resolution of the CRP-mediated process related to ongoing loss of respiratory function. Data regarding treatment initiation and effect on vital capacity confirm that respiratory function is measurably failing early in the disease course as NP001 slows VC loss early on," McGrath added. "These observations are important even if vital capacity is near normal at date of diagnosis. Given its objectivity, the VC test used as a biomarker may allow for the direct evaluation of innate immune activity in relation to ALS disease progression."¹

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Because CRP elevation as an immune regulator alone was not controlling ALS disease progression, investigators examined plasma TGFB1 to see whether there would be evidence of alpha 2 macroglobulin (A2M) activation, another component of the humoral innate immune system. Following exposure to NP001, plasma TGFB1 levels increased by more than 95%, suggesting that the therapy caused an A2M dimerization with the release of TGFB1. Furthermore, elevated levels of TGFB1 observed 1 month after the final dose suggested that the other function of A2M dimers, the clearance of misfolded proteins, may have reset the innate immune activation cycle.

At the conclusion of the analysis, investigators noted that larger properly powered placebo-controlled trials would be needed to test the theory that clinical VC responses to NP001 would be related to the regulation of the innate immune system. Given that GCP is an acute phase reactant, inherently variable plasma CRP levels that differed between patients could have possibly confounded results tied to the selection of patients with slightly elevated CRP values.

"Given elevated levels of necessary anti-inflammatory proteins induced well after dosing, we postulate it may be possible to regulate immune function to the point where no further damage would be forthcoming in patients adequately controlled with NP001 treatment," Ari Azhir, PHD, chief executive officer, Neuvivo, said in a statement.¹ "A notable area of interest would be in additional neurodegenerative diseases with evidence of CRP elevation."

REFERENCES
1. New study of Neuvivo’s NP001 is first to link regulation of the innate immune system with respiratory function in ALS patients. News release. Neuvivo. March 30, 2023. Accessed April 12, 2023. https://www.prnewswire.com/news-releases/new-study-of-neuvivos-np001-is-first-to-link-regulation-of-the-innate-immune-system-with-respiratory-function-in-als-patients-301785352.html
2. McGrath MS, Zhang R, Bracci PM, Azhir A, Forrest BD. Regulation of the innate immune system as a therapeutic approach to supporting respiratory function in ALS. Cells. 2023;12(7). doi:10.3390/cells12071031