Clinicians C Potential in the Emerging ALS Prognostic Biomarker Serum CRP

macrophage activation ROS NP001

Quiet, please. NP001 aims to help reduce neuroinflammation in ALS by encouraging activated macrophages to return to the resting (M2) state (Giese et al., 2004). The potential treatment strategy targets macrophages that may enter the CNS and damage motor neurons during the disease. [Video: Macrophage activation. Humanitas Research Hospital, YouTube.]

The inflammatory biomarker C-reactive protein (CRP) may help inform the outcome of patients with ALS according to a study published on April 3 in JAMA Neurology. The study, led by NeuroMuscular Omnicentre’s Christian Lunetta in Italy, found that circulating levels of CRP in the blood inversely correlated with functional impairment (ALS-FRS score) and survival (hazard ratio, 1.129; 95% CI, 1.033-1.234; P = .007). 394 patients with ALS participated.

The results confirm that the measurement of this inflammatory substance in the blood may help clinicians prognose ALS by identifying patients with a higher progression rate. The approach, which involves a standard blood test used to check for inflammation, may also facilitate the evaluation of potential therapies for ALS by enabling the stratification of patients in clinical trials.

The study stems from a post-hoc analysis of a phase 2 clinical trial led by Forbes Norris MDA/ALS Research Center’s Robert Miller in San Francisco, California which suggested that increased levels of CRP may help identify patients that might benefit from Neuraltus Pharmaceutical’s potential anti-inflammatory treatment strategy NP001 (see January 2013 conference news; Miller et al., 2015).

CRP: An ALS, first responder?

In 2012, Robert Miller and colleagues reported that NP001 did not meet endpoints in a phase 2 clinical trial for ALS. A subsequent post-hoc analysis, however, which included historic controls, indicated that a subset of patients taking the highest dose of NP001 (2mg/kg) experienced a halt in progression during the 6 month treatment period (see January 2013 conference news; Miller et al., 2015). Taking a closer look, Miller’s team discovered that these patients exhibited increased levels of inflammatory substances including CRP.

A post-hoc analysis. 25% of patients with ALS taking the highest dose of NP001 did not decline during the 6 month study period compared to 10% of historical controls (p=0.02). Subsequent analysis indicated that these patients exhibited at or above median levels of inflammatory substances including CRP [Miller et al., 2015 under a CC BY-NC-ND 3.0 license.]

The results suggested that these substances may help clinicians identify people who may benefit from potential treatment strategies including NP001 that aim to slow progression of ALS by reducing neuroinflammation. The strategy, known as responder analysis, is being increasingly used to develop treatment strategies for a wide range of diseases including cancer, diabetes and cardiovascular disease. The approach builds on a previous analysis led by Tel Aviv Sourasky Medical Center’s Vivian Drory in Israel that found that increased levels of C-reactive protein inversely correlated with functional impairment (ALS-FRS score) in patients with ALS (Keizman et al., 2009).

Now, a research team led by Robert Miller and Jon Katz at the California Pacific Medical Center are re-evaluating NP001 in patients with ALS with increased CRP at the phase 2 stage (see April 2016 news). The clinical trial will in part, determine whether patients with increased levels of this inflammatory substance may benefit from NP001. 120 patients with ALS in the US and Canada are expected to participate. The study is scheduled to be completed by September 2017.


Lunetta C, Lizio A, Maestri E, Sansone VA, Mora G, Miller RG, Appel SH, Chiò A. Serum C-Reactive Protein as a Prognostic Biomarker in Amyotrophic Lateral Sclerosis. JAMA Neurol. 2017 Apr 3. [PubMed].

Miller RG, Block G, Katz JS, Barohn RJ, Gopalakrishnan V, Cudkowicz M, Zhang JR, McGrath MS, Ludington E, Appel SH, Azhir A; Phase 2 Trial NP001 Investigators. Randomized phase 2 trial of NP001-a novel immune regulator: Safety and early efficacy in ALS. Neurol Neuroimmunol Neuroinflamm. 2015 Apr 9;2(3):e100. [PubMed].

Miller RG, Zhang R, Block G, Katz J, Barohn R, Kasarskis E, Forshew D, Gopalakrishnan V, McGrath MS. NP001 regulation of macrophage activation markers in ALS: a phase I clinical and biomarker study. Amyotroph Lateral Scler Frontotemporal Degener. 2014 Dec;15(7-8):601-9. [PubMed]

Keizman D, Rogowski O, Berliner S, Ish-Shalom M, Maimon N, Nefussy B, Artamonov I, Drory VE. Low-grade systemic inflammation in patients with amyotrophic lateral sclerosis. Acta Neurol Scand. 2009 Jun;119(6):383-9. [PubMed].

disease-als inflammation macrophage NP001 topic-biomarkers topic-clinical
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