Randomized phase 2 trial of NP001-a novel immune regulator: Safety and early efficacy in ALS

Abstract

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.

Figures

Figure 1. Study design and patient flow

ALSFRS-R = Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised.

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. 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.