Exploratory Post Hoc Analysis of Neutrophil-to-lymphocyte Ratio as a Novel Response Biomarker for Edaravone Oral Suspension-treated Patients with Amyotrophic Lateral Sclerosis vs Untreated Propensity Score-matched PRO-ACT Historical Placebo Controls
Benjamin Brooks1, Angela Genge2, Fumiaki Tanaka3, Yuuichirou Katou4, Yoshiteru Ushirogawa4, Fumihiro Takahashi5, Manabu Hirai5, Stephen Apple5
1Clinical Trials Planning LLC, 2Montreal Neurological Institute and Hospital, 3Yokahama City University Graduate School of Medicine, 4Mitsubishi Tanabe Pharma Corporation, 5Mitsubishi Tanabe Pharma America
Objective:
Assess Neutrophil-to-Lymphocyte Ratio (NLR) response to edaravone oral suspension treatment in patients with amyotrophic lateral sclerosis (ALS) and whether baseline NLR may predict NLR response vs propensity score-matched Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) placebo controls.
Background:
The US Food and Drug Administration (FDA) approved an on/off dosing regimen of Radicava ORS® (edaravone) oral suspension for patients with ALS. Edaravone oral suspension-treated patients with ALS from Studies MT-1186-A01/A02/A03/A04 showed a 7.3-month significantly prolonged mean survival vs matched PRO-ACT controls (P<0.001) over 34 months. Elevated NLR is a potential prognostic biomarker for ALS, correlating with clinical deterioration. In some non-ALS oxidative stress disease models, edaravone treatment was associated with NLR decline, paralleling clinical improvement.
Design/Methods:
MT-1186-A01 (NCT04165824) was a phase 3, open-label, 48-week study conducted to evaluate the long-term safety and tolerability of FDA-approved on/off edaravone oral suspension; MT-1186-A03 (NCT04577404) was its 96-week extension. MT-1186-A02 (NCT04569084) was a phase 3b, double-blind study in patients randomized to an investigational drug once daily or FDA-approved on/off edaravone oral suspension regimen; MT-1186-A04 (NCT05151471) was its 48-week extension. MT-1186-A01/A02/A03/A04 patients were propensity score-matched 1:1 on 11 baseline variables with historical, PRO-ACT controls (patients given placebo may have received riluzole).
Results:
Patients from Studies MT-1186-A01/02/03/04 (n=221) showed a numeric trend towards decreasing NLR at 48 weeks (least squares mean difference= −0.2851) vs matched PRO-ACT controls (n=221) (P=0.065). Patients were grouped by baseline NLR<3 or NLR≥3. Edaravone-treated patients with NLR<3 showed significantly lower NLR at 48 weeks (P=0.038) vs PRO-ACT controls.
Conclusions:
Edaravone oral suspension treatment in MT-1186 studies vs PRO-ACT controls supports the possible role of NLR as a novel ALS prognostic biomarker. These analyses were non-randomized comparisons, and there was a potential time bias between matched groups. Further studies are needed to validate NLR as a prognostic biomarker across ALS populations.
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