Can red blood cell function assays assess response to red cell-modifying therapies?

Area of Science:

• Hematology
• Biomarkers
• Drug Discovery

Background:

• Red blood cell (RBC)-modifying therapies offer new hope for sickle cell disease (SCD) patients.
• Lack of validated RBC function biomarkers hinders FDA approval and clinical use of these therapies.
• Flow Adhesion (FA) and Mechanical Fragility (MF) biomarkers stratify SCD individuals into distinct phenotypes, potentially predicting treatment outcomes.

Purpose of the Study:

• To evaluate if standardized FA and MF bioassays can differentiate cellular-level responders from non-responders to vepoloxamer.
• To assess vepoloxamer's effectiveness in a Phase 3 clinical trial for SCD.

Main Methods:

• Utilized standardized FA and MF biomarkers to analyze RBCs from SCD subjects.
• Assessed vepoloxamer's effect on blood samples in vitro.
• Employed Wilcoxon signed-rank and Mann-Whitney tests to analyze adhesion and mechanical fragility data.
• Set a significance level at p-value < 0.05.

Main Results:

• Vepoloxamer treatment in vitro reduced RBC adhesion by over 75% in 54% of patient samples.
• Sickle erythrocytes (SSRBCs) exhibited altered membranes post-treatment, increasing resistance to hemolysis.
• Treated SSRBCs demonstrated functional characteristics similar to normal adult RBCs (AARBCs).

Conclusions:

• Standardized FA and MF biomarkers show promise in predicting patient response to vepoloxamer.
• These biomarkers may serve as valuable tools for identifying responders to RBC-modifying therapies.
• This study supports the utility of functional RBC biomarkers in clinical settings.