Dexpramipexole (KNS-760704), an orally bioavailable synthetic aminobenzothiazole, showed an excellent safety profile and was coincidentally noted to significantly decrease absolute eosinophil counts (AECs) in a phase 3 trial for amyotrophic lateral sclerosis. Proof-of-concept study was designed to evaluate dexpramipexole (150 mg orally twice daily) as a glucocorticoid-sparing agent in HES. Dual primary end points of the study were 1) the proportion of subjects with 50% decrease in the minimum effective GC dose (MED) to maintain AEC <1000/L and control clinical symptoms, and 2) the MED after 12 weeks of dexpramipexole (MEDD) as a percentage of the MED at week 0. The secondary objectives were 1) to evaluate the safety of dexpramipexole in patients with HES and 2) to assess the effects of dexpramipexole on blood and bone marrow eosinophilia. Out of 10 subjects, 40% (95% confidence interval CI, 12%, 74%) achieved a 50% reduction in MED, and the MEDD/MED ratio was significantly <100% (median, 66%; 95% CI, 6%, 98%; P = .03). All adverse events were self-limited, and none led to drug discontinuation. Bone marrow biopsy samples after 12 weeks of dexpramipexole showed selective absence of mature eosinophils in responders. Dexpramipexole treatment resulted in markedly decreased eosinophils in the bone marrow aspirate and biopsy smears of all 4 responders compared to 2/6 non-responders. The residual eosinophilic elements in responders were markedly left-shifted by morphological evaluation, consisting mostly of early eosinophilic precursors (eosinophilic promyelocytes), suggesting maturational arrest in bone marrow eosinophilopoiesis. Surface expression of a late eosinophilic marker Siglec-9 also decreased substantially in bone marrow eosinophils from 3/4 responders as compared to 1/6 non-responders after 12 weeks on study drug. The surface expression of EMR-1 and IL-5Ra (markers expressed on all maturing eosinophils), showed no statistically significant pattern in either group. Other cell lineages in the bone marrow, including mast cells and CD34+ progenitor cells, were unaffected by dexpramipexole. The results of this study revealed that dexpramipexole appears promising as a glucocorticoid-sparing agent without apparent toxicity in a subset of subjects with glucocorticoid-responsive HES. Although the exact mechanism of action is unknown, preliminary data suggest that dexpramipexole may affect eosinophil maturation in the bone marrow. In a separate study, patients with familial eosinophilia were investigated with the aim to identify the cells driving the eosinophilia. Familial eosinophilia is a rare autosomal dominant inherited disorder characterized by the presence of lifelong peripheral eosinophilia (>1500/L). Mapped to chromosome 5q31-q33, the genetic cause of FE is unknown, and prior studies have failed to demonstrate a primary abnormality in the eosinophil lineage. Microarray analysis and real-time PCR were used to examine transcriptional differences in peripheral blood mononuclear cells (PBMC), and in purified cell subsets from affected and unaffected family members belonging to a single large kindred. Cytokine levels in serum and PBMC culture supernatants were assessed by suspension array multiplexed immunoassays. The results showed that whereas IL-5 mRNA expression was significantly increased in freshly isolated PBMC from affected family members, this was not accompanied by increased mRNA expression of other Th2 cytokines (IL-4 or IL-13). Serum levels of IL-5 and IL-5 receptor , but not IgE, were similarly increased in affected family members. Of note, IL-5 mRNA expression was significantly increased in purified CD3+ CD4+, CD14+, CD19+, and ILC2 cells from affected family members, as were IL-5 protein levels in supernatants from both stimulated PBMC and ILC2 cultures. The results of the study were consistent with the hypothesis that the eosinophilia in FE is secondary to dysregulation of IL-5 production in PBMC and their component subsets.
