Dexpramipexole as an oral steroid-sparing agent in hypereosinophilic syndromes

Abstract

Hypereosinophilic syndromes (HESs) are a heterogeneous group of disorders characterized by peripheral eosinophilia and eosinophil-related end organ damage. Whereas most patients respond to glucocorticoid (GC) therapy, high doses are often necessary, and side effects are common. 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. This proof-of-concept study was designed to evaluate dexpramipexole (150 mg orally twice daily) as a GC-sparing agent in HESs. Dual primary end points were (1) the proportion of subjects with ≥50% decrease in the minimum effective GC dose (MED) to maintain AEC <1000/μL and control clinical symptoms, and (2) the MED after 12 weeks of dexpramipexole (MEDD) as a percentage of the MED at week 0. 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. Affected tissue biopsy samples in 2 subjects showed normalization of pathology and depletion of eosinophils on dexpramipexole. Bone marrow biopsy samples after 12 weeks of dexpramipexole showed selective absence of mature eosinophils in responders. Dexpramipexole appears promising as a GC-sparing agent without apparent toxicity in a subset of subjects with GC-responsive HESs. Although the exact mechanism of action is unknown, preliminary data suggest that dexpramipexole may affect eosinophil maturation in the bone marrow. This study was registered at www.clinicaltrials.gov as #NCT02101138.

Conflict of interest statement

Conflict-of-interest disclosure: D.G.A., M.E.B., C.P., M.S., G.T.H., and S.I.D. are Knopp Bioscience employees and have an equity interest in Knopp. M.E.B. and S.I.D. are inventors named on patents involving dexpramipexole. The remaining authors declare no competing financial interests.

© 2018 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Trial design, subject enrollment, and disposition. (A) Study design. (B) Subject enrollment. Prednisone taper (GC1 and GC2). The dose of prednisone (or equivalent) was adjusted at weekly clinic visits according to the blood AEC and clinical signs and symptoms. GC dose was tapered by 5 mg weekly until 15 mg daily and then by 2.5 mg weekly. The decision to decrease to the next lower dose was based on the AEC and presence or absence of HES symptoms. If the AEC rose to ≥1000/µL or HES symptoms were present, then prednisone (or equivalent) was increased to the previous dose. If a subject’s AEC continued to climb or symptoms persisted despite a dose increase, then the GC dose was increased further or the subject was withdrawn from the study at the investigator’s discretion.

Figure 2.

Individual subject responses to dexpramipexole. (A-C) AEC (left axis, black line) and percentage baseline GC dose (right axis, gray shading) are shown for individual subjects over the first 12 months of the study grouped by responders (A), nonresponders (B), and delayed responders (C). The dotted vertical line indicates the primary study end point. Dexpramipexole administration is indicated by the horizontal line/arrow above the graph.

Figure 3.

Histologic evidence of resolved eosinophilic esophagitis and duodenitis after dexpramipexole treatment. (A-D) Representative photomicrographs of the proximal esophagus (A-B) and duodenum (C-D), before treatment and at week 20 on dexpramipexole. (A) Squamous mucosa with active esophagitis and increased eosinophils (up to 20 per high-power field). (C) Duodenal mucosa with focally increased numbers of eosinophils (up to 100 per high-power field) and mild duodenitis. (B,D) At week 20 (on dexpramipexole), the squamous esophageal mucosa and the duodenal specimen demonstrate absence of eosinophilic infiltrates and normalization of tissue architecture. Esophageal mucosa at original magnification ×40 (B, inset) also shows lack of eosinophilic infiltrates. Images were acquired with a Nikon Eclipse 50i microscope equipped with an Olympus DP71 camera and software. Final image preparation was performed with Adobe Photoshop CS3 extended Version 10.0.1. Original magnifications: panel A, ×20/0.2 numerical aperture (NA); panel B, ×20/0.95 NA (inset, ×40); panel C, ×40/0.45 NA; panel D, ×40/1.40 NA. All panels, hematoxylin and eosin stain.

Figure 4.

Bone marrow cellular composition at baseline and 12 weeks after treatment with dexpramipexole. (A) Eosinophils, mast cells, CD34+ cells, and eosinophil precursors in the 4 responders and 6 delayed or nonresponders at baseline (predrug) and again at week 12 (on dexpramipexole). (B-I) Bone marrow aspirate and biopsy specimens in a responder (subject 15) at baseline and again at 12 weeks on dexpramipexole. Pretreatment bone marrow aspirate (B; Wright-Giemsa staining) and biopsy (D; hematoxylin and eosin staining) show increased eosinophils. Week 12 (on dexpramipexole) counterparts (C,E) demonstrate absence of eosinophils. Rare eosinophilic promyelocytes were noted after treatment (E, inset). The number of tryptase-positive mast cells (F-G) and CD34+ precursors (H-I) in the biopsy specimens did not to change with treatment. Original magnification ×500 for panels B-E; magnification ×200 for panels F-I. Cell enumeration and flow cytometric assay details are included in supplemental Methods. BM, bone marrow; W, week.

Figure 5.

Eosinophilic surface marker expression in the bone marrow. Panels show expression (by flow cytometric analysis) of Siglec-8, IL-5Rα, and/or EMR1 on bone marrow eosinophils before and after drug treatment. Siglec-8 and EMR1 expression was lower in 3 out of 4 responders at week 12 (on dexpramipexole), whereas IL-5Rα expression showed no consistent pattern. In nonresponders, none of the 3 parameters showed a consistent pattern at week 12 on dexpramipexole. EOS, eosinophils; MFI, mean fluorescence intensity; W, week.