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Dexpramipexole as an Oral Steroid-sparing Agent in Hypereosinophilic Syndromes

Sandhya R. Panch, Michael E. Bozik, Thomas Brown, Michelle Makiya, Calman Prussin, Donald G. Archibald, Gregory T. Hebrank, Mary Sullivan, Xiaoping Sun, Lauren Wetzler, JeanAnne Ware, Michael P. Fay, Cynthia E. Dunbar, Steven I. Dworetzky, Paneez Khoury, Irina Maric and Amy D. Klion
This article has an Erratum 132(13):1461

Key points

  • Glucocorticoid-sparing treatment alternatives are a critical need for patients with hypereosinophilic syndromes (HES).

  • The orally bioactive drug, dexpramipexole, demonstrated clinical efficacy with an excellent safety profile in a subset of patients with HES.

Abstract

Hypereosinophilic syndromes (HES) 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 amino-benzothiazole, showed an excellent safety profile and was coincidentally noted to significantly decrease absolute eosinophil counts (AEC) 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 HES. Dual primary endpoints 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% CI: 12%, 74%) achieved ≥50% reduction in MED, and the MEDD: MED ratio was significantly less than 100% (median=66%; 95% CI: 6%, 98%, p=0.03). All adverse events were self-limited, and none led to drug discontinuation. Affected tissue biopsies in 2 subjects showed normalization of pathology and depletion of eosinophils on dexpramipexole. Bone marrow biopsies 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 HES. Although the exact mechanism of action is unknown, preliminary data suggest that dexpramipexole may affect eosinophil maturation in the bone marrow. Study registered at clinicaltrials.gov: NCT02101138

  • Submitted February 23, 2018.
  • Accepted May 2, 2018.