Study to Evaluate Safety and Efficacy of Dexpramipexole (KNS-760704) in Subjects With Hypereosinophilic Syndrome

Hypereosinophilic syndromes (HES) are a heterogeneous group of disorders characterized by peripheral eosinophilia and evidence of eosinophil-related end organ damage. Although a high proportion of patients respond initially to corticosteroid therapy, high doses are often necessary to control the eosinophilia and clinical symptoms, and many patients become relatively refractory to therapy and/or develop serious side effects. Dexpramipexole (KNS 760704) is a synthetic aminobenzothiazole shown to safely reduce blood eosinophils counts in individuals with amyotrophic lateral sclerosis (ALS) in several clinical trials. The purpose of this proof-of- concept study is to evaluate the effect of dexpramipexole, an orally bioavailable small molecule, on circulating and tissue eosinophils in 10 subjects with HES. Following completion of eligibility assessments, subjects with absolute eosinophil count (AEC) \< 1000/uL will enter a lead-in period, during which a standardized weekly corticosteroid taper will be undertaken to establish a "minimally effective corticosteroid dose" in each study subject. For subjects whose symptoms are stable but AEC \> 1000/uL at the time of enrollment, the steroid dose at the time of enrollment will be defined as the minimally effective corticosteroid dose and no taper will be performed. Once the minimally effective corticosteroid dose is established, treatment with dexpramipexole 150 mg twice daily will begin. A standardized corticosteroid taper will begin after 12 weeks of treatment with dexpramipexole to determine the "minimally effective corticosteroid dose on dexpramipexole". Eosinophil counts and routine chemistries will be monitored weekly during corticosteroid tapering. End organ assessment, including echocardiogram, pulmonary function testing, and other studies as appropriate will be performed at study baseline, initiation of dexpramipexole therapy, 3 months after initial dosing with dexpramipexole, and the end of study visit. Bone marrow assessment will be performed prior to and after 12 weeks of dexpramipexole. Drug levels will be assessed prior to dexpramipexole and at week 12 and week 24 of dosing. The primary efficacy endpoint will be the number of subjects with a greater than or equal to 50 % change in prednisone (or equivalent) dose to maintain absolute eosinophil count (AEC) at or below baseline (pre-enrollment) levels and control clinical symptoms (responder analysis). Assuming that 10 patients received study drug per protocol, at least 4 of them will need to meet this endpoint to significantly show (at the usual two-sided 5% level, equivalent to the onesided 2.5% level) that at least 10% of patients respond to dexpramipexole (exact binomial test). Safety will be assessed as the incidence of adverse events (AEs) (including serious adverse events \[SAEs\]), vital signs, clinical laboratory assessments, physical examination, electrocardiogram (ECG) tests, and body weight. Exploratory endpoints will include determination of the effect of dexpramipexole on measures of eosinophil activation, cytokine/chemokine profile and other immunologic parameters, and reduction of tissue eosinophils.