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.

- INCLUSION CRITERIA:

A subject will be eligible for participation in the study only if all of the following
criteria apply:

1. The subject is male or female, age greater than or equal to 18 years

2. The subject has a documented history of HES requiring greater than or equal to 10 mg
prednisone (or equivalent) to maintain disease control.

HES is defined as 1) peripheral blood eosinophilia (>1500 eosinophils/microL) on at
least two occasions, 2) signs and symptoms of organ system involvement attributable to
the eosinophilia, and 3) exclusion of secondary causes of eosinophilia, such as
parasitic helminth infection, drug hypersensitivity and neoplasms, for which
appropriate therapy is directed at the underlying cause

3. HES symptoms are stable on the current corticosteroid dose.

4. The subject agrees to storage of samples for study.

5. Females are eligible for this study if they are:

(1) of non-childbearing potential (i.e., women who have had a hysterectomy or tubal
ligation or are postmenopausal as defined by no menses in 1 year); OR

(2) of childbearing potential but willing to practice effective contraception or abstinence
during administration of the study drug and for 3 months after administration of the
investigational study drug (dexpramipexole).

Participation of Women:

Contraception: Pre-clinical animal data demonstrated some fetal risk, suggesting there may
a human reproductive risk. Subjects must agree not to become pregnant. Females of
childbearing potential must have a pregnancy test before the first dose of dexpramipexole.
Because of the risk involved, subjects and their partners must use two methods of birth
control. They must continue to use both methods for 3 months after stopping the study drug.
Two methods of birth control may be selected from the list included below:

- Hormonal contraception

- Male or female condoms with or without a spermicide

- Diaphragm or cervical cap with a spermicide

- Intrauterine device (IUD)

If pregnancy is suspected or should occur, subjects must notify the study staff
immediately.

EXCLUSION CRITERIA:

A subject will not be eligible to participate in the study if any of the following
conditions are fulfilled at the time of enrollment:

1. Life-threatening HES or other condition that, in the Investigator s opinion, places
the subject at undue risk by participating in the study

2. Pregnant or breast-feeding

3. History of malignancy, including solid tumors and hematologic malignancies (except
basal cell and squamous cell cancers of the skin that have been completely excised and
cured)

4. HIV infection or any other known immunodeficiency.

5. Biopsy-proven eosinophilic granulomatosis with polyangiitis

6. Positive test for FIP1L1/PDGFRA fusion gene

7. Absolute neutrophil count <2000/microL at screening, or any documented history of
neutropenia

8. Renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) of less
than or equal to 80 mg/dL at screening (estimation of creatinine clearance using the
MDRD formula).

9. Cardiac abnormality defined as:

1. Moderate to severely decreased cardiac function (left ventricular ejection
fraction (LVEF) < 20% or history of LVEF <20% within the past 6 months or NYHA
class IIIb or IV)

2. History of angina or acute myocardial infarction in the past 6 months

3. History or long QT syndrome or arrhythmia.

4. A prolongation of QT/QTc interval (e.g., repeated demonstration of a QT/QTc
interval >450 ms before study treatment administration) at screening, admission
or pre-dose on Day 1.

5. Any clinically important abnormalities in resting ECG that may interfere with the
interpretation of QTc interval changes at screening, admission or pre-dose on Day
1.

This includes subjects with any of the following:

i. PR interval >210 ms;

ii. QRS >110 ms;

iii. Heart rate <45 bpm or >100 bpm (average of 3 assessments).

10. Recent history or suspicion of drug or alcohol abuse in the preceding 6 months

11. Treatment with an investigational drug in the previous 30 days