Study to Evaluate Safety and Efficacy of Benralizumab in Subjects With Hypereosinophilic Syndrome

Hypereosinophilic syndrome (HES) is a rare group of heterogeneous disorders characterized by
marked peripheral eosinophilia (>1500/(micro)L) and evidence of eosinophil-associated tissue
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. IL-5
receptor (alpha) (IL-5R (alpha) expression in humans is restricted to eosinophils, basophils,
mast cells and their precursors and is, therefore, an ideal target for the therapy of HES. To
date, there have been no safety concerns with benralizumab (anti-IL-5R(alpha)) in phase 1, 2
and 3 trials in asthma and efficacy data is promising. In order to explore the safety and
efficacy of benralizumab in the treatment of HES, 20 adults (men and non-pregnant women,
18-75 years of age) with HES who are symptomatic with AEC >1000/(micro)L on stable HES
therapy for at least 1 month will be recruited for this randomized, placebo-controlled,
double-blind phase 2 trial. Benralizumab (30 mg) or placebo will be administered sc at weeks
0, 4, and 8. Eosinophil counts will be blinded for a subject and background HES therapy will
not be tapered until that subject has been on study for 13 weeks. At weeks 12, 16, and 20,
all subjects will receive a sc injection of benralizumab. Subjects demonstrating a response
at the 24 week visit (eosinophil count <1000/(alpha) L and stable or improved clinical
symptoms without an increase in background HES therapy) will continue to receive additional
30 mg sc injections every 4 weeks. Following the initial dose of benralizumab or placebo and
the first open-label dose of benralizumab, subjects will be followed daily for 3 days, weekly
for 4 weeks, and every 2 weeks for 8 weeks. Subsequent visits will be at 4 weeks intervals
for responders and 12 weeks intervals for non-responders for a minimum of two years. Subjects
with stable and complete response for greater than or equal to 2 years may be eligible to
receive benralizumab at a dosing interval of every 8 weeks. Subjects will receive
diphtheria-tetanus-acellular pertussis (TdaP) booster immunization at the 22 week visit.
Titers will be measured 6 weeks after immunization.The primary endpoint of the study is a 50%
reduction in peripheral blood eosinophilia on stable background therapy at 12 weeks
post-initiation of study drug. Secondary endpoints will include absolute eosinophil count,
the frequency and severity of adverse events, reduction in signs and symptoms of HES, tissue
eosinophilia, numbers of eosinophils, mast cells and their precursors in bone marrow, levels
of markers of eosinophil and mast cell activation, eosinophil count and background HES
therapy at 1 year, pharmacokinetics and anti-drug antibody (ADA) levels and eosinophil count
after 24 weeks of every 8 week dosing. Exploratory endpoints will address predictors of
response to benralizumab and the impact of eosinophil depletion on vaccine responses and
glucose homeostasis. Subjects who complete the study and for whom benralizumab provides
sustained clinical benefit, may be eligible to receive drug on an open-label extension
protocol until regulatory approval and commercial availability of the marketed drug to
prescribing physicians (for any indication), or until development of benralizumab is
discontinued by MedImmune.

- INCLUSION CRITERIA:

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

1. Male or female subject greater than or equal to18 and less than or equal to 65 years
of age at screening.

2. A female subject is eligible for this study only if she is not pregnant or
breast-feeding and one of the following:

1. Of childbearing potential but agrees to practice effective contraception, as
determined by the PI, or abstinence throughout the study and for 3 months after
administration of the last dose of investigational study drug

2. Of non-child-bearing potential

Females of non-child-bearing potential are defined as females with functioning ovaries with
a documented history of tubal ligation or hysterectomy or females who are post-menopausal,
as defined by 12 months of spontaneous amenorrhea with an appropriate clinical profile,
e.g. age appropriate, >45 years, in the absence of hormone replacement therapy. In
questionable cases, a blood sample for follicle stimulating hormone and estradiol will be
obtained to confirm child-bearing potential.

Acceptable methods of contraception may include one or more of the following:

1) male partner who is sterile prior to the female subject s entry into the study and is
the sole sexual partner for the female subject; 2) implants of levonorgestrel; 3)
injectable progestogen, 4) an intrauterine device with a documented failure rate of <1%;
and 5) double barrier methods including diaphragm or condom with a spermicide.

3) A male subject is eligible for this study only if he is one of the following:

1. Surgically sterile

2. Agrees to practice effective contraception (see above) or abstinence throughout the
study and for 3 months after the last administration of the investigational study drug

4) Documented diagnosis of HES (history of persistent eosinophilia >1500/(micro) L
without secondary cause and evidence of end organ manifestations attributable to the
eosinophilia)

5) Signs or symptoms of HES and AEC >1000/(micro) L on stable HES therapy for greater
than or equal to 1 month at the time of enrollment

6) Participation in protocol 94-I-0079 (Activation and function of eosinophils in
conditions with blood or tissue eosinophilia)

7) Agrees to storage of samples for study

Participation of Women:

Contraception: The effects of benralizumab on the developing human fetus are unknown.
For this reason, men and women of childbearing potential must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry and for the duration of study participation. Females of childbearing-age must
have a negative pregnancy test result prior to receiving benralizumab. During the
course of the study, if a woman becomes pregnant or suspects she is pregnant, she
should inform the study staff and her primary care physician immediately. If a subject
becomes pregnant, the investigational drug will be discontinued immediately, and the
subject will be counselled as to how to resume approved therapeutic options in
consultation with an obstetric provider.

EXCLUSION CRITERIA:

A subject will be excluded from participation in the study if any of the following
criteria apply at the time of enrollment:

1. Subjects with life-threatening or other serious illness or clinical manifestation
of HES deemed inappropriate for inclusion in study per the principal
investigator, including but not restricted to severe cardiac involvement and
prior thromboembolic disease.

2. Human immunodeficiency virus (HIV) or other known immunodeficiency

3. Positive hepatitis B surface antigen, or hepatitis C virus antibody serology, or
a positive medical history for hepatitis B or C. Patients with a history of
hepatitis B vaccination without history of hepatitis B are allowed to enroll

4. Presence of FIP1L1/PDGFRA or another known imatinib-sensitive mutation

5. Diagnosis of systemic mastocytosis or serum tryptase level >40 ng/mL

6. Known lymphoma, hematological malignancy, advanced and metastatic solid tumors
and/or subjects who are under chemotherapy, radiotherapy or interleukin 2
treatment

7. Known history of allergic or anaphylactic reaction to previous antibody therapy,
including intravenous immunoglobulin and licensed or experimental monoclonal
antibodies.

8. A helminth parasitic infection diagnosed within 24 weeks prior to the date
informed consent is obtained

9. Acute bacterial or viral infection (subjects may be enrolled once the acute
infection has resolved).

10. Receipt of intravenous immunoglobulin (IVIG) within 30 days prior to the date
informed consent is obtained

11. Receipt of any marketed (eg omalizumab) or investigational biologic within 4
months or 5 half-lives prior to the date informed consent is obtained, whichever
is longer

12. Receipt of live attenuated vaccines 30 days prior to the date of randomization

13. Receipt of inactive/killed vaccinations (e.g. inactive influenza) are allowed
provided they are not administered within 1 week before/after any study visit

14. Receipt of any investigational nonbiologic within 30 days or 5 half-lives prior
to the date informed consent is obtained, whichever is longer

15. History of alcohol or drug abuse within 12 months prior to the date informed
consent is obtained

16. Previous treatment with benralizumab (MEDI-563).

Co-enrollment Guidelines: Co-enrollment in other trials is restricted, other than
enrollment on observational studies or those evaluating the use of a licensed
medication. Study staff should be notified of co-enrollment as it may require the
approval of the Investigator.

Justification for Exclusion of Children:

Because there are insufficient data regarding dosing or adverse events available in
adults with HES to judge the potential risk in children, children are excluded from
this study.