A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED,
PHASE 2A STUDY TO ASSESS THE EFFICACY AND SAFETY OF
REGN3500 MONOTHERAPY AND COMBINATION OF REGN3500 PLUS
DUPILUMAB IN ADULT PATIENTS WITH MODERATE-TO-SEVERE
ATOPIC DERMATITIS

A patient must meet the following criteria to be eligible for inclusion in the
study:
1. Male or female, 18 to 75 years
2. Chronic AD, according to American Academy of Dermatology Consensus Criteria
(Eichenfield, 2014), that has been present for at least 3 years before the
screening visit
3. EASI score *16 at the screening and baseline visits
4. IGA score *3 (on the 0 to 4 IGA scale, in which 3 is moderate and 4 is
severe) at screening
and baseline visits
5. *10% BSA of AD involvement at the screening and baseline visits
6. Baseline peak Pruritus NRS score for maximum itch intensity *4
NOTE: Baseline peak Pruritus NRS score for maximum itch intensity will be
determined
based on the average of daily NRS scores for maximum itch intensity (the daily
score
ranges from 0 to 10) during the 7 days immediately preceding randomization. A
minimum
of 4 daily scores out of the 7 days is required to calculate the baseline
average score. For
patients who do not have at least 4 daily scores reported during the 7 days
immediately
preceding the planned randomization date, randomization should be postponed
until this
requirement is met, but without exceeding the 35-day maximum duration for
screening.
7. Documented recent history (within 6 months before the screening visit) of
inadequate
response to topical AD medication(s) or for whom topical treatments are
medically
inadvisable (eg, intolerance, because of important side effects, or safety
risks).
NOTE:
* Inadequate response is defined as failure to achieve and maintain remission
or a low
disease activity state (comparable to IGA 0<=clear to 2<=mild) despite treatment
with a
daily regimen of topical corticosteroids (TCS) of medium to higher potency (±
topical
calcineurin inhibitors [TCI] as appropriate), applied for at least 28 days or
for the
maximum duration recommended by the product prescribing information (eg, 14 days
for super-potent TCS), whichever is shorter.
* Patients with documented systemic treatment for AD (eg, systemic
immunosuppressant
drugs like cyclosporine, methotrexate, corticosteroids, etc) in the past 6
months are also
considered to be inadequate responders to topical treatments and are
potentially eligible
for treatment with dupilumab and REGN3500 after appropriate washout.
* Important side effects or safety risks are those that outweigh the potential
treatment
benefits and include intolerance to treatment, hypersensitivity reactions,
significant
skin atrophy, and systemic effects, as assessed by the investigator or by the
patient*s
treating physician.
* Acceptable documentation includes contemporaneous chart notes that record
topical
medication prescription and treatment outcome, or investigator documentation
based
on communication with the patient*s treating physician. If documentation is
inadequate, potential patients may be offered a course of treatment with a
daily regimen
of TCS of medium or higher potency (±TCI as appropriate), applied for at least
28 days
during the screening period or for the maximum duration recommended by the
product
prescribing information, whichever is shorter. Patients who demonstrate
inadequate
response during this period, as defined above, will be eligible for inclusion
in the study
following appropriate washout.
8. Have applied a stable dose of topical bland emollient (moisturizer) at least
twice daily for
at least the 7 consecutive days immediately before randomization
(ie, baseline/randomization visit would be the eighth day; see exclusion
criterion 7
regarding restrictions on the kind of emollients permitted during the study).
9. Willing and able to comply with all clinic visits and study-related
procedures
10. Provide informed consent signed by study patient or legally acceptable
representative
11. Able to understand and complete study-related questionnaires

A patient who meets any of the following criteria will be excluded from the
study:
1. Prior participation in an anti-IL-33 class antibody (including not limited
to REGN3500) or anti-IL4R* class antibody (including but not limited to
dupilumab) clinical study; past treatment with or current treatment with
dupilumab or another anti-IL4R* treatment
2. Body mass index <16 kg/m2
3. Treatment with an investigational drug within 8 weeks or within 5 half-lives
(if known), whichever is longer, before the baseline visit
4. Having used any of the following treatments within 4 weeks before the
baseline visit or any condition that, in the opinion of the investigator, is
likely to require such treatment(s) during the first 4 weeks of study treatment:
- Immunosuppressive/immunomodulating drugs (eg, systemic corticosteroids,
cyclosporine, mycophenolate-mofetil, IFN-*, Janus kinase inhibitors,
azathioprine, methotrexate, etc)
- Phototherapy for AD
5. Treatment with TCS, TCI, or topical crisaborole within 1 week before the
baseline visit
6. Treatment with biologics as follows:
- Any cell-depleting agents including but not limited to rituximab: within 6
months before the baseline visit, or until lymphocyte count returns to normal,
whichever is longer
- Other biologics: within 5 half-lives (if known) or 16 weeks prior to baseline
visit, whichever is longer
7. Initiation of treatment of AD with prescription moisturizers or moisturizers
containing additives such as ceramide, hyaluronic acid, urea, or filaggrin
degradation products during the screening period (patients may continue using
stable doses of such moisturizers if initiated before the screening visit)
8. Regular use (more than 2 visits per week) of a tanning booth/parlor within 4
weeks of the baseline visit
9. Planned or anticipated use of any prohibited medications and procedures
during study treatment
10. Treatment with a live (attenuated) vaccine within 12 weeks before the
baseline visit
11. Active chronic or acute infection requiring treatment with systemic
antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals within
2 weeks before the baseline visit, or superficial skin infections within 1 week
before the baseline visit
NOTE: patients may be re-screened after infection resolves
12. Known or suspected history of immunosuppression, including history of
invasive opportunistic infections (eg, tuberculosis [TB]*, histoplasmosis,
listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis) despite
infection resolution: or unusually frequent, recurrent, or prolonged
infections, per investigator judgment
*Patients with a positive TB QuantiFERON test result at screening will be
excluded from the study.
13. History of human immunodeficiency virus (HIV) infection or positive HIV
serology at screening
14. Positive with hepatitis B surface antigen (HBsAg), hepatitis B core
antibody (HBcAb), or hepatitis C virus antibody (HCV Ab) at the screening visit
15. At baseline, presence of any conditions listed as criteria for study drug
discontinuation
16. Presence of skin comorbidities that may interfere with study assessments
17. History of cancer, with the exceptions of:
- Patients with adequately treated basal cell carcinoma or carcinoma in situ of
the cervix.
- Patients with other malignancies that have been successfully treated for >10
years prior to screening where, in the judgement of both the investigator and
the treating physician, appropriate follow-up has revealed no evidence of
recurrence through time of screening.
18. Diagnosed active endoparasitic infections; suspected or high risk of
endoparasitic infection, unless clinical and (if necessary) laboratory
assessment have ruled out active infection before randomization
19. History of alcohol or drug abuse within 2 years of the screening visit
20. Severe concomitant illness(es) that, in the investigator*s judgment, would
adversely affect the patient*s participation in the study.
Examples include, but are not limited to, patients with short life expectancy,
patients with uncontrolled diabetes (hemoglobin A1c *9%), patients with
uncontrolled cerebrocardiovascular conditions (eg, myocardial infarction,
unstable arterial hypertension, unstable angina, cerebrovascular accident, and
stage III or IV cardiac failure according to the New York Heart Association
classification), severe renal conditions (eg, patients on dialysis),
hepatobiliary conditions (eg, Child-Pugh class B or C), neurological conditions
(eg, demyelinating diseases), active major autoimmune diseases (eg, lupus,
inflammatory bowel disease, rheumatoid arthritis, etc), other severe
endocrinological, gastrointestinal, metabolic, pulmonary, or lymphatic
diseases. The specific justification for patients excluded under this criterion
will be noted in study documents (chart notes, case report forms [CRFs], etc)
21. Any other medical or psychological condition (including relevant laboratory
abnormalities at screening) that, in the opinion of the investigator, may
suggest a new and/or insufficiently understood disease, may present an
unreasonable risk to the study patient as a result of his/her participation in
this clinical study, may make patient*s participation unreliable, or may
interfere with study assessments. The specific justification for patients
excluded under this criterion will be noted in study documents (chart notes,
CRFs, etc).
22. Planned or anticipated major surgical procedure during the patient*s
participation in this study
23. Patient is a member of the investigational team or his/her immediate family
24. Pregnant or breastfeeding women, or women planning to become pregnant or
breastfeed during the study
25. Women of childbearing potential (WOCBP)* who are unwilling to practice
highly effective contraception prior to the initial dose/start of the first
treatment, during the study, and for at least 20 weeks after the last dose of
study drug. Highly effective contraceptive measures include:
a. stable use of oral contraceptives associated with inhibition of ovulation
(such as contraceptives containing estrogen/progesterone or high dose
progesterone) initiated 2 or more menstrual cycles prior to screening
b. intrauterine device (IUD); intrauterine hormone releasing system (IUS)
c. bilateral tubal ligation
d. vasectomized partner with confirmed sterility (ie, patient*s medical record)
e. and/or sexual abstinence*, *
f. contraception for male patients is not required§
*Postmenopausal women must be amenorrheic for at least 12 months (without an
alternative medical cause) in order not to be considered of childbearing
potential. Amenorrheic status should be confirmed by demonstrating
follicle-stimulating hormone (FSH) levels consistent with postmenopausal status
according to laboratory ranges. Pregnancy testing and contraception are not
required for women with documented hysterectomy or tubal ligation.
* Sexual abstinence is considered a highly effective method only if defined as
refraining from heterosexual intercourse during the entire period of risk
associated with the study treatments. The
reliability of sexual abstinence needs to be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the
patient
*Periodic abstinence (calendar, symptothermal, postovulation methods),
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea
method are not acceptable methods of contraception. Female condom and male
condom should not be used together.
§Based on the known target biology of the study drugs and the extremely low
levels of study drug expected to reach the fetus via seminal fluid, the use of
contraception in treated males to prevent female partner and/or fetal exposure
is considered unnecessary.
26. Known sensitivity to doxycycline and/or tetracycline or to any of the
components of the investigational product formulation
27. Patients who are committed to an institution by virtue of an order issued
either by the judicial or the administrative authorities will be excluded from
this study (as required by country regulations).