Moderate to Severe Atopic Dermatitis

Primary objective(s)  To characterize the dose-response relationship of ZPL389 in subjects with moderate to severe AD assessed by IGA response after 16 weeks of treatment Secondary objective(s)  To characterize the dose-response relationship of ZPL389 in subjects with moderate to severe AD assessed using the percent change from Baseline in Eczema Area and Severity Index (EASI) score after 16 weeks of treatment  To evaluate the efficacy across different dose levels as assessed by EASI and IGA compared to placebo over time  To assess the safety and tolerability of different doses of ZPL389 as compared to placebo

ZPL389

ZPL389

Hard capsules

3, 10, 30 and 50

Primary Outcome Measures :
IGA response at Week 16 [ Time Frame: week 16 ]
IGA is an Investigator's global assessment of severity of atopic dermatitis.


Secondary Outcome Measures :
Percentage change from baseline in EASI score at week 16 [ Time Frame: week 16 ]
Eczema Area and Severity Index (EASI) is used to assess the extend and severity of AD

EASI score and response over time [ Time Frame: at each visit per protocol, up to week 20 ]
Eczema Area and Severity Index (EASI) score

IGA score and response over time [ Time Frame: at each visit per protocol, up to week 20 ]
Investigator's Global Assessment (IGA) score

frequency of adverse events [ Time Frame: up to week 20 ]
Clinical safety and tolerability will be assessed by adverse events monitoring

1. Written informed consent must be obtained before any assessment is performed.
2. Females and males aged 18 years or older at the time of Screening
3. Chronic AD; according to American Academy of Dermatology Consensus Criteria
(Eichenfield et al 2014), that has been present for at least 1 year before the baseline visit.
4. Moderate to severe AD defined as:
 Eczema Area and Severity Index (EASI) ≥16 at Screening and at Baseline
 IGA 3 or 4 on a 5-point scale (where 3 is moderate and 4 is severe) at Screening and
Baseline
 BSA involvement ≥10% at Screening and Baseline
5. Average peak pruritus score ≥3 as assessed by NRS over the last 7 days prior to Baseline
6. Documented recent history (within 6 months before the screening visit) of inadequate
response to treatment with topical medications for AD or for whom topical treatments are
otherwise medically inadvisable (e.g., because of important side effects or safety risks).
7. Candidate for systemic treatment
8. Have applied a stable dose of bland topical emollient once daily for at least the 7
consecutive days immediately before the baseline visit
9. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, diary
completion and other study procedures.

1. Any skin disease that, in the opinion of the investigator, would confound the diagnosis or
evaluation of AD disease activity (e.g., Netherton Syndrome, Cutaneous T-Cell
Lymphoma, extensive contact dermatitis, chronic actinic dermatitis)
2. Current skin infection at Baseline
3. Use of other investigational drugs within 5 half-lives of enrollment, or within
30 days /until the expected PD effect has returned to baseline, whichever is longer.
4. History of hypersensitivity to any of the study drug constituents or to drugs of similar
chemical classes.
5. Subjects taking medications prohibited by the protocol (see Table 5-1)
6. Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or
hypomagnesemia, history of cardiac failure, or history of clinically
significant/symptomatic bradycardia or any of the following:
 Long QT syndrome, family history of idiopathic sudden death or congenital long QT
syndrome
 Concomitant medication(s) with a “Known Risk of Torsades de Pointes” that cannot
be discontinued or replaced by safe alternative medication.
7. Resting QTcF ≥450 msec (male) or ≥470 msec (female) at Screening or Baseline or
inability to determine the QTcF interval
8. Cardiac or cardiac repolarization abnormality, including any of the following:
 History of myocardial infarction, angina pectoris, or coronary artery bypass graft
within 6 months prior to starting study treatment
 Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left
bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block,
Mobitz type II and third degree AV block)
9. Subjects with pre-existing conditions that may confound ability to diagnose drug-induced
liver injury (DILI) or subjects with factors that increase susceptibility to DILI, including
but not limited to:
 Ongoing liver disease
 Cirrhosis, compensated or decompensated
 History of hepatitis B or C
 Positive hepatitis B surface antigen (HBsAg), antiHB core antigen antibody (antiHBc) or anti-HB surface antigen antibody (anti-HBs) or positive hepatitis C test result
(Subjects positive for anti-HBs after Hep B vaccination but negative for HBsAg and
anti-HBc are eligible; Table 16-1)
 Hepatitis A or B vaccination in last 3 months
 Unhealthy alcohol use
 Known gallbladder or bile duct disease
 Acute or chronic pancreatitis
 Acute decompensated heart failure
 Chronic treatment with medication with hepatotoxic potential
10. Subjects who have a laboratory abnormality at Screening as follows:
 ALT/AST, ALP or TBL above upper limit of normal (ULN)
 Total white blood cell count (WBC) <2.5 x 109
cells/L
 Absolute neutrophil count (ANC) <1.5 x 109
/L (one re-test is allowed during the
screening period)
 Hemoglobin <11.0 g/dL
 Platelets <100.0 x 109
/L
 Potassium and magnesium outside normal range
 Estimated Glomerular Filtration Rate by the Modification of Diet in Renal Disease
(MDRD) equation <60 mL/minute/1.73 m2
11. History of lymphoproliferative disease or any known malignancy or history of malignancy
of any organ system within the past 5 years (except for skin Bowen’s disease, or local
basal cell carcinoma of the skin or actinic keratosis that have been treated with no
evidence of recurrence in the past 12 weeks; carcinoma in situ of the cervix or noninvasive malignant colon polyps that have been removed)
12. Past medical history record of, or current infection with, human immunodeficiency virus
(HIV)
13. Any surgical, medical (e.g., uncontrolled hypertension, heart failure or diabetes),
psychiatric or additional physical condition that the Investigator feels may jeopardize the
subject in case of participation in this study
14. Pregnant or nursing (lactating) women
15. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using required methods of contraception during dosing
and for 4 weeks after stopping of investigational medication. Required contraception
methods include:
 Total abstinence (when this is in line with the preferred and usual lifestyle of the
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation
methods) and withdrawal are not acceptable methods of contraception
 Female sterilization (bilateral oophorectomy with or without hysterectomy, total
hysterectomy or tubal ligation) at least six weeks before taking investigational drug.
In case of oophorectomy alone, the reproductive status of the woman must have been
confirmed by follow up hormone level assessment
 Male sterilization (at least 6 months prior to screening). For female subjects on the
study, the vasectomized male partner should be the sole partner for that subject
 Use of oral, injected or implanted hormonal methods of contraception, except in poor
CYP2D6 metabolizers. In the case of this method, the addition of a male condom
is required
 placement of an intrauterine device (IUD) or intrauterine system
In case of use of oral contraception women should have been stable on the same pill for a
minimum of 3 months before taking investigational drug.
In subjects who are poor CYP2D6 metabolizers, hormonal contraception is not allowed
and other contraceptive options as per the protocol should be followed.
In case local regulations deviate from the contraception methods listed above, local
regulations apply and will be described in the ICF.
Women are considered post-menopausal and not of child bearing potential if they have had
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g.
age appropriate, history of vasomotor symptoms) or have had surgical bilateral
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the
woman has been confirmed by follow up hormone level assessment is she considered not
of child bearing potential.
16. Sexually active males unless they use a condom during intercourse while taking drug and
for 4 weeks after stopping investigational medication and should not father a child in this
period. A condom is required to be used also by vasectomized men in order to prevent
delivery of the drug via seminal fluid. In case local regulations deviate from the
contraception methods listed above, local regulations apply and will be described in the
ICF.
17. Prior exposure to ZPL389 treatment.