Public Disclosure Synopsis
Protocol C3291029 – 10 May 2018 – Final

PFIZER INC.
These results are supplied for informational purposes only.
Prescribing decisions should be made based on the approved package insert.
GENERIC DRUG NAME: Crisaborole
PROTOCOL NO.: C3291029
PROTOCOL TITLE:
A Phase 1, Single-Center, Randomized, Vehicle-Controlled, Parallel-Cohort Study of
Crisaborole Ointment 2% to Evaluate the Skin Irritation Potential in Adult Japanese Healthy
Subjects, and to Evaluate the Safety, Tolerability and Pharmacokinetics in Adult Japanese
Subjects with Mild to Moderate Atopic Dermatitis
Study Center:

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Study Initiation and Final Completion Dates:
13 September 2017 and 27 November 2017
Phase of Development:
Phase 1
Study Objectives:
Primary Objective for Cohort 1:
To investigate the skin irritation potential of a single topical dose of crisaborole ointment
2% and vehicle in adult Japanese healthy subjects.

Secondary Objective for Cohort 1:
To investigate the safety and tolerability of a single topical dose of crisaborole ointment
2% and vehicle in adult Japanese healthy subjects.

Primary Objective for Cohort 2:

To investigate the safety and tolerability of multiple topical doses of crisaborole ointment
2% twice daily (BID) in adult Japanese subjects with mild to moderate atopic
dermatitis (AD).

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Secondary Objective for Cohort 2:

To characterize the plasma pharmacokinetic (PK) profile of crisaborole and its identified
main oxidative metabolites (AN7602 and AN8323) following multiple topical doses ofcrisaborole ointment 2% BID in adult Japanese subjects with mild to moderate AD.

METHODS
Study Design:This was a Phase 1, single-center, randomized, vehicle-controlled, parallel-cohort study ofcrisaborole ointment 2% conducted in 2 cohorts evaluating the skin irritation potential in
adult Japanese healthy subjects in Cohort 1, and safety, tolerability and PK in adult Japanese
subjects with mild to moderate AD in Cohort 2. Both cohorts could be run in parallel suchthat completion of Cohort 1 was not required in order to proceed with Cohort 2 (Table 1).
Table 1.

Description of Cohorts

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CohortCohort 1
Cohort 2

N
Investigational Product
Skin irritation cohort in healthy subjects
20
Crisaborole ointment 2% and vehicle
Safety, tolerability and PK cohort in
12
Crisaborole ointment 2% (n=10)
subjects with mild to moderate AD
Vehicle (n=2)
Abbreviations: AD=atopic dermatitis; N=number of subjects; n=number of subjects with prespecified criteria;
PK=pharmacokinetic.

Cohort 1:
This was a randomized, observer and subject-blind, vehicle-controlled cohort, of theinvestigational products (crisaborole ointment 2% and vehicle) under occlusive patch
conditions to evaluate skin irritation potential and safety in Japanese healthy male subjects
aged 20 to 55 years, inclusive. Approximately 20 subjects could be enrolled into the cohort.
All subjects were to have skin area fields designated for investigational product patches at
2 randomly assigned, adjacent sites, for the purpose of determining irritation potential.
The investigational products were to be applied topically once on Day 1 and remain underocclusion for 48 hours. The skin irritancy was to be evaluated approximately 30 minutes
after removal of the patches (Day 3, around 48 hours after investigational product patch
application) and 24 hours after removal of the patches (Day 4, approximately 72 hours after
the investigational product application). A follow-up telephone call (end of study) wasscheduled by study site staff to the subjects on Day 29 (+7 days) to assess adverse events(AEs).
All applications of investigational products were to be conducted by the study site staff. The
observer and subjects were blinded to minimize evaluation bias for skin irritation.
Cohort 2:
This was a randomized, double-blind cohort of crisaborole ointment 2% BID to evaluate thesafety, tolerability and PK in adult Japanese subjects with mild to moderate AD. The cohort
enrolled male and female subjects with AD aged 20 to 55 years, inclusive, at the time of
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Protocol C3291029 – 10 May 2018 – Finalscreening. Approximately 12 subjects having at least 25% treatable percent body surface
area (%BSA) were to be enrolled into the study. The treatable %BSA was calculated at
Screening and Day 1. The investigational product was to be applied BID to thetreatable %BSA areas identified on Day 1 for a duration of 8 days; on Days 1 and 8,
investigational product was to be administered once daily in the morning. All investigational
product doses were to be dispensed and applied by study site staff.
Subjects were to be screened within 28 days prior to application of investigational product on
Day 1 to confirm that they met the subject eligibility criteria for the study. Subjects wereadmitted to the Clinical Research Unit (CRU) on Day -1 and were to remain confined in the
CRU until completion of all assessments on Day 9. A follow-up telephone call(end of study) was planned by study site staff to the subjects on Day 36 (+7 days) to assess
AEs.

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Refer to Table 2 and Table 3 for a complete list of assessments performed during the study
for Cohort 1 and Cohort 2, respectively.

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Table 2.

Schedule of Activities - Cohort 1

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Screening

-1

1

2

3

4/ET

29 (+7 Days)
FU Contactb(EOS)

Informed consent
X
CRU confinement
Xc
Xd



Inclusion/exclusion criteria
X
X
X
Medical history
X
X
Physical examination
X
X
X
Safety laboratory
X
Xe
Demographics
X
Height and weightX
Vital signsf
X
ECGg
X
HIV, HepBsAg, HepBcAb, HCVAb and syphilis testing
X
Urine drug testingX
Xh
Visual assessment of application field
X
X
Treatments/patch application
Xi
i
i
Patch removal
X
Skin irritation assessment
Xj
Xj
k
Review and record prior and concomitant medications
X
X
X
X
X
X
Assess for AEs and SAEsl
X
X
X
X
X
X
X
Abbreviations: =ongoing/continuous event; AE=adverse event; CRU=clinical research unit; ECG=electrocardiogram; EOS=end of study; ET=earlytermination; FU=follow-up; HIV=human immunodeficiency virus; HepBsAg=hepatitis B surface antigen; HepBcAb=hepatitis B core antibody;
HCVAb=hepatitis C antibody; labs=laboratory evaluations; SAE=serious adverse event.
a. Day relative to start of study treatment (Day 1).
b. Follow-up contact was completed on Day 29 (28+7 calendar days after the application of the investigational product patches on Day 1) to capture any
potential AEs.
c. Subjects were admitted to the CRU on Day -1.
d. Subjects were discharged from CRU on Day 4 after completion of all assessment on Day 4.
e. Day -1 clinical labs did not have to be repeated if clinical labs were completed within 7 days prior to Day -1.
f. Vital signs (pulse rate and blood pressure) taken supine position after subject had been calmly lying for 5 minutes.
g. Single ECG was collected.
h. Day -1 urine drug testing did not have to be repeated if urine drug testing was completed within 7 days prior to Day -1.
i. Day 1 patches remained in place through Day 3.
j. Skin irritation assessment of the patch sites were conducted on Day 3 (approximately 30 minutes after removal of the patches) and Day 4 (approximately

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Table 2.

24 hours after removal of the patches).
All medications and non-medication therapies used within 28 days prior to the planned first dose.
If AEs/SAEs occurred at a patch site, the patch site location was recorded.

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l.

Schedule of Activities - Cohort 1

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Table 3.

Schedule of Activities - Cohort 2

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Daya
Informed consent
CRU confinement
Inclusion/exclusion criteria
Medical history
Confirmation of diagnosis of AD
Physical examination
Physical examinationf (skin examination)
Assess ISGA
Record treatable AD areas
Calculate and record treatable %BSAg
Safety laboratory
Demographics
Height and weight
Vital signsi
ECG
Urine pregnancy test
Contraception check
FSHk
HIV, HepBsAg, HepBcAb, HCVAb andsyphilis testing
Urine drug testing
AM dosing: weigh dose and apply
PM dosing: weigh dose and apply
Obtain PK samples
Review and record prior and concomitant
medications
Assess for AEs and SAEs

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Screening
X
X
X
X
X
X
X
X
X
X
X
X
Xj
X
X
X
X
X

–1

1

2

3

4

5

6

7

8/ET

9

Xc
X
X


X















Xd

Xe

X
X

X
X
X
X
X
X

X
Xh
X
Xj

X
Xj

X
X

X

X

Xl
X

o

X

Xm
X

X

X

X

X

36 (+7 Days)
FU Contactb(EOS)

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X
X
Xn
X

X
X

X
X

X
X

X
X
X

X
X
Xn
X

X

X

X

X

X

X

X

X
Xm
X

Xn
X

X

X

X

X

X

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Protocol C3291029 – 10 May 2018 – Final

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Table 3.

Schedule of Activities - Cohort 2

Abbreviations: =ongoing/continuous event; %BSA=percent body surface area; AE=adverse event; AD=atopic dermatitis; AM=ante meridiem; CRU=clinicalresearch unit; ECG=electrocardiogram; EOS=end of study; ET=early termination; FSH=follicle-stimulating hormone; FU=follow-up; HIV=humanimmunodeficiency virus; HepBsAg=hepatitis B surface antigen; HepBcAb=hepatitis B core antibody; HCVAb=hepatitis C antibody; ISGA=investigator’s static
global assessment; PK=pharmacokinetic; Prep D1=dipotassium edetic acid; PM=post meridiem; SAE=serious adverse event.
a. Day relative to start of study treatment (Day 1).
b. Follow-up contact was completed on Day 36 (28+7 calendar days after the last application of the investigational product) to capture any potential AEs and to
confirm appropriate contraception usage.
c. Subjects were admitted to the CRU on Day -1.
d. Subjects were discharged from CRU on Day 9 after completion of all assessment on Day 9.
e. A physical examination was conducted at ET.
f. A skin examination was conducted by dermatologist.
g. Treatable % BSA is defined as the percent of a subject’s total body surface area that is AD-involved, excluding the scalp and venous access areas.
h. Only weight was measured on Day 1.
i. Vital signs (pulse rate and blood pressure) taken supine position after subject had been calmly lying face up for 5 minutes.
j. ECG was collected in single.
k. Any female subject who had been amenorrheic for at least 12 consecutive months.
l. Day -1 urine drug testing did not have to be repeated if urine drug testing was completed within 7 days prior to Day -1.
m. Obtained PK samples at predose, 3 hours and 12 hours post Day 1 and Day 8 AM dose.
n. Obtained PK samples prior to AM dose on Day 2 and Day 7 (at 24 hours post Day 1 and Day 6 AM dose). Obtained PK samples on Day 9 at 24 hours post
Day 8 AM dose.
o. All medications and non-medication therapies used within 28 days prior to Screening.

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Number of Subjects (Planned and Analyzed):
A total of approximately 32 subjects were planned in this study. For Cohort 1, a sample sizeof approximately 20 subjects were selected empirically, for Cohort 2, a sample size of
approximately 12 subjects (10 subjects for crisaborole ointment 2% and 2 subjects forvehicle) were selected empirically. In Cohort 1, a total of 39 subjects were screened, out of
which 20 subjects were assigned to study treatment. In Cohort 2, a total of 19 subjects werescreened, out of which 12 subjects were assigned to study treatment; 10 subjects tocrisaborole ointment 2% and 2 subjects to vehicle.
Diagnosis and Main Criteria for Inclusion and Exclusion:
Cohort 1
Main Inclusion Criteria: Healthy male Japanese subjects who, at the time of screening, were
between the ages of 20 and 55 years, inclusive.

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Main Exclusion Criteria: Subjects who had any visible skin disease at the application sitewhich, in the opinion of the investigative personnel, could have interfered with the evaluationof the test site reaction, who had psoriasis and/or active AD/eczema, and who had a historyof AD
Cohort 2
Main Inclusion Criteria: Male or female Japanese subjects aged 20 years to 55 years(inclusive) at the time of screening, and in generally good health except for AD. Good healthis defined as no clinically relevant abnormalities identified by a detailed medical history,
physical examination, including blood pressure and pulse rate measurement,
12-lead electrocardiogram (ECG), and clinical laboratory tests. Diagnosis of AD based on
the criteria of Hanifin and Rajka (1980). Subjects had at least 25% treatable %BSA on Day 1(excluding the scalp and designated venous access areas) and an investigator’s static global
assessment (ISGA) score of mild (2) or moderate (3) on Day 1.
Main Exclusion Criteria: Subject who had any clinically significant medical disorder,
condition, disease (including active or potentially recurrent dermatological conditions otherthan AD), significant physical examination or laboratory findings that may have interferedwith study objectives, in the investigator’s opinion.
Study Treatment:
The investigational products were crisaborole ointment 2% and matching vehicle.
Crisaborole ointment 2%, was formulated to contain PF-06930164 (2% wt/wt), white
petrolatum, propylene glycol, mono- and diglycerides, paraffin wax, butylatedhydroxytoluene, and edetate calcium disodium.
Vehicle (no active drug in the formulation) contained white petrolatum, propylene glycol,
mono- and diglycerides, paraffin wax, butylated hydroxytoluene, and edetate calcium
disodium.

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Crisaborole ointment 2% and vehicle were provided in 60 g tubes by the sponsor. The tubes
were labeled according to local regulatory requirements. Subjects received theinvestigational product once on Day 1 to the designated areas of the back according to therandomization sequence and remained under occlusion for 48 hours in accordance with askin irritation manual.
Safety and Pharmacokinetic Endpoints:
Primary Endpoint for Cohort 1:Skin irritation index.

Secondary Endpoint for Cohort 1:Assessment of AEs.

Primary Endpoint for Cohort 2:Assessment of AEs, clinical laboratory tests, vital signs, and 12-lead ECG.

Secondary Endpoint for Cohort 2:

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PK parameters: Maximum observed plasma concentration (Cmax), time to reach maximum
observed plasma concentration (Tmax), area under the plasma concentration-time curvefrom 0 time until the last measurable concentration (AUClast), area under the plasma
concentration-time curve from time 0 to the 24 hours postdose (AUC24), area under theplasma concentration-time curve from time 0 to time tau (τ), the dosing interval, whereτ=12 hours for BID dosing (AUCtau) on Day 1 and Day 8, and accumulation ratio forCmax (Rac [Cmax]) and accumulation ratio for AUCtau (Rac [AUCtau]) on Day 8.

Efficacy evaluations were not performed for this study.
Safety Evaluations:
Safety evaluations included skin irritation assessment (Cohort 1), AEs, safety laboratory tests,
vital signs (heart rate, blood pressure), and 12-lead ECGs. Vital signs and 12-lead ECGs
were observed at Screening in Cohort 1 and at Screening, on Day 1 and Day 8 in Cohort 2.
Statistical Methods:
The PK concentration population was defined as all subjects randomized and treated who had
at least 1 concentration. The PK parameter analysis population was defined as all subjects
randomized and treated who had at least 1 of the PK parameters of primary interest.
PK analysis was based on the PK analysis set.
PK data was descriptively summarized by study day and analyte for crisaborole and its
metabolites respectively. Comparison between study days was performed by descriptive
analysis of the within-subject ratio of Day 8/Day 1 PK parameters.
The safety analysis population was defined as all subjects who received at least 1 dose of
study medication. All subjects who received at least 1 dose of study medication wereclassified according to the actual study treatment received. The safety analysis set was theTemplate version 1.7

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primary population for treatment administration/compliance and safety. The safety analysis
was conducted for Cohort 1 and Cohort 2, separately.
The analysis of AEs was based on the safety analysis population. Descriptive summaries andlisting of the AE/serious adverse event (SAE) data was provided by treatment. In addition,
AEs that occurred in the treatment area were separately summarized by treatment. AEs werereported in accordance with the sponsor data standards. The analysis of laboratory data wasbased on the safety analysis population. Laboratory data was descriptively summarized andlisted by treatment in accordance with the sponsor data standards. Baseline was the last
predose measurement. For each subject in Cohort 1, the maximum irritation score of the skinirritation assessment through all visits (ie, Day 3 and Day 4) was calculated. The skinirritation index was calculated as the sum of the individual maximum irritation scores divided
by the number of evaluable subjects who had the skin irritation assessment and multiplied by
100.
RESULTS

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Subject Disposition and Demography:
Subject disposition is summarized in Table 4 and Table 5 for Cohort 1 and Cohort 2,
respectively. In Cohort 1, a total of 39 subjects were screened out of which 20 subjects wereassigned to study treatment. All subjects assigned to study treatment received study drug.
No subjects discontinued from Cohort 1. All subjects who received study medication wereanalysed for safety.
In Cohort 2, a total of 19 subjects were screened, out of which 12 subjects were assigned to
study treatment; 10 subjects to crisaborole ointment 2% and 2 subjects to vehicle. All
subjects assigned to study treatment received at least 1 dose of study drug. Overall
10 subjects completed the study (9 in the crisaborole ointment 2% group, 1 in the vehicle
group). Overall 2 subjects discontinued in the treatment phase, 1 subject in the crisaborole
ointment 2% group and 1 subject in the vehicle group; both due to AEs. Of the subjects
assigned to crisaborole ointment 2%, all were included in the PK concentration analysis set
and 9 subjects were included in the PK parameter analysis set. All 12 subjects who received
at least 1 study drug were analysed for safety.

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Table 4.

Subject Disposition (Cohort 1)

Parameters

Crisaborole Ointment 2% and Vehicle(N=20)n%

Screened:
39
Screen failure: 11
Not assigned:
8
Conflicting work schedule:
2
Exceeded enrollment limit:
6
Assigned to treatment
20 (100.0)
Treated20 (100.0)
Not treated0
Discontinued (treatment phase)0
Discontinued (follow-up phase)0
Safety analysis set
20 (100.0)
Abbreviations: N=number of subjects; n=number of subjects with specified criteria.

Table 5.

Subject Disposition (Cohort 2)

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Parameters

Crisaborole Ointment 2%(N=10)
n%

Vehicle
(N=2)
n%

Total
(N=12)n%

Screened:
19
Screen failure: 4
Not assigned:
3
Exceeded enrollment limit:
3
Assigned to treatment
10 (100.0)
2 (100.0)
12 (100.0)
Treated10 (100.0)
2 (100.0)
12 (100.0)
Not treated000Discontinued (treatment phase)
1 (10.0)a
1 (50.0) a
2 (16.7)aCompleted (treatment phase)
9 (90.0)
1 (50.0)
10 (83.3)
Discontinued (follow-up phase)000PK concentration analysis set
10 (100.0)00PK parameter analysis set
9 (90.0)00
Safety analysis set
10 (100.0)
2 (100.0)
12 (100.0)
Abbreviations: N=number of subjects; n=number of subjects with specified criteria; PK=pharmacokinetics.
a. Discontinued due to adverse events.

For both cohorts, all subjects were male and the majority of subjects were aged 20 to
44 years. In Cohort 2, the majority of subjects had a moderate ISGA score (83.3% overall)and the mean treatable %BSA was 63.92% overall (range: 35.0% to 87.0%).
Pharmacokinetic Results:
Plasma Crisaborole: Following a single application of crisaborole ointment 2% in adultJapanese subjects with mild to moderate AD, maximum crisaborole plasma concentrations
were observed 3 hours postdose. Based on the trough plasma concentrations on Days 7, 8,
and 9, steady state seems to have been achieved by Day 7.

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Exposures based on geometric mean AUCtau and Cmax values were 928.9 ng•h/mL and
163.7 ng/mL respectively, on Day 1 following a single dose and 1123 ng•h/mL and
164.9 ng/mL on Day 8 following multiple BID dose administration (Table 6). Overall there
was minimal accumulation of crisaborole on Day 8 following multiple BID administration
with geometric mean accumulation ratios based on AUCtau (Rac AUCtau) and Cmax (Rac Cmax)
of 1.209 and 1.007 respectively.
Between-subject variability in plasma crisaborole exposure on Day 1 and Day 8 wasmoderate to high based on geometric %CV, ranging between 56% to 71% for Cmax and 51%
to 65% for AUCtau.
Table 6.

Summary of Plasma Crisaborole Pharmacokinetic Parameters Following
Single (Day 1) and Multiple (Day 8) BID Administration

Parameter Summary Statisticsa for Crisaborole by Dosing Day
Day 1
Day 8
N
9
9
AUCtau (ng•h/mL)
928.9 (65)1123 (51)
AUClast (ng•h/mL)
1171 (60)1527 (48)
AUC24 (ng•h/mL)
1171 (60)1527 (48)
Cmax (ng/mL)
163.7 (71)164.9 (56)Tmax (h)3.00 (3.00-3.00)
3.00 (3.00-3.00)
Rac CmaxNA
1.007 (32)
Rac AUCtau
NA
1.209 (25)Abbreviations: %CV=percent coefficient of variation; AUC24=area under the plasma concentration-time curvefrom time 0 to the 24 hours postdose; AUClast=area under the plasma concentration-time curve from 0 time until
the last measurable concentration (Clast); AUCtau=area under the plasma concentration-time curve from time 0 totime tau (τ), the dosing interval, where τ=12 hours for BID dosing; BID=twice daily; Cmax=maximum observed
plasma concentration; h=hour; N=number of subjects in the PK parameter analysis population as outlined in the
SAP contributing to the summary statistics; NA=not applicable; PK=pharmacokinetic; Rac Cmax=accumulation
ratio for Cmax; Rac AUCtau=accumulation ratio for AUCtau; SAP=statistical analysis plan; Tmax=time to reachmaximum observed plasma concentration.
a. Geometric mean (Geometric %CV) for all except: median (range) for Tmax.

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Parameter, Units

Plasma AN7602 (Metabolite): Following a single application of crisaborole ointment 2%,
Cmax for the AN7602 metabolite were observed 3 hours postdose. Based on the troughplasma concentrations on Days 7, 8, and 9, steady state seems to have been achieved by
Day 7.
Exposures based on geometric mean AUCtau and Cmax values were 500.4 ng•h/mL and
94.97 ng/mL respectively on Day 1 and 434.9 ng•h/mL and 68.83 ng/mL on Day 8 following
multiple BID dose administration of crisaborole ointment 2% (Table 7). Overall there was
no accumulation of AN7602 metabolite on Day 8 with both of the Rac AUCtau and Rac Cmax
<1.
Between-subject variability in plasma AN7602 exposure on Day 1 and Day 8 was moderate
to high based on geometric percent coefficient of variation (%CV), ranging between 59% to
75% for Cmax and 50% to 66% for AUCtau.

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Table 7.

Summary of Plasma AN7602 Metabolite Pharmacokinetic Parameters
Following Single (Day 1) and Multiple (Day 8) Administration of
Crisaborole Ointment 2% (BID)

Parameter Summary Statisticsa for AN7602 by Dosing Day
Day 1
Day 8
N
9
9
AUCtau (ng•h/mL)
500.4 (66)434.9 (50)
AUClast (ng•h/mL)
601.9 (60)565.5 (44)
AUC24 (ng•h/mL)
601.9 (60)565.5 (44)Cmax (ng/mL)
94.97 (75)68.83 (59)Tmax (h)3.00 (3.00-3.00)
3.00 (3.00-3.00)
Rac CmaxNA
0.7247 (24)
Rac AUCtau
NA
0.8688 (19)Abbreviations: %CV=percent coefficient of variation; AUC24=area under the plasma concentration-time curvefrom time 0 to the 24 hours postdose; BID=twice daily; AUClast=area under the plasma concentration-time
curve from 0 time until the last measurable concentration (Clast); AUCtau=area under the plasma
concentration-time curve from time 0 to time tau (τ), the dosing interval, where τ=12 hours for BID dosing;Cmax=maximum observed plasma concentration; h=hour; N=number of subjects in the PK parameter analysis
population as outlined in the SAP contributing to the summary statistics; NA=not applicable;
PK=pharmacokinetic; Rac Cmax=accumulation ratio for Cmax; Rac AUCtau=accumulation ratio for AUCtau;
SAP=statistical analysis plan; Tmax=time to reach maximum observed plasma concentration.
a. Geometric mean (Geometric %CV) for all except: median (range) for Tmax.

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Parameter, Units

Plasma AN8323 (Metabolite): Following a single application of crisaborole ointment 2%,
Cmax for the AN8323 metabolite was observed between 3 and 12 hours postdose. Based on
the trough plasma concentrations on Days 7, 8, and 9, steady state was achieved by Day 7.
Plasma exposures based on geometric mean AUCtau and Cmax values for the AN8323
metabolite were higher than those observed for crisaborole and the AN7602 metabolite withmean values of 29360 ng•h/mL and 3064 ng/mL respectively on Day 1 following a single
administration of crisaborole ointment 2% and 90360 ng•h/mL and 8080 ng/mL on
Day 8 following multiple BID administration of crisaborole ointment 2% (Table 8). Unlike
crisaborole and AN7602 metabolite, there was some accumulation observed for the AN8323
metabolite on Day 8 with geometric mean Rac AUCtau and Rac Cmax of 3.080 and 2.638
respectively.
Between-subject variability in plasma AN8323 exposure on Day 1 and Day 8 was moderate
to high based on geometric %CV, ranging between 71% to 97% for Cmax and 68% to 92% for
AUCtau.

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Table 8.

Summary of Plasma AN8323 Metabolite Pharmacokinetic Parameters
Following Single (Day 1) and Multiple (Day 8) Dosing of
Crisaborole Ointment 2% (BID)

Parameter Summary Statisticsa for AN8323 by Dosing Day
Day 1
Day 8
N
9
9
AUCtau (ng•h/mL)
29360 (92)90360 (68)
AUClast (ng•h/mL)
57560 (84)169100 (68)
AUC24 (ng•h/mL)
57560 (84)169100 (68)Cmax (ng/mL)
3064 (97)8080 (71)
Tmax (h)3.00 (3.00-12.0)
3.00 (3.00-12.0)
Rac CmaxNA
2.638 (52)
Rac AUCtau
NA
3.080 (48)Abbreviations: %CV=percent coefficient of variation; AUC24=area under the plasma concentration-time curvefrom time 0 to the 24 hours postdose; AUClast=area under the plasma concentration-time curve from 0 time until
the last measurable concentration (Clast); AUCtau=area under the plasma concentration-time curve from time 0 totime tau (τ), the dosing interval, where τ=12 hours for BID dosing; BID=twice daily; Cmax=maximum observed
plasma concentration; h=hour; N=number of subjects in the PK parameter analysis population as outlined in the
SAP contributing to the summary statistics; NA=not applicable; PK=pharmacokinetic; Rac Cmax=accumulation
ratio for Cmax; Rac AUCtau=accumulation ratio for AUCtau; SAP=statistical analysis plan; Tmax=time to reachmaximum observed plasma concentration.
a. Geometric mean (Geometric %CV) for all except: median (range) for Tmax.

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Parameter, Units

Safety Results:
There were no deaths, SAEs or AEs of severe intensity reported in this study. There were no
discontinuations due to AEs in Cohort 1. There were no treatment-emergent AEs (TEAEs)
in Cohort 1. There were 2 subjects that discontinued treatment due to AEs in Cohort 2. An
overview of subjects that discontinued treatment due to an AE in Cohort 2 is summarized inTable 9.
Table 9.

Overview of Subjects That Discontinued Treatment due to an Adverse
Event; All-Causalities (Cohort 2)

Number (%) of Subjects

Crisaborole Ointment
Vehicle
2%
n (%)
n (%)
Subjects discontinued from study due to AEs
1 (10.0)a
1 (50.0)b
Abbreviations: AEs=adverse events; n=number of subjects; TEAE=treatment-emergent adverse event.
a. Permanent discontinuation due to mild TEAE of application site pain.
b. Permanent discontinuation due to moderate TEAE of atopic dermatitis.

The incidence of TEAEs (all-causalities and treatment-related) by treatment group for
Cohort 2 are summarized in Table 10. A total of 13 TEAEs were reported in 9 subjects in thecrisaborole ointment 2% group; all of which were of mild intensity. The most frequently
reported all-causalities TEAEs by preferred term were application site irritation (7 subjects)
and application site pain (4 subjects) in the crisaborole ointment 2% group. Except for eyelid
oedema, all TEAEs in the crisaborole ointment 2% group were considered treatment-related.
In the vehicle group, 6 TEAEs were reported in all subjects.

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Table 10. Treatment-Emergent Non Serious Adverse Events by System Organ Class and Preferred Term (Cohort 2)

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Number of Subjects Evaluable for AEs

Crisaborole Ointment 2%(N=10)

Vehicle
(N=2)

Total
(N=12)

n (%)
n1
n2
n (%)
n1
n2
n (%)
n1
n2
Number (%) of Subjects or Occurrences:by System Organ Class and Preferred Term
9 (90.0)
2 (100.0)
11 (91.7)
With AEs1(10.0)
100
00
1 (8.3)1
0
Eye disorders1(10.0)
1
0
0
0
0
1
(8.3)
1
0
Eyelid oedema
9(90.0)
24
24
2(100.0)6
6
11(91.7)
30
30
General disorders and administration site conditions
1 (10.0)
11
1 (50.0)1
1
2 (16.7)
2
2
Application site coldness
7(70.0)
15
15
1(50.0)
1
1
8(66.7)
16
16
Application site irritation
4 (40.0)88
1 (50.0)2
2
5 (41.7)
10
10
Application site pain
00
01
(50.0)
2
2
1
(8.3)
2
2
Application site pruritus
0001(50.0)
1
0
1
(8.3)
1
0
Infections and infestations
00
0
1(50.0)
1
0
1
(8.3)
1
0
Nasopharyngitis
0001(50.0)
1
1
1
(8.3)
1
1
Skin and subcutaneous tissue disorders0001(50.0)
1
1
1
(8.3)
1
1
Dermatitis atopic
Totals for the number of subjects at a higher level were not necessarily the sum of those at the lower levels since a subject might report 2 different AEs within
the higher level category.
Includes data up to lag days after last dose of study drug.
Except for n1 and n2 subjects were only counted once per treatment for each row.
Percentages of gender specific events were calculated using the corresponding gender count as denominator.
MedDRA Version 20.1 coding dictionary applied.
Abbreviations: AEs=adverse events; MedDRA=Medical Dictionary of Regulatory Activities; N=number of subjects; n1=the number of occurrences oftreatment-emergent all causalities AEs; n2=the number of occurrences of treatment-emergent causally related to treatment AEs; n=the number of subjects in thisreporting group affected by any occurrence of this AE, all causalities.

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Skin irritation assessment of the patch sites were conducted on Day 3 and Day 4 by a blinded
observer who was a dermatologist for Cohort 1. The maximum irritation score was 0 or 0.5
for all subjects with the vehicle patch (Table 11). Also, the maximum irritation score was
0 or 0.5 for all subjects of the crisaborole ointment 2% except for the 3 subjects with amaximum irritation score of 2. The skin irritation indexes were 5.0 with a safety category ofsafe for the vehicle patch and 40.0 with a safety category of risky for the crisaborole
ointment 2% patch.
Table 11. Summary of Skin Irritation Response (Cohort 1)

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Assessment Scores

Day 3
Day 4
Maximum Irritation Score
N=20
N=20
N=20
n (%)
n (%)
n (%)
Investigational Product: Crisaborole Ointment 2% Patch0
19 (95.0)
13 (65.0)
13 (65.0)
0.5
0 (0.0)4 (20.0)
4 (20.0)10 (0.0)0 (0.0)0 (0.0)2
1 (5.0)3 (15.0)
3 (15.0)30 (0.0)0 (0.0)0 (0.0)4
0 (0.0)0 (0.0)0 (0.0)Median
0.00
0.00
0.00
Mean
0.10
0.40
0.40
SD
0.447
0.718
0.718
Range (min, max)
(0.0, 2.0)
(0.0, 2.0)
(0.0, 2.0)
Skin irritation index
00
40.0
Safety category of skin irritation index
0
0
Risky
Investigational Product: Vehicle Patch0
19 (95.0)
19 (95.0)
18 (90.0)
0.5
1 (5.0)1 (5.0)2 (10.0)10 (0.0)0 (0.0)0 (0.0)20 (0.0)0 (0.0)0 (0.0)30 (0.0)0 (0.0)0 (0.0)4
0 (0.0)0 (0.0)0 (0.0)Median
0.00
0.00
0.00
Mean
0.03
0.03
0.05
SD
0.112
0.112
0.154
Range (min, max)
(0.0, 0.5)
(0.0, 0.5)
(0.0, 0.5)
Skin irritation index
00
5.0
Safety category of skin irritation index
00
Safe
Categorized as 'Safe' (0 - 5), 'Acceptable' (5 <-15), 'Improvable' (15< -30) or 'Risky' (30 < -400).
Skin Irritation Index=(Sum of individual maximum irritation scores/number of evaluable subjects) × 100.
Abbreviations: max=maximum; min=minimum; N=number of subjects; SD=standard deviation.

Laboratory test abnormalities were >1.2 × upper limit of normal (ULN) eosinophils (%)(7 subjects in the crisaborole ointment 2% group), <0.8 × lower limit of normal lymphocytes(%) (4 subjects in the crisaborole ointment 2% group and 1 subject in the vehicle group), and>1.5 × ULN leukocytes (109/L) (1 subject in the vehicle group). Of note, there were no AEs
related to hematology reported in this study. No clinically significant changes were observedin the laboratory data. No clinically significant changes were observed in vital signs data.
None of the ECG values meeting predefined criteria were considered clinically significant
nor reported as AEs.

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CONCLUSIONS:

Crisaborole plasma exposure based on geometric mean AUCtau and Cmax values were
928.9 ng•h/mL and 163.7 ng/mL respectively on Day 1 following a single
administration and 1123 ng•h/mL and 164.9 ng/mL on Day 8 following multiple BID
administration of crisaborole ointment 2%. Overall there was minimal accumulationof crisaborole on Day 8 following multiple BID administration with geometric mean
Rac AUCtau and Rac Cmax of 1.209 and 1.007 respectively.



Plasma exposure for the AN7602 metabolite of crisaborole based on geometric mean
AUCtau and Cmax values were 500.4 ng•h/mL and 94.97 ng/mL respectively on Day 1
and 434.9 ng•h/mL and 68.83 ng/mL respectively on Day 8 following multiple dose
administration of crisaborole ointment 2% BID. Overall there was no accumulationof AN7602 metabolite on Day 8 with both of the Rac AUCtau and Rac Cmax <1.



Plasma exposures based on geometric mean AUCtau and Cmax values for the AN8323
metabolite were much higher than those observed for crisaborole and the AN7602
metabolite with mean values of 29360 ng•h/mL and 3064 ng/mL respectively on
Day 1 following a single BID administration of crisaborole ointment 2% and 90360
ng•h/mL and 8080 ng/mL on Day 8 following multiple BID administration ofcrisaborole ointment 2%. Unlike crisaborole and AN7602 metabolite, there wassome accumulation observed for the AN8323 metabolite on Day 8 with geometricmean Rac AUCtau and Rac Cmax of 3.080 and 2.638 respectively.

Based on the trough concentrations on Days 7, 8, and 9, steady state was achieved by
Day 7 for crisaborole and its metabolites.

Crisaborole ointment 2% BID was found to be well tolerated and have a favorable
safety profile in Japanese subjects with mild to moderate AD. There were no TEAEs
in Cohort 1 and all TEAEs in the crisaborole ointment 2% group in Cohort 2 weremild in severity, though the skin irritation index for crisaborole ointment 2% patch
was 40.0 and was categorized as risky. No deaths or SAEs were reported in thisstudy. There were no clinically significant changes for laboratory values, vital signs
or ECG.

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