Final Clinical Study Report
Protocol B7981019

CLINICAL STUDY REPORT SYNOPSIS
Sponsor: Pfizer Inc
Investigational Product: Ritlecitinib (PF-06651600)
Clinical Study Report Synopsis: Protocol B7981019
Protocol Title: A Phase 2b Randomized, Double‑Blind, Placebo‑Controlled, Multicenter,
Dose‑Ranging Study to Evaluate the Efficacy and Safety Profile of PF‑06651600 With a
Partially Blinded Extension Period to Evaluate the Efficacy and Safety of PF‑06651600 and
PF‑06700841 in Subjects With Active Non‑Segmental Vitiligo
Investigators: Refer to Appendix 16.1.4.1 for a list of investigators involved in this study.
Study Centers: This study was conducted at 80 sites (6 in Australia, 3 in Belgium, 16 in
Canada, 6 in Germany, 1 in Italy, 5 in Japan, 5 in Republic of Korea, 5 in Spain, 3 in Taiwan,
and 30 in the United States). Refer to Appendix 16.1.4.1 for a list of sites involved in thisstudy.
Publications Based on the Study: None
Study Initiation Date: 26 November 2018
Study Completion Date: 05 February 2021
Report Date: 15 September 2021
Previous Report Date(s): 27 August 2021
Phase of Development: Phase 2b
Study Objectives and Endpoints: The study objectives and endpoints are provided inTable S1 for the Dose-Ranging (DR) Period and in Table S2 for the Extension (Ext) Period.
DR Period
Table S1. Study Objectives and Endpoints During Dose-Ranging Period
Type
Primary
Efficacy

Objectives

Endpoints

To evaluate the efficacy of
ritlecitinib dose/dosing
regimens at Week 24 inadult participants withactive non-segmental
vitiligo.



Percent change from Baseline (%CFB) in central
facial-vitiligo area scoring index (F-VASI) at
Week 24.

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CLINICAL STUDY REPORT SYNOPSIS
Table S1. Study Objectives and Endpoints During Dose-Ranging PeriodType

Objectives

Endpoints

SafetyTo evaluate the safety andtolerability of ritlecitinib
over time in adultparticipants with active
non-segmental vitiligo.

Secondary
Key Secondary
Efficacy

Other Secondary
EfficacyTo evaluate the efficacy of 
ritlecitinib compared withplacebo as measured by
F-VASI at Week 24 in adultparticipants with active
non-segmental vitiligo.

Proportion of participants achieving central read
F-VASI75 (at least 75% improvement in central read
F-VASI from baseline [BL]) at Week 24.

Proportion of participants achieving total-vitiligo areascoring index (T-VASI)50 at Week 24.
%CFB in T-VASI, central and local F-VASI, andself-assessment-vitiligo extent score (SA-VES), andabsolute CFB in T-VASI at designated time points(except for Week 24 for central F-VASI).
Proportion of participants achieving
T-VASI50/75/90/100 (at least 50%/75%/90%/100%
improvement from BL in T-VASI), and central andlocal F-VASI50/75/90/100 at designated time points(except for Week 24 in T-VASI50 and central
F-VASI75).
CFB in vitiligo specific quality of life (VitiQoL) at
designated time points.
Proportion of participants achieving a static
investigator global assessment (sIGA) 0 or 1, and at
least a 2-point improvement at Week 24.

To evaluate the efficacy of
ritlecitinib compared withplacebo as measured byother clinical assessments
over time in adultparticipants with active
non-segmental vitiligo.








Key Exploratory
Efficacy

To evaluate the efficacy of
ritlecitinib compared withplacebo by other efficacy
markers in adultparticipants with active
non-segmental vitiligo.






Pharmacodynamic(PD)

Incidence of treatment-emergent adverse events(TEAEs) and serious adverse events (SAEs) up to
Week 24.
Incidence of specific clinical laboratory abnormalities
including but not limited to anemia, neutropenia,
thrombocytopenia, lymphopenia, changes in lipid
profile, and liver function tests (LFTs) up to Week 24.

To assess PD anddisease-related biomarkers
over time in adultAbsolute CFB in central and local F-VASI at
designated time points.
Proportion of participants achieving “very much
improved” or “much improved” on patient global
impression of change in vitiligo (PGIC-V).
Proportion of participants achieving a score of 4 (“alot less noticeable”) or 5 (“no longer noticeable”) on
Vitiligo Noticeability Scale (VNS).
Change of extent of depigmentation in target
lesion(s).
CFB in PD and disease-related protein and/or nucleic
acid biomarkers at designated time points up to
Week 24 as specified in the protocol, including but

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CLINICAL STUDY REPORT SYNOPSIS
Table S1. Study Objectives and Endpoints During Dose-Ranging PeriodType

Objectives

Endpoints

participants with active
non-segmental vitiligo.

Pharmacokinetic(PK)

To characterize PK of
ritlecitinib over 24 weeks inadult participants withactive non-segmental
vitiligo.

not limited to,.
CFB inat designated time
points up to Week 24 as specified in protocol.
CFB inat
designated time points up to Week 24 as specified in
the protocol.
Plasma concentrations of ritlecitinib at designatedtime points up to Week 24 as specified in the
protocol.

Extension Period
Table S2. Study Objectives and Endpoints During Extension Period
Type
Primary
SafetyObjectives

Endpoints

To evaluate the safety andtolerability of ritlecitinib andbrepocitinib in adultparticipants with active
non-segmental vitiligo.

Incidence of TEAEs and SAEs during the Ext Period.
Incidence of specific clinical laboratory abnormalities
including but not limited to anemia, neutropenia,
thrombocytopenia, lymphopenia, changes in lipid
profile, and LFTs during the Ext Period.

 To evaluate the long-term
efficacy of ritlecitinib,
efficacy of ritlecitinib andadd-on narrow band
ultraviolet B (nbUVB), in
adult participants withactive non-segmental
vitiligo.
 To evaluate the efficacy of
brepocitinib in a subset of
adult participants withactive non-segmental
vitiligo.

%CFB in T-VASI during the Ext Period.
Proportion of participants achieving
T-VASI50/75/90/100, and central and local
F-VASI50/75/90/100 during the Ext Period.
%CFB in T-VASI, central and local F-VASI, and
SA-VES and absolute CFB in T-VASI, central and local
F-VASI during the Ext Period.
CFB in VitiQoL during the Ext Period.
Proportion of participants achieving a sIGA 0 or 1, andat least a 2-point improvement during the Ext Period.
Proportion of participants achieving “very much
improved” or “much improved” on PGIC-V.
Proportion of participants achieving a score of 4 (“a lot
less noticeable”) or 5 (“no longer noticeable”) on VNS.

To assess PD anddisease-related biomarkers in
adult participants with active
non-segmental vitiligo.



Key Exploratory
Efficacy

PD







CFB in PD and disease-related protein and/or nucleic
acid biomarkers at designated time points during the Ext
Period as specified in the protocol, including but notlimited to.

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CLINICAL STUDY REPORT SYNOPSIS
Table S2. Study Objectives and Endpoints During Extension PeriodType

Objectives

Endpoints


PK

To characterize PK of
ritlecitinib and brepocitinib in
adult participants with active
non-segmental vitiligo.



CFB inat designated time points during the Ext
Period as specified in the protocol.
CFB inat designated time points
during the Ext Period as specified in the protocol.
Plasma concentrations of ritlecitinib and brepocitinib as
specified in the protocol.

METHODS
Study Design: This Phase 2b study evaluated the safety, tolerability, efficacy, PK, and PD of
ritlecitinib in participants with active non-segmental vitiligo. In addition, this study provided
opportunities for participants to receive additional treatment in the Ext Period: ritlecitinib
treatment with or without nbUVB add-on therapy, or brepocitinib.
The 24-week double-blind DR Treatment Period assessed the efficacy and safety of
ritlecitinib in participants with active non-segmental vitiligo. Participants were randomized to
1 of 5 treatment groups or placebo: 2 groups with a ritlecitinib induction dose (200 mg once
daily [QD] or 100 mg QD) for 4 weeks followed by maintenance dosing of 50 mg QD for
20 weeks, 3 groups with ritlecitinib dosing for 24 weeks (50 mg QD, 30 mg QD, and 10 mg
QD), and matching placebo for 24 weeks (These 6 groups are hereafter referred to as
200/50 mg; 100/50 mg; 50 mg; 30 mg; 10 mg; placebo).
This study included an Ext Period to evaluate additional safety and tolerability of ritlecitinibwith or without nbUVB add-on therapy. Participants in Extension Group 2 (ExtGp2)(+nbUVB) who had <10% improvement in %CFB in T-VASI at Extension Week (ExtWeek)
12 (BL=DR Period Week 24) were discontinued from treatment. The Ext Period also
evaluated the safety, efficacy and tolerability of brepocitinib-only treatment (ExtGp1) inparticipants with vitiligo after a 4-week drug holiday with no study intervention. The drug
holiday provided a wash-out period for 4 weeks between the DR Period and Ext Period only
in ExtGp1.
There were 6 groups with QD dosing in the Ext Period. The groups for ritlecitinib with
nbUVB add-on therapy (with ritlecitinib induction dosing of 200 mg for 4 weeks followed bymaintenance dosing of 50 mg for 20 weeks [ExtGp2]) and the brepocitinib-only (induction
dosing of 60 mg for 4 weeks followed by maintenance dosing of 30 mg for 16 weeks[ExtGp1]) were open-label. The other 3 ritlecitinib groups (induction dosing of 200 mg for
4 weeks followed by maintenance dosing of 50 mg for 20 weeks [ExtGp3], 50 mg for
24 weeks [ExtGp4], and 30 mg for 24 weeks [ExtGp5]) were blinded. The observation-only(no treatment) group (ExtGp6) was open-label. Participants who completed the initial
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CLINICAL STUDY REPORT SYNOPSIS
24 weeks of the protocol could enter the Ext Period. Participants who discontinued prior to
Week 24 Visit were not eligible for the Ext Period.
Group mapping for the Ext Period was performed based on individual response at Week 16of the DR Period, ie, participants were allocated to treatment in the Ext Period based onwhether they were responders (who achieved ≥50% improvement in T-VASI from Baseline)
or non-responders (who achieved 50% improvement in T-VASI from Baseline) at DR
Period Week 16.
Schematics of the study design are shown for the DR and Ext Periods in Figure S1.
Figure S1. Study Design for Dose Ranging Period (Left) and Extension Period (Right)

a. Participants who had <10% improvement in T-VASI at ExtWeek 12 from the BL value at DR Period Week 24 werediscontinued from the treatment and entered early termination and Follow Up Period.
b. Visits were conducted every 4 weeks until end of study or until ≥30% depigmentation from BL T-VASI occurred,
whichever was shorter. No follow up visits were deemed to be performed for participants in ExtGp6.

Diagnosis and Main Criteria for Inclusion: Male or female adult (18-65 years of age)participants with active non-segmental vitiligo were included in this study.
Study intervention: Participants received blind-label ritlecitinib tablets 10 mg and 50 mg,
matching placebo, or open-label breopcitinib tablets 5 mg and 25 mg (Table S3), according
to the assigned treatment in Figure S1; all doses were oral, and dosing was QD.
Table S3. Study Intervention Description
Study Intervention Description
Placebo 6 mm Tablet
Placebo 10 mm Tablet
Placebo 10 mm Tablet
Placebo 10 mm Tablet
PF-06651600-15 10 mg Round White to Off-White Tablet
PF-06651600-15 50 mg Round White to Off-White Tablet
PF-06651600-15 50 mg Round White to Off-White Tablet

Vendor Lot
Numbernot
applicable
(N/A)
N/A
N/A
N/A
N/A
N/A
N/A

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Pfizer Lot
Number17-002906

Strength/Potency
0 mg

DosageForm
Tablet17-002907
17-002908
17-002909
17-004591
18-000211
18-001308

0 mg
0 mg
0 mg
10 mg
50 mg
50 mg

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Protocol B7981019

CLINICAL STUDY REPORT SYNOPSIS
Table S3. Study Intervention Description
Study Intervention Description
Placebo 10 mm Tablet
Placebo 10 mm Tablet
Placebo 6 mm Tablet
PF-06651600-15 50 mg Round White to Off-White Tablet
Placebo 10 mm Tablet
PF-06651600-15 50 mg Round White to Off-White Tablet
PF-06651600-15 10 mg Round White to Off-White Tablet
Placebo 10 mm Tablet
Placebo 10 mm Tablet
Placebo 10 mm Tablet
PF-06700841-15 5 mg Round White to Off-White Tablet
PF-06700841-15 25 mg Round White to Off-White Tablet
PF-06700841-15 5 mg Round White to Off-White Tablet
PF-06700841-15 25 mg Round White to Off-White Tablet

Vendor Lot
Number
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A

Pfizer Lot
Number18-001560
18-001561
18-003539
18-003615
19-000972
19-001388
18-003410
18-003540
17-001174
17-001175
18-000453
18-000455
19-000338
19-000340

Strength/Potency
0 mg
0 mg
0 mg
50 mg
0 mg
50 mg
10 mg
0 mg
0 mg
0 mg
5 mg
25 mg
5 mg
25 mg

DosageForm
TabletTabletTabletTabletTabletTabletTabletTabletTabletTabletTabletTabletTabletTabletEfficacy Evaluations: Efficacy endpoints evaluated were F-VASI – central and local,
T-VASI, sIGA, target lesion(s) assessment, and patient report outcome (PRO) measures
including SA-VES, VitiQoL, PGIC-V, and VNS, etc.
PK Evaluations: PK samples were collected and analyzed using a validated analyticalmethod.
In the DR Period, blood samples for PK were collected pre-dose on Day 1 and at Weeks 4, 8,
12, and 24; at 0.5 hours post-dose at Weeks 8 and 12; and 0.5, 1, 2, and 4 hours post-dose at
Weeks 4 and 24.
In ExtGp2, ExtGp3, ExtGp4, and ExtGp5, blood samples for PK were collected pre-dose at
ExtWeeks 4, 8, 12 and 24; at 0.5 hours post-dose at ExtWeeks 8 and 12; and 0.5, 1, 2, and4 hours post-dose at ExtWeeks 4 and 24.
In ExtGp1, blood samples for PK were collected pre-dose at ExtWeeks 4, 8, 12, 16, and 24;
at 0.5 hours post-dose at ExtWeeks 12 and 16; and 0.5, 1, 2, and 4 hours post-dose at
ExtWeeks 8 and 24.
PD Evaluations: Blood samples for the analyses ofwere collected and analyzed.
Safety Evaluations: Safety evaluations included adverse events (AEs), SAEs, clinicallaboratory tests, vital signs, electrocardiograms (ECGs), audiometry, and special safetyassessment of dermatological events, etc.

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CLINICAL STUDY REPORT SYNOPSIS
Statistical Methods: The defined analysis sets are provided in Table S4.
Table S4. Analysis Sets - DR and Ext Periods
Analysis Set
Full Analysis Set (FAS) - DR
PeriodExtension Analysis Set
Group 1 (EASG1)

Definition
All participants who received at least 1 doseof randomized study intervention and had a
BL and at least 1 post-BL measurement (after
taking randomized study intervention)
All participants who received at least 1 doseof study intervention.
All participants who received at least 1 doseof planned study intervention in the Ext
Period.
All participants assigned to Group 1 in the
EAS

Extension Analysis Set
Groups 2&3 (EASG23)

All participants assigned to Groups 2 and 3 in
the EAS

Extension Analysis Set
Group 3 (EASG3)
PK Concentration Population

All participants assigned to Group 3 in the
EAS
All participants who received at least 1 doseof ritlecitinib and in whom at least
1 concentration value was reported

Safety Analysis Set (SAS)Extension Analysis Set(EAS)

Baseline
Day 1 of the DR Period

Day 1 of the DR Period
Week 24 of the DR Period(or previous non-missing
visit)
Week 24 of the DR Period(or previous non-missing
visit)
Week 24 of the DR Period(or previous non-missing
visit)
Day 1 of the DR Period

Efficacy Analysis
DR PeriodPrimary Endpoint: The primary endpoint was analyzed using an analysis ofcovariance (ANCOVA) model which included treatment, baseline efficacy score, andFitzpatrick skin type as covariates. Observed case (OC) analysis was used to manage
missing data for analyses involving ANCOVA models.
Multiple comparisons were conducted applying a Hochberg procedure using observed
p-values. Three pairwise comparisons were adjusted for multiplicity for the primary
endpoint only in this order: ritlecitinib 200 mg/50 mg vs placebo, ritlecitinib
100 mg/50 mg vs placebo and then ritlecitinib 50 mg vs placebo.
Also, a 4-parameter Bayesian maximum effect (Emax) model was used to characterize
the dose response in participants treated with ritlecitinib up to Week 24.



Key Secondary Endpoint: The key secondary endpoint was analyzed by firsttreating the missing data (non-coronavirus infectious disease 2019 [COVID-19]
related) as non-responders and then applying Chan and Zhang exact confidence
interval (CI) method at Week 24 (and other intermediate time points). Missing data
due to COVID-19 for central F-VASI75 were removed from analysis.
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CLINICAL STUDY REPORT SYNOPSISOther Secondary Endpoints: The secondary endpoints were analyzed by firsttreating the missing data as non-responders and then applying Chan and Zhang exact
CI method at Week 24 (and other intermediate time points). Missing data due to
COVID-19 for the binary endpoints were removed from analysis.
%CFB and CFB in T-VASI at Week 24 were analyzed using the same statisticalmodel as the primary endpoint.

Ext Period: Descriptive statistics were provided for the exploratory efficacy analysis. The
continuous variables were summarized with n, mean, median, standard deviation (SD), etc.
PK Analysis: PK concentrations were summarized and presented with summary statistics
and non-compartmental PK parameter estimates were provided when appropriate.
Safety Analysis: AEs were summarized descriptively through appropriate data tabulations,descriptive statistics, categorical summaries, and graphical presentations. Safety data otherthan AEs were listed and summarized by treatment.
RESULTS
Participant Disposition and Demography: A total of 578 participants were screened, andthere were 212 screen failures.


DR Period: 366 participants were randomized to the DR Period, 364 (99.5%) ofwhom received treatment and were included in the SAS, including 66 (18.1%)
participants who discontinued study intervention. Participants in the DR Period had amean age of 44.98 years and 53.0% were female. Most participants were White(67.6%), and Not Hispanic or Latino (83.2%).



Ext Period: 295 participants entered the Ext Period, 293 of whom were mapped totreatment (ExtGp3, n=187; ExtGp2, n=43; ExtGp1, n=55; ExtGp4 = 6; ExtGp5 = 2;
ExtGp6 = 0) based on whether they were responders or non-responders, and were
included in the EAS, including 56 (19.1%) participants who discontinued study
intervention. There was a lower percentage of female participants (38.2%) in ExtGp1
compared with ExtGp2 (55.8%), and ExtGp3 (57.2%).

Efficacy Results
DR PeriodPrimary Endpoint: Adjusted for multiple comparisons, the %CFB in central
F-VASI at Week 24 was significantly greater for ritlecitinib doses 200/50 mg,
100/50 mg and 50 mg compared with placebo (least squares [LS] meandifference: -23.2, -23.2, and -20.6, respectively (Hochberg p < 0.05).

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The dose-response for central F-VASI by 4-parameter Bayesian Emax modelingshowed the estimated effect on %CFB in central F-VASI for a 75 mg dose
was -23.70; the additive effect of induction dosing was estimated to be -5.83.


Key Secondary Endpoint: The proportion of participants that achieved central
F-VASI75 was higher in the ritlecitinib 200/50 mg, 100/50 mg, and 50 mg groups
than placebo (difference from placebo: 12.1%, 8.5%, and 7.7%, respectively;
one-sided p < 0.05) at Week 24.

Other Secondary EndpointsoNo ritlecitinib group differentiated from placebo for the proportion ofparticipants that achieved T-VASI50 at Week 24.

o

The only groups that differentiated from placebo in LS mean %CFB in T-VASI
were the ritlecitinib 30 mg group at Week 4 (one-sided p = 0.0490) and the
100/50 mg group at Week 24 (one-sided p = 0.0357).

oRegarding LS mean %CFB in central F-VASI, ritlecitinib 200/50 mg and100/50 mg groups (with induction dose) produced an earlier separation fromplacebo than ritlecitinib 50 mg and 30 mg groups (no induction dose), both in allparticipants and in participants with BL central F-BSA ≥0.5.

oRegarding LS mean %CFB in local F-VASI, there was mostly no difference
between any ritlecitinib group and placebo at any visit considering all
participants, while in participants with BL central F-BSA ≥0.5 separation fromplacebo was seen with ritlecitinib 200/50 mg, 100/50 mg, and 50 mg at multiple
time points.

oThere was significant (unadjusted one-sided p < 0.05) difference between
placebo and all ritlecitinib groups in LS mean %CFB in SA-VES from Week 4 to
Week 24.

o

The only groups that showed a larger LS mean absolute CFB in T-VASI thanplacebo were the 30 mg group at Week 4 (p = 0.0231) and the 100/50 mg groupat Week 24 (p = 0.0274).

o

The proportion of participants meeting T-VASI50 was similar between all
ritlecitinib groups and placebo at all time points, and no participant in any
ritlecitinib group met T-VASI75/90/100 during DR Period.

oParticipants in the ritlecitinib 200/50 mg and 100/50 mg groups, who received an
induction dose for 4 weeks, showed separation from placebo in central
F-VASI50 as early as Week 16, continuing through Week 24. Ritlecitinib 50 mg
and 30 mg showed separation from placebo in central F-VASI50 at Week 24. No
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ritlecitinib dose separated from placebo in the proportion of participants
achieving central F-VASI90 and no participant in any group met central
F-VASI100.

o

Ritlecitinib did not increase the proportion of participants that achieved local
F-VASI50/75/90/100 at any time up to Week 24, compared with placebo.

oThere were no differences between ritlecitinib and placebo in LS mean CFB in
the VitiQoL total score, or in any of the 3 individual domain scores at any time.

oNo participant treated with ritlecitinib achieved sIGA 0 (‘clear’) or 1 (‘almost
clear’) and at least a 2-point improvement.

Exploratory EndpointsoTargeted lesions: Ritlecitinib 200/50 mg, 100/50 mg, 50 mg, and 30 mg
promoted repigmentation in stable lesions. In active lesions, depigmentation was
reduced with ritlecitinib 200/50 mg, 100/50 mg, and 30 mg. The magnitude of
the reduction was small in active lesions, compared with stable lesions.

o

PGIC-V: Only ritlecitinib 100/50 mg differentiated from placebo in the
proportion of participants that achieved “very much improved” or “muchimproved” on PGIC-V at Week 24.

o

VNS: There was no separation between any ritlecitinib dose and placebo in the
proportion of participants achieving a score of 4 or 5 on the VNS.

Ext Period
ExtGp3 - Long Term Effect of Ritlecitinib Treatment


Central and Local F-VASIoAll treatment sequences in ExtGp3 showed greater improvement in %CFB andabsolute CFB in central F-VASI and local F-VASI from Week 24 to Week 48
than between Day 1 and Week 24. There was no plateau in improvement at
Week 48.

oLong-term ritlecitinib treatment (from Week 24 to Week 48) increased the
proportion of participants who achieved central F-VASI50/75/90 and local
F-VASI50/75/90, with the greatest improvement occurring post-Week 32.

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CLINICAL STUDY REPORT SYNOPSISo

All treatment sequences in ExtGp3 showed greater improvement in %CFB in
T-VASI and absolute CFB in T-VASI from Week 24 to Week 48 than between
Day 1 and Week 24.

oLong-term ritlecitinib treatment (from Week 24 to Week 48) increased the
proportion of participants that achieved T-VASI25/50/75 at Week 48 comparedwith Week 24.



SA-VES: From Week 24 to Week 48, most treatment sequences in ExtGp3 showed
an increase in LS mean %CFB in SA-VES.



VitiQoL: Continued improvement in the mean CFB VitiQoL total score was mostly
observed in all treatment sequences in ExtGp3.



PGIC-V and VNS: The proportion of responders on the PGIC-V and VNS increased
from Week 24 to Week 48 in all treatment sequences in ExtGp3.

ExtGp2 vs ExtGp3 - Additive Effect of nbUVB Treatment
The OC analysis showed an apparent additive effect of nbUVB; however, the LOCF
analysis, which included 9 discontinued participants in ExtGp2 who met the discontinuation
criterion of <10% improvement in %CFB in T-VASI at ExtWeek 12, showed that theadditive effect of nbUVB was less pronounced and even no additive effect. The results fromOC analysis are summarized below.
Central F-VASIo

The LS mean %CFB in central F-VASI was larger in ExtGp2 compared with
ExtGp3 at ExtWeek 16 (p = 0.0078) and ExtWeek 24 (p = 0.0090).

o

The addition of nbUVB treatment to ritlecitinib 200/50 mg did not increase theproportion of participants who achieved central F-VASI50/75/90/100 over
24 weeks.



Local F-VASI: The addition of nbUVB treatment to ritlecitinib 200/50 mg increased
the %CFB in local F-VASI, and the proportion of participants achieving local
F-VASI50/75/90.

T-VASI: The addition of nbUVB treatment to ritlecitinib 200/50 mg increased the%CFB in T-VASI, and the proportion of participants achieving T-VASI50 at
Week 24; there was no additive effect on T-VASI75/90/100.



VitiQoL: The LS mean CFB in vitiQoL total score from DR Week 24 to ExtWeek 24
was larger in ExtGp2 than ExtGp3.

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SA-VES: The addition of nbUVB treatment to ritlecitinib 200/50 mg increased the LSmean %CFB in SA-VES during the 24-week Ext Period.



PGIC-V and VNS: The proportion of responders on the PGIC-V and VNS was higher
in ExtGp2 than ExtGp3.

ExtGp1 - Effect of brepocitinib: the LS mean %CFB in central F-VASI consistently
increased from ExtWeek 4 to ExtWeek 24.
PK Results

The median plasma ritlecitinib concentrations were similar between Week 4 andWeek 24 in participants who received the same dose throughout the DR Period(ie, 50 mg, 30 mg, 10 mg), while the median plasma concentrations were higher at
Week 4 than Week 24 in participants who received a 200 mg or 100 mg induction
dose.



Independent of which treatment was received in the DR Period, participants who
received ritlecitinib 200/50 mg, with or without nbUVB in the Ext Period, hadmedian ritlecitinib concentrations comparable to those for the 200/50 mg groupduring the DR Period.

Median maximum brepocitinib plasma concentrations (Cmax) were observed at 1 hourpost-dose at Weeks 8 and 24 following 60 mg and 30 mg doses.

PD Results: During the DR Period at Week 24, the median %CFB values ofin the200/50 mg (-23.7) and 100/50 mg (-14.5) groups, which received 50 mg for
20 weeks, were similar in magnitude to the 50 mg (-18.5) group, which received
50 mg for 24 weeks. During the Ext Period, the 200 mg/50 mg was the only
ritlecitinib group to retain ≥95% of observations at ExtWeek 24, and small reductions
in median %CFB of
were observed at ExtWeeks 4 and 24.

: There were no significant changes infrom BL during either the DR or Ext Period
except for the following:o: Reductions inwere observed at Week 4, but the values returned to BL at Week 24.

o: Reductions inwere observed at Week 4 ina dose dependent manner; these reductions inwas still present in the
200/50 mg, 100/50 mg and 50 mg groups at Week 24.

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Safety Results
DR Period - TEAEs and SAEs
In general, no dose dependency was observed among the 6 different groups in terms of
TEAEs.
In total, there were 277 (76.1%) participants with 756 all-causality TEAEs, and
126 (34.6%) participants with 195 treatment-related AEs.



There were 4 (1.1%) participants with SAEs; none were treatment-related.



The majority of all TEAEs (both all-causality and treatment-related) across treatmentgroups were mild or moderate in severity. Severe AEs were reported in 11 (3.0%)
participants, and in 3 participants severe AEs were treatment-related.



There were no deaths (DR or Ext Period).



There were 19 (5.2%) and 12 (3.3%) participants who were discontinued from thestudy due to all-causality and treatment-related AEs, respectively. 27 (7.4%) and
8 (2.2%) participants had dose reduced or temporary discontinuation due toall-causality and treatment-related AEs, respectively.

Eleven (3.0%) participants discontinued study intervention due to COVID-19 related
reasons.



The 3 most frequently reported preferred term TEAEs were: nasopharyngitis, upper
respiratory tract infection (URTI), and headache (all-causality); nasopharyngitis,
diarrhea, and headache (treatment-related).

Ext Period – TEAEs and SAEs
Overall, no trend was observed among the 3 different groups (brepocitinib, ritlecitinib withor without nbUVB) in terms of TEAEs.


In total, there were 194 (66.2%) participants with 454 all-causality TEAEs, and68 (23.2%) participants with 99 treatment-related TEAEs.



There were 2 (0.7%) participants with SAEs, and in 1 participant the SAE (frombrepocitinib group) was treatment-related.



The majority of all TEAEs (both all-causality and treatment-related) across treatmentgroups were mild or moderate in severity. There were 8 (2.7%) participants withsevere AEs (2 from brepocitinib group and 6 from ExtGp3), and in 1 participant(from brepocitinib group) the severe AE was treatment-related.
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There were 10 (3.4%) and 8 (2.7%) participants who were discontinued from thestudy due to all-causality and treatment-related AEs, respectively. 18 (61%) and7 (2.4%) participants had dose reduced or temporary discontinuation due toall-causality and treatment-related AEs, respectively.

Nine (3.1%) participants discontinued study intervention due to COVID-19 related
reasons.



The 3 most frequently reported all-causality preferred term TEAEs were urinary tract
infection, URTI, and headache. The 2 treatment-related TEAEs that occurred in>1.0% of participants across treatment groups were decreased neutrophil count andheadache.

ExtGp3 (DR and Ext) – TEAEs and SAEs


Overall, there were 162 (86.6%) participants with 647 all-causality TEAEs, and82 (43.9%) participants with 152 treatment-related TEAEs.



There were 4 (2.1%) participants with SAEs; none were treatment-related.



The majority of all TEAEs (both all-causality and treatment-related) during the entire
study were mild or moderate in severity. There were 12 (6.4%) participants withsevere AEs; none were treatment-related. The frequency of severe AEs was similar in
the DR (3.7%) and Ext (3.2%) Periods.



Six (3.2%) participants in ExtGp3 were discontinued from the study due to TEAEs(all treatment-related; 5 were discontinued due to AEs reported during the Ext
Period). 20 (10.7%) and 3 (1.6%) participants had dose reduced or temporary
discontinuation due to all-causality and treatment-related AEs, respectively.

The 3 most frequently reported preferred TEAEs (both all-causality andtreatment-related) were nasopharyngitis, URTI, and headache.

Laboratory Evaluations: Without regard to BL abnormality, 233 (64.0%) participants in the
DR Period and 208 (71.5%) participants in the Ext Period experienced laboratory
abnormalities. The proportion was similar across treatment groups in both the DR and Ext
Periods.
ChemistryoThere were no clinically meaningful changes in lipid profile across treatmentgroups in the DR or Ext Period.

o

No trends in creatine kinase (CK) were noted with ritlecitinib in the DR or Ext
Period. A total of 27 participants in the DR Period and 15 participants in the Ext
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Period had CK 3 × upper limit of normal (ULN); 7 participants in the study had
CK >10 × ULN. No clinically significant events of myoglobinuria, acute renal
failure or heart failure were noted.

oA total of 15 ritlecitinib treated participants experienced isolated and transientdecline from BL in serum creatinine-based estimated glomerular filtration rate(eGFR) ≥30%. None of the declines were associated with similar changes incystatin-C based eGFR or resulted in adverse renal events or discontinuationfrom the study.

oIn terms of alanine aminotransferase, aspartate aminotransferase, or total
bilirubin, no trends were noted, and there was no participant with cases that met
Hy’s law criteria.

Hematology: The mean absolute values of hematology parameters (platelets,
lymphocytes, neutrophils, hemoglobin, hematocrit, erythrocytes, andreticulocytes/erythrocytes) for all participants stayed within the normal ranges in the
DR and Ext Periods.
oNo participant met common terminology criteria for adverse events (CTCAE,
v5.0 hereafter) ≥Grade 2 thrombocytopenia. Isolated Grade 1 AEs ofthrombocytopenia (1) and platelet decrease (1) were reported without any otheraccompanying clinical symptoms.

oNo participant met CTCAE ≥Grade 4 criteria for lymphocytes. There were
6 participants with lymphocyte events that were AEs, none were severe.

o

No participant met CTCAE ≥Grade 4 criteria for neutrophils in ritlecitinib
groups. There were 12 participants with neutrophil events that were AEs, none
were severe.

o

No participant met CTCAE Grade 3/4 criteria for hemoglobin. A total of
2 participants met CTCAE Grade 2.

Other Safety Evaluations


There were 6 participants with clinically significant improvement from BL and
4 participants with clinically significant worsening from BL in hearing. All the
4 worsening cases were unilateral and mild in severity, and assessed as not related tothe study intervention by an external consultant.



There were 2 participants with non-melanoma skin cancers, both unrelated to study
intervention.



Seven participants had confirmed cases of herpes simplex.
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CLINICAL STUDY REPORT SYNOPSISFive participants had confirmed cases of herpes zoster.



Twelve participants had rash.



Cases from 26 participants were adjudicated, including malignancy (2), opportunistic
infections of special interest infection (3), histopathology event (1), neuro-audiology(3), and neurology (18).



There were 4 confirmed cases of COVID-19.



No clinically significant vital sign abnormalities were observed.



There were 2 participants with clinically meaningful changes in ECG, both unrelated
to study intervention.

Conclusions
Efficacy

Ritlecitinib 200/50 mg, 100/50 mg, and 50 mg met the primary endpoint of %CFB incentral F-VASI at Week 24 and the key secondary endpoint of the proportion ofparticipants with central F-VASI75 at Week 24.
oIn participants with BL central F-BSA ≥0.5, the %CFB in central and local
F-VASI at Week 24 was significantly different from placebo in the ritlecitinib
200/50 mg, 100/50 mg, and 50 mg groups.

oLong-term (up to 48 weeks) ritlecitinib treatment produced greater improvement
in %CFB in central F-VASI, with the greatest improvement occurring post
Week 32; there was no plateau in improvement at Week 48.

oResults were similar at Week 48 for the %CFB in central and local F-VASI when
including only participants with BL central F-BSA ≥0.5.

o

The benefit of nbUVB treatment added to ritlecitinib treatment was limited andthe comparison rendered inaccurate due to the protocol-required forced
discontinuation in the nbUVB arm.

Induction dosing (4 weeks of ritlecitinib 200 mg or 100 mg, followed by 50 mg for
20 weeks) produced an earlier separation from placebo in %CFB in central F-VASI
than continuous dosing of 50 mg for 24 weeks; however, results were similar at
Week 24 for ritlecitinib treatments with and without induction dosing.



Ritlecitinib treatment promoted repigmentation in stable lesions and stabilized (ie,prevented or reduced further depigmentation) in active lesions over 24 weeks.
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Consistent improvement was seen in the PROs SA-VES, VitiQoL, PGIC-V, and VNS
with long-term (48 week) ritlecitinib treatment.

Safety

Ritlecitinib was generally safe and well-tolerated during the 24-week DR Period, withno unexpected safety findings in participants treated continuously with ritlecitinib forup to 48 weeks.
oThere were no dose-dependent trends in SAEs, severe AEs, AEs leading todiscontinuation, other significant AEs (infections, dermatological events,
including herpes zoster AEs, and hearing test abnormalities), or in the mostfrequently reported AEs across treatment groups in the DR and Ext Periods.
There were no SAEs reported that were assessed as related to ritlecitinib. There
were no deaths.

o

The incidence of AEs was similar during induction and maintenance dosing;participants who received 200 mg induction dosing in both the DR and Ext
Periods (200/50 mg200/50 mg sequence) did not have an increased number of
TEAEs.

o

The overall incidence and number of AEs was lower during the Ext Period(Weeks 24 to 48) compared with the DR Period (Day 1 to Week 24).



No clinically meaningful trends for hematology, liver function, kidney function,
lipids, or chemistry lab parameters were observed in participants treated withritlecitinib during the 24-week DR Period, and no new clinically meaningful trends inthe lab parameters were detected in participants treated continuously with ritlecitinib
for up to 48 weeks.

For the 55 participants that received brepocitinib during the Ext Period, the incidenceof AEs (including SAEs, severe AEs, AEs leading to discontinuation, othersignificant AEs) was similar to the other treatment groups in the Ext Period, and no
new clinically meaningful trends for hematology, liver, renal, lipids or chemistry lab
parameters were observed.

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