Final Clinical Study Report
Protocol B7981015

CLINICAL STUDY REPORT SYNOPSIS
Sponsor: Pfizer Inc.
Investigational Product: PF-06651600 (ritlecitinib)
Clinical Study Report Synopsis: Protocol B7981015
Protocol Title: A Phase 2b/3 Randomized, Double-Blind, Placebo-Controlled, DoseRanging Study to Investigate the Efficacy and Safety of PF-06651600 in Adult andAdolescent Alopecia Areata (AA) Subjects With 50% or Greater Scalp Hair Loss
Investigators: Refer to Appendix 16.1.4.1 for a list of investigators involved in this study.
Study Center(s): Refer to Appendix 16.1.4.1 for a list of sites involved in this study.
Publications Based on the Study: None
Study Initiation Date: 03 December 2018
Study Completion Date: 24 June 2021
Report Date: 11 March 2022
Previous Report Date(s): 22 December 2021
Phase of Development: Phase 2b/3

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CLINICAL STUDY REPORT SYNOPSIS
Primary and Secondary Study Objectives and Endpoints:
Table S1. Study Objectives and Endpoints
Primary Objective
To evaluate the efficacy of ritlecitinib compared toplacebo in adult and adolescent AA participants with
50% or greater scalp hair loss on regrowth of lost hair(measured by an absolute Severity of Alopecia Tool
(SALT) Score ≤20) at Week 24.
Note: For the European Medicines Agency (EMA)
and competent authorities in the Voluntary
Harmonisation Procedure (VHP) countries,a theprimary objective was to evaluate the efficacy of
ritlecitinib compared to placebo in adult andadolescent AA participants with 50% or greater
scalp hair loss on regrowth of lost hair (measured
by an absolute SALT Score ≤10) at Week 24.
Key Secondary Objective
To evaluate the efficacy of ritlecitinib compared toplacebo in adult and adolescent AA participants with
50% or greater scalp hair loss on regrowth of lost hair(as measured by an absolute SALT Score ≤10) at
Week 24.
Note: This key secondary objective was utilized as
the primary objective for the EMA and competentauthorities in the VHP countries. Additionally, thiskey secondary objective did not apply for the Foodand Drug Administration (FDA)/ Pharmaceuticaland Medical Devices Agency (PMDA).
To evaluate the effect of ritlecitinib on patient
centered outcomes (as measured by Patient’s Global
Impression of Change [PGI-C] response) at Week 24.
Note: This key secondary objective was only
applicable for the EMA and competent authorities
in the VHP countries.
Secondary Objectives
To characterize the exposure response of ritlecitinib
on regrowth of lost hair.

To assess the efficacy of ritlecitinib on regrowth oflost hair during the treatment period over time.

Primary EndpointResponse based on an absolute SALT Score ≤20 at
Week 24.
Note: For the EMA and competent authorities in the
VHP countries, response based on an absolute SALT
Score ≤10 at Week 24 was analyzed as the primary
endpoint in a separate analysis.

Key Secondary EndpointResponse based on an absolute SALT Score ≤10 at Week
24.
Note: This key secondary endpoint was utilized as theprimary endpoint for the EMA and competent authorities
in the VHP countries. Additionally, this key secondary
endpoint did not apply for the FDA/PMDA.

PGI-C response defined as a score of “moderately
improved” or “greatly improved” at Week 24.
Note: This key secondary endpoint was only applicablefor the EMA and competent authorities in the VHP
countries.

Secondary Endpoints

Response based on an absolute SALT Score ≤20 at
Week 24 was used to characterize the exposure response.
Note: For the EMA and competent authorities in the
VHP countries, response based on an absolute SALT
score ≤10 at Week 24 was used to characterize theexposure response.
Response based on an absolute SALT score ≤20 at
Weeks 4, 8, 12, 18, 28, 34, 40, and 48.b,cResponse based on an absolute SALT score ≤10 at
Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 48.dResponse based on 75% improvement in SALT score frombaseline (BL) (SALT75) at Weeks 4, 8, 12, 18, 24, 28, 34,
40, and 48.
Change from Baseline (CFB) in SALT scores at Weeks 4,
8, 12, 18, 24, 28, 34, 40, and 48.
Response based on at least a 2-grade improvement from
BL or a score of 3 in eyebrow assessment (EBA) score at
Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 48.
Response based on at least a 2-grade improvement from
BL or a score of 3 in eyelash assessment (ELA) score at

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CLINICAL STUDY REPORT SYNOPSIS
Table S1. Study Objectives and EndpointsTo evaluate the effect of ritlecitinib on
patient-centered outcomes and payer relevantmeasures to assess treatment benefit from thepatient perspective and to demonstrate value.e

Safety ObjectiveTo evaluate the safety and tolerability of
ritlecitinib in the treatment period over time.

Pharmacokinetic (PK) Objective
To characterize pharmacokinetics of ritlecitinib.
Exploratory Objectives

To collect banked biospecimens for exploratory
research, unless prohibited by local regulations
or ethics committee decision.


To assess the efficacy of ritlecitinib on regrowthof lost hair during the treatment period over time.

To evaluate the effect of ritlecitinib on
patient-centered outcomes and payer relevantmeasures to assess treatment benefit from thepatient perspective and to demonstrate value.

Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 48.
PGI-C response defined as a PGI-C score of “moderately
improved” or “greatly improved” at Weeks 4, 8, 12, 18, 24,
34, 40, and 48.e
CFB in alopecia areata patient priority outcomes (AAPPO)
scales at Weeks 4, 8, 12, 18, 24, 34, 40, and 48.
Safety Endpoints

Incidence of treatment-emergent adverse events (TEAE).

Incidence of serious adverse events (SAE) and adverse
events (AE) leading to discontinuation.

The incidence of clinically significant abnormalities invital signs.

The incidence of clinically significant abnormalities inclinical laboratory values.
PK EndpointsPlasma concentrations of ritlecitinib at Weeks 4, and 8 or
12.
Exploratory EndpointsCollection of banked biospecimens unless prohibited by
local regulations or ethics committee decision. Additional
information on collection and potential use is provided inin the study protocol.
Response based on 50% improvement in SALT score from
BL (SALT50) at Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 48.
Absolute SALT scores at BL, Weeks 4, 8, 12, 18, 24, 28,
34, 40, and 48.
Improvement on PGI-C defined as “slightly improved”,“moderately improved”, or “greatly improved” at Weeks 4,
8, 12, 18, 24, 34, 40, and 48.
Improvement on Patient Satisfaction with Hair Growth(P-Sat) items, defined as slightly, moderately, or verysatisfied, at Weeks 4, 8, 12, 18, 24, 34, 40, and 48.

CFB in EQ-5D-5L in adults or EQ-5D-Y in adolescents at
Weeks 4, 12, 24, and 48.

CFB in alopecia areata resource utilization (AARU) at
Weeks 12, 24, 34, and 48.

CFB in work productivity and activity impairment:alopecia areata (WPAI:AA) at Weeks 12, 24, 34, and 48.

CFB in the depression subscale score of the Hospital
Anxiety and Depression scale (HADS) at Weeks 4, 8, 12,24, and 48.f

CFB in the anxiety subscale score of the HADS at
Weeks 4, 8, 12, 24, and 48.f
Improvement on HADS among participants with a BL
subscale score indicative of depression who achieved a“normal’ subscale score indicative of an absence ofdepression at Weeks 4, 8, 12, 24, and 48.f
Improvement on HADS among participants with a BL
subscale score indicative of anxiety who achieved a“normal’ subscale score indicative of an absence of anxiety
at Weeks 4, 8, 12, 24, and 48.f

CFB in the 36 Item Short Form Health Survey version 2(SF36v2) Acute at Weeks 4, 8, 12, 24, and 48.


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CLINICAL STUDY REPORT SYNOPSIS
Table S1. Study Objectives and Endpoints




a.
b.
c.

d.

e.

f.

To evaluate the effect of ritlecitinib on theclinician global impression of severity of scalp
hair loss.
To evaluate efficacy of ritlecitinib in AA naildisease over time.
To assess pharmacodynamic and disease-related
biomarkers over time.



CFB in Clinician Global Impression – Alopecia Areata(CGI-AA) at Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 48.



CFB in fingernails affected by AA at Weeks 12, 24, 34, 40,
and 48.

CFB in interferon gamma-induced protein-10 (IP-10) at
Weeks 4, 8, 12, and 24.

CFB in percent and absolute lymphocyte subsets (TBNK)
at Weeks 4, 12, 24, and 48.

CFB in immunoglobulins (IgA, IgG, IgM) at Weeks 24 and48.
The VHP countries participating in this study are Czech Republic, Germany, Hungary, Poland, and Spain.
For the EMA and competent authorities in the VHP countries, when SALT ≤10 is utilized for the primary endpoint,
SALT ≤20 at Week 24 will be analyzed as a secondary endpoint.
When SALT ≤20 response at Week 24 is utilized as the primary endpoint, responses based on absolute SALT score≤20 at Weeks 18, 12, 8 and 4 will be analyzed controlling for Type I error utilizing an appropriate testing procedure.
When SALT ≤10 response at Week 24 is utilized as the primary endpoint, the response based on absolute SALT
score ≤20 at Week 24 will be analyzed controlling for Type I error utilizing an appropriate testing procedure.
When SALT ≤20 response at Week 24 is utilized as the primary endpoint, the response based on absolute SALT
score ≤10 at Week 24 will be analyzed controlling for Type I error utilizing an appropriate testing procedure. When
SALT ≤10 response at Week 24 is utilized as the primary endpoint, the responses based on absolute SALT score ≤10
at Weeks 18, 12, 8 and 4 will be analyzed controlling for Type I error utilizing an appropriate testing procedure.
For the EMA and competent authorities in the VHP countries, the evaluation of the effect of ritlecitinib on patient
centered outcomes (as measured by PGI-C response at Week 24) is a key secondary objective. The PGI-C responseat Week 24 will be analyzed as a key secondary endpoint utilizing an appropriate testing procedure to control overall
Type I error.
For the EMA and competent authorities in the VHP countries, endpoints utilizing the HADS will be analyzed as
secondary endpoints.

METHODS
Study Design
This study evaluated the efficacy and safety of multiple doses/regimens of ritlecitinib(PF-06651600) compared with placebo in adult and adolescent participants with alopecia
areata (AA) having 50% or greater scalp hair loss over 24 weeks of treatment (PlaceboControlled Period). This was followed by a 24-week Extension Period, during which allparticipants received ritlecitinib, including participants who had received placebo during theinitial 24 weeks (Figure S1).
In this report, treatment groups during the Placebo-Controlled Period are referred to as
200/50 mg, 200/30 mg, 50 mg, 30 mg, 10 mg, and placebo. Treatment groups during the
Extension Period are referred to in the same way, except for participants from placebo whotransitioned to active treatment, referred to as pbo-200/50 mg, and pbo-50 mg (Figure S1).

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CLINICAL STUDY REPORT SYNOPSIS
Figure S1. Study Design

Diagnosis and Main Criteria for Inclusion
Inclusion Criteria
Key inclusion criteria were:

Male or female participants ≥12 years of age at time of informed consent/assent.



Adolescent participants below the age of 18 years were only enrolled in this study if
permitted by the sponsor, local competent authority, and Institutional Review Board(IRB)/Ethics Committee (EC).

Otherwise, only participants ≥18 years of age (or age specified by applicable reviewer)
were enrolled in those countries, regions, or sites. Within VHP countries in the European
Union (EU), participants had to be between 18 and 74 years of age (inclusive) at the timeof informed consent.



Had to meet the following AA criteria:a. A clinical diagnosis of AA with no other etiology of hair loss (eg, telogen
effluvium, androgenic alopecia, etc.).
b. ≥50% hair loss on the scalp (measured by SALT), including alopecia totalis (AT)(complete [100%] scalp hair loss) and alopecia universalis (AU) (complete

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CLINICAL STUDY REPORT SYNOPSIS[100%] scalp, facial, and body hair loss), without evidence of terminal hairregrowth within 6 months at both Screening and BL visits.
o Photographs taken at Screening were submitted to the Sponsor or designee forverification of SALT score ≥50 and hair loss due to AA. Participants were notrandomized until verification was confirmed.
c. Current episode of hair loss 10 years.
Exclusion Criteria
Key exclusion criteria were:

Other types of alopecia (including, but not limited to, traction and scarring alopecia,
telogen effluvium). Participants with known androgenic alopecia were excluded.



Other scalp disease that could impact AA assessment (eg, scalp psoriasis, dermatitis,etc.).



Active systemic diseases that could cause hair loss (eg, lupus erythematosus, thyroiditis,
systemic sclerosis, lichen planus, etc.).



Any of the psychiatric conditions as described in the protocol.



Hearing loss with progression over the previous 5 years, sudden hearing loss, middle orinner ear disease, or other auditory condition considered acute, fluctuating, or
progressive.

Previous use of any JAK inhibitor for use in any disease indication or any non-B-cellselective lymphocyte-depleting agent.

Current or recent history of clinically significant severe, progressive, or uncontrolled
renal, hepatic, hematological, gastrointestinal, metabolic, endocrine (particularly thyroid
disease which can be associated with hair loss), pulmonary, cardiovascular, psychiatric,
immunologic/rheumatologic or neurologic disease; or have any other severe acute or
chronic medical or psychiatric condition or laboratory abnormality that could increase therisk associated with study participation or study intervention administration, or interferewith the interpretation of study results; or in the opinion of the investigator or Pfizer (ordesignee), the participant was inappropriate for entry into this study.

Any present malignancies or history of malignancies, except for adequately treated or
excised non-metastatic basal cell or squamous cell cancer of the skin or cervicalcarcinoma in situ.

History of any lymphoproliferative disorder, history of lymphoma, history of leukemia,
or signs and symptoms suggestive of current lymphatic or lymphoid disease.
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CLINICAL STUDY REPORT SYNOPSIS

History (single episode) of disseminated herpes zoster or disseminated herpes simplex, ora recurrent (more than one episode of) localized, dermatomal herpes zoster.



Adolescent participants 12 to <18 years old without a documented history of varicellazoster virus (VZV) vaccination or presence of VZV immunoglobulin (IgG) antibodies
(Ab).



History of systemic infection requiring hospitalization, parenteral antimicrobial therapy,
or as otherwise judged clinically significant by the investigator within 6 months prior to
Day 1.



Active acute or chronic infection requiring treatment with oral antibiotics, antivirals,
antiparasitics, antiprotozoals, or antifungals within 4 weeks prior to Day 1 or superficial
skin infection within 1 week prior to Day 1. NOTE: participants could be rescreened after
the infection resolved.

Known immunodeficiency disorder, including positive serology for humanimmunodeficiency virus (HIV) at Screening or a first-degree relative with a hereditaryimmunodeficiency.

Infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) according to theProtocol-specified testing algorithm.

Evidence of untreated or inadequately treated active or latent Mycobacterium
tuberculosis (TB) infection as evidenced by the any of the criteria listed in the Protocol.

Study Treatment
Table S2. Investigational Product Description
Investigational Product Description
Placebo 10 mm tablet

Vendor Lot
Numbern/aPlacebo 6 mm tablet

n/aPF-06651600-15 10 mg
Round white to off-white tablet

n/aPF-06651600-15 50 mg
Round white to off-white tablet

n/a

Pfizer Lot Number

Strength/ Potency

Dosage Form

18-001558
18-001559
18-001560
18-001556
18-001557
19-000043
17-001175
18-001563
18-001564
18-003539
16-005309
17-002906
18-003614
18-001307
19-000951
17-004591
18-003616
18-000399

0 mg

Tablet0 mg

Tablet

10 mg

Tablet50 mg

TabletPFIZER CONFIDENTIAL
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CLINICAL STUDY REPORT SYNOPSIS
Table S2. Investigational Product Description
Investigational Product Description

Vendor Lot
Number

Pfizer Lot Number

Strength/ Potency

Dosage Form

19-001387
17-004590
18-001308

Efficacy Evaluations
Efficacy evaluations were done at study visits as described in Table S1.
SALT is a quantitative assessment of AA severity based on scalp terminal hair loss.
SALT ≤20 indicates less than or equal to 20% scalp hair loss; SALT ≤10 indicates less thanor equal to 10% scalp hair loss.
The PGI-C asks the subject to evaluate the improvement or worsening of their AA as
compared with the start of the study using a single-item, “Since the start of the study, myalopecia areata has: …”. The participant selected one of seven responses ranging from“greatly improved” to “greatly worsened.” PGI-C response was defined as a score of“moderately improved” or “greatly improved”.
ELA is a numeric rating scale (NRS) developed to characterize eyelash hair loss. The
numeric rating scale ranges from 0 (no eyelash hair) to 3 (normal eyelash hair).
EBA is an NRS developed to characterize eyebrow hair loss. The numeric rating scale ranges
from 0 (no eyebrow hair) to 3 (normal eyebrow hair).
AAPPO is a self-administered questionnaire that measures hair loss, emotional symptoms,
and activity limitations over the past week.
CGI-AA is a single clinician-reported item developed to assess the clinical impression ofseverity of scalp hair loss.
The number of fingernails affected by AA were counted at BL and all subsequent visits.
Patient-centered outcomes and payer-relevant measures included P-Sat, EQ-5D-5L(EQ-5D-Y), AARU, WPAI:AA, HADS, and SF36v2 up to Week 48.
Pharmacokinetic and Pharmacodynamic Evaluations:
To characterize the PK of ritlecitinib, plasma concentrations of ritlecitinib were measured
pre-dose on Day 1 and pre-dose, 30 min, and 1, 2 or 3 hours post-dose at Weeks 4, 8, and 12.
Pharmacodynamic evaluations were as described in Table S1.

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CLINICAL STUDY REPORT SYNOPSIS
Safety Evaluations
Safety evaluations included the incidence of TEAEs, SAEs, and AEs leading todiscontinuation. Also included were the incidence of clinically meaningful abnormalities invital signs, electrocardiogram (ECG), audiological evaluation, physical examination, andclinical laboratory values.
Statistical Methods
This study will support submission in several regions with different requirements. Different
testing procedures for multiple comparisons were specified for the overall study, for the
FDA/PMDA, and for the EMA and competent authorities in the VHP countries.
For the overall study, the SALT ≤20 response at Week 24 was the primary endpoint and the
SALT ≤10 response at Week 24 was analyzed as a key secondary endpoint. The hypotheses,
tested at an overall significance level ( of 0.05, were that each ritlecitinib group wassuperior to placebo. A total of 8 hypotheses were tested (H1-H4, H1p-H4p). The family-wise
Type I error was strongly controlled using a gatekeeping approach as shown in Figure S2.
Figure S2. Schematic and Graphical Presentation for Multiple Testing Procedure
Incorporating a Key Secondary Endpoint

The numbers on each edge indicate the transition rule for the weights on alpha allocation once a hypothesis was rejected.

For the FDA/PMDA, the SALT ≤20 response at Week 24 was the primary endpoint and no
endpoint was analyzed as key secondary. The hypotheses, tested at an overall significancelevel ( of 0.00125, were that each ritlecitinib group was superior to placebo. A total of 4
hypotheses were tested (H1-H4). The family-wise Type I error was strongly controlled using
a gate-keeping approach as shown in Figure S3.

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CLINICAL STUDY REPORT SYNOPSIS
Figure S3. Schematic and Graphical Presentation for Multiple Testing Procedure
Without a Key Secondary Endpoint

The numbers on each edge indicate the transition rule for the weights on alpha allocation once a hypothesis was rejected.

For the EMA and competent authorities in the VHP countries, the SALT ≤10 response at
Week 24 was the primary endpoint and PGI-C response at Week 24 was analyzed as a key
secondary endpoint. The hypotheses, tested at an overall significance level ( of 0.01, werethat each ritlecitinib group was superior to placebo. A total of 8 hypotheses were tested(H1-H4, H1p-H4p). The family-wise Type I error was strongly controlled using agate-keeping approach as shown in Figure S2.
RESULTS
Participant Disposition
A total of 1097 participants were screened and 718 participants were randomized totreatment. Of these, 715 (99.6%) received treatment (3 participants were not treated) and 101(14.1%) discontinued treatment. The number of participants discontinuing during thePlacebo-Controlled Period was similar across treatment groups, except for 30 mg, which had
a higher (11.4%) discontinuation rate. During the Extension Period (Week 25-48),
discontinuation rates ranged from 3.8% (50 mg) to 8.5 % (200/30 mg). Overall, 614 (85.5%)of participants completed treatment (Table S3).
During the Placebo-Controlled Period (up to Week 24), the most common reasons fordiscontinuation were ‘withdrawal by participant’, ‘AE’, and ‘physician decision’ (which
included discontinuation due to COVID-19-related reasons).

In the Extension Period (Weeks 25-48), the primary reasons for discontinuation were‘lack of efficacy’, ‘withdrawal by participant’, ‘AE’, and ‘other’. Overall, the mostcommon reasons for discontinuation were ‘withdrawal by participant’, ‘AE’, ‘Lost to
Follow-up’, ‘lack of efficacy’, and ‘physician decision’(which included discontinuation
due to COVID-19-related reasons).

Overall, few (24 [3.3%]) participants discontinued due to COVID-19-related reasons, anddiscontinuation was similar across treatment groups. The most common reasons fordiscontinuation due to COVID-19-related reasons were ‘withdrawal by participant’ and
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CLINICAL STUDY REPORT SYNOPSIS‘physician decision’. The majority of these discontinuations occurred in the PlaceboControlled period (up to Week 24) (20 [2.8%] participants).

Table S3. Disposition Events Summary up to Week 48 (FAS) (Protocol B7981015)
Ritlecitinib Ritlecitinib Ritlecitinib Ritlecitinib Ritlecitinib PlaceboPlaceboTotal
200/50 mg 200/30 mg 50 mg QD 30 mg QD 10 mg QD >Ritlecitinib >Ritlecitinib (N=718)
QD
QD(N=130)(N=132)(N=63)
200/50 mg 50 mg QD(N=132)(N=130)QD(N=66)(N=65)
Number (%) ofParticipants

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

Disposition
Phase: Up to
Week 24
Discontinued

10 (7.6)6 (4.6)9 (6.9)15 (11.4)

5 (7.9)2 (3.1)5 (7.6)52 (7.2)

AdverseEvent

3 (2.3)0

2 (1.5)4 (3.0)2 (3.2)0

1 (1.5)12 (1.7)

Lack of
Efficacy

0

0

0

0

0

1 (1.5)0

1 (0.1)

Lost toFollow-Up

1 (0.8)0

1 (0.8)2 (1.5)

1 (1.6)00

5 (0.7)

NonComplianceWith Study
Drug

0

0

0

0

0

0

0

0

PhysicianDecision01 (0.8)2 (1.5)5 (3.8)00

1 (1.5)9 (1.3)Pregnancy

1 (0.8)000

1 (1.6)0

1 (1.5)3 (0.4)

ProtocolDeviation

1 (0.8)1 (0.8)

0

0

0

0

0

2 (0.3)

Withdrawal
By Participant

4 (3.0)4 (3.1)4 (3.1)4 (3.0)1 (1.6)

1 (1.5)2 (3.0)20 (2.8)

Other

0

0

0

0

0

0

0

0

6 (4.5)

11 (8.5)5 (3.8)9 (6.8)5 (7.9)3 (4.6)4 (6.1)43 (6.0)

AdverseEvent0

2 (1.5)2 (1.5)1 (0.8)00

2 (3.0)7 (1.0)Lack of
Efficacy

2 (1.5)1 (0.8)0

3 (2.3)3 (4.8)0

1 (1.5)10 (1.4)

Lost toFollow-Up

00

2 (1.5)1 (0.8)1 (1.6)2 (3.1)0

6 (0.8)

Disposition
Phase:EXTENSION(Week 25-48)
Discontinued

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Table S3. Disposition Events Summary up to Week 48 (FAS) (Protocol B7981015)
Ritlecitinib Ritlecitinib Ritlecitinib Ritlecitinib Ritlecitinib PlaceboPlaceboTotal
200/50 mg 200/30 mg 50 mg QD 30 mg QD 10 mg QD >Ritlecitinib >Ritlecitinib (N=718)
QD
QD(N=130)(N=132)(N=63)
200/50 mg 50 mg QD(N=132)(N=130)QD(N=66)(N=65)
Number (%) ofParticipants

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

NonComplianceWith StudyDrug0

1 (0.8)

0

0

0

0

0

1 (0.1)

PhysicianDecision01 (0.8)0

1 (0.8)1 (1.6)00

3 (0.4)Pregnancy

0

0

0

0

0

0

0

0

ProtocolDeviation

0

0

0

0

0

0

0

0

Withdrawal
By Participant

3 (2.3)2 (1.5)1 (0.8)1 (0.8)0

1 (1.5)

1 (1.5)9 (1.3)Other

1 (0.8)4 (3.1)0

2 (1.5)000

7 (1.0)16 (12.1)

18 (13.8)

17 (13.1)

29 (22.0)

10 (15.9)

5 (7.7)9 (13.6)

104 (14.5)

AdverseEvent

3 (2.3)2 (1.5)4 (3.1)5 (3.8)2 (3.2)0

3 (4.5)19 (2.6)

Lack of
Efficacy

2 (1.5)1 (0.8)04 (3.0)3 (4.8)1 (1.5)

1 (1.5)12 (1.7)

Lost toFollow-Up

1 (0.8)1 (0.8)3 (2.3)4 (3.0)2 (3.2)2 (3.1)0

13 (1.8)

NonComplianceWith StudyDrug0

1 (0.8)

0

0

0

0

0

1 (0.1)

PhysicianDecision02 (1.5)2 (1.5)6 (4.5)

1 (1.6)0

1 (1.5)12 (1.7)

1 (0.8)00

1 (0.8)1 (1.6)0

1 (1.5)4 (0.6)

ProtocolDeviation

1 (0.8)1 (0.8)

0

0

0

0

0

2 (0.3)

Withdrawal
By Participant

7 (5.3)6 (4.6)6 (4.6)6 (4.5)

1 (1.6)2 (3.1)3 (4.5)31 (4.3)

Disposition
Phase: Overall
Discontinued

Pregnancy

Other

1 (0.8)4 (3.1)2 (1.5)3 (2.3)000

10 (1.4)

Completed

116 (87.9)

112 (86.2)

113 (86.9)

103 (78.0)

53 (84.1)

60 (92.3)

57 (86.4)

614 (85.5)

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Table S3. Disposition Events Summary up to Week 48 (FAS) (Protocol B7981015)
Ritlecitinib Ritlecitinib Ritlecitinib Ritlecitinib Ritlecitinib PlaceboPlaceboTotal
200/50 mg 200/30 mg 50 mg QD 30 mg QD 10 mg QD >Ritlecitinib >Ritlecitinib (N=718)
QD
QD(N=130)(N=132)(N=63)
200/50 mg 50 mg QD(N=132)(N=130)QD(N=66)(N=65)
Number (%) ofParticipants

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

Information in 'Adverse Event' row was from Disposition CRF page.
Included data up to Week 48 and follow-up period (if applicable).
PFIZER CONFIDENTIAL SDTM Creation: 13JUL2021 (13:20) Source Data: adds Table Generation: 09AUG2021(22:47)(Database snapshot date : 12JUL2021) Output File: ./nda1_cdisc/B7981015/adds_s001
Table 14.1.1.2.2 Ritlecitinib is for Pfizer internal use.

Participant Demography and Other Baseline Characteristics
Overall, demographic characteristics were balanced across treatment groups.


The majority of participants (613 [85.4%]) were adults ≥18 years of age. The mean ageof all participants was 33.7 years.

The study randomized 105 adolescents (12 to 17 years of age), at sites in Australia, Chile,
China, Japan, Mexico, Russian Federation, Republic of Korea and the US. Since
randomization was stratified, the distribution of adolescent participants across treatmentgroups was similar.



There were more female (62.1%) than male (37.9%) participants. Most participants wereWhite (68.0%), 25.9% were Asian, and 3.8% were Black or African American; 12.1%
were Hispanic/LatinoThe median duration since AA diagnosis (6.9 years) was similar across treatment groups.
The median duration of the current AA episode was 2.5 years.

The distribution of participants by AA severity was balanced across treatment groups. Thiswas consistent with the stratified randomization planned to achieve a target enrollment ofapproximately 40% AT/AU and 15% adolescent participantsAA history was similar across treatment groups. A total of 330 (46.0%) participants wereclassified as AT/AU, based on a BL SALT score of 100%. Randomization was stratified
by AT/AU and the distribution of participants classified as AT/AU versus non-AT/nonAU was similar across treatment groups.

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The mean (SD) BL SALT score was similar across treatment groups, ranging from 88.3
(16.87) to 93.0 (11.50).

Efficacy Results
Treatment with ritlecitinib 200/50 mg, 200/30 mg, 50 mg and 30 mg resulted in greater scalp
hair regrowth at Week 24 compared with placebo, as measured by significantly greater
proportion of response based on SALT ≤20 (or SALT ≤10, as appropriate).
Primary and Key Secondary Endpoints
The study was tested at an overall significance level ( of 0.05. While this significance level
was deemed sufficient for a declaration of effect, more stringent levels have been advised byregulatory agencies for submission of this study to support marketing authorization, namely
α=0.01 for the EMA and competent authorities in the VHP countries and α=0.00125 for the
FDA.
The key efficacy results are therefore summarized separately for the overall study, for the
FDA/PMDA and for the EMA and competent authorities in the VHP countries, based on therespective planned analyses. Key efficacy results of the primary and key secondary endpoints
were:





For the overall study, ritlecitinib 200/50 mg, 200/30 mg, 50 mg and 30 mg met the
primary endpoint (response based on SALT ≤20 at Week 24) and the key secondary
endpoint (response based on SALT ≤10 at Week 24) at an overall significance level ()of 0.05.
For the FDA/PMDA, ritlecitinib 200/50 mg, 200/30 mg, 50 mg and 30 mg met the
primary endpoint (response based on SALT ≤20 at Week 24) at an overall significancelevel () of 0.00125.
For the EMA and competent authorities in the VHP countries, ritlecitinib 200/50 mg,
200/30 mg, 50 mg and 30 mg met the primary endpoint (response based on SALT ≤10 at
Week 24) and the key secondary endpoint (PGI-C response at Week 24) at an overallsignificance level () of 0.01.

Ritlecitinib 10 mg was included in the study to support the estimation of the exposure
response, therefore comparison of 10 mg with placebo was not included in the overall
assessment of efficacy. Comparative statistics between 10 mg and placebo groups are shownin efficacy tables for completeness only but were not part of the overall testing plan.
SALT ≤20 Response at Week 24
Analyzed as a primary endpoint for the study and for the FDA/PMDA, the proportion ofparticipants with response based on a SALT score ≤20 at Week 24 in ritlecitinib 200/50 mg(30.65%), 200/30 mg (22.31%), 50 mg (23.39%), and 30 mg (14.29%) was significantly
different from placebo (1.54%) Figure S4.

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Figure S4. Response Based on Salt Score ≤20 up to Week 48 (FAS)

SALT ≤10 Response at Week 24
Analyzed as the primary endpoint for the EMA and competent authorities in the VHP
countries, the proportions of participants with response based on a SALT score ≤10 at Week
24 in ritlecitinib 200/50 mg (21.29%), 200/30 mg (12.87%), 50 mg (13.42%), and 30 mg(10.62%) were significantly different from placebo (1.54%) (Figure S5). Similar results wereobtained when this endpoint was analyzed as a key secondary endpoint for the overall study.

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Figure S5. Response Based on SALT Score ≤10 up to Week 48 (FAS)PGI-C Response at Week 24
A significantly larger PGI-C response rate was seen in ritlecitinib 200/50 mg (52.19%),200/30 mg (45.40%), 50 mg (49.17%), and 30 mg (41.95%) at Week 24 compared withplacebo (9.23%). This was a key secondary endpoint for the EMA and competent authorities
in the VHP countries (Figure S6).

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Figure S6.

PGI-C Response up to Week 48 (FAS)

Examination of Subgroups for Primary and Key Secondary Endpoints
The difference between each ritlecitinib group and placebo in the proportion of response
based on SALT ≤20/SALT ≤10/PGI-C response at Week 24 was generally consistent acrossmost subgroups for all doses.
Considering subgroups by age, the differences in the proportions of response based on
SALT ≤20/SALT ≤10/PGI-C response at Week 24 between ritlecitinib and placebo weresimilar in adolescents and adults.

Considering subgroups by severity of AA at BL:
o The proportion of SALT ≤20 response at Week 24 for ritlecitinib versus placebo was
lower in participants with AT/AU than in those with non-AT/AU. For ritlecitinib
200/50 mg, 200/30 mg, 50 mg, and 30 mg, the 95% CI for the difference inproportion of responders based on SALT 20 at Week 24 between ritlecitinib andplacebo excluded zero in both subgroups, indicating a treatment effect in bothparticipants with AT/AU and non-AT/AU at a nominal significance level () of 0.05.

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CLINICAL STUDY REPORT SYNOPSISo The difference in SALT ≤10 response at Week 24 for ritlecitinib versus placebo was
lower in participants with AT/AU than in those without AT/AU. In participants with
non-AT/AU, the 95% CI for the difference in the proportion of responders based on
SALT ≤10 at Week 24 between ritlecitinib and placebo excluded zero for ritlecitinib
200/50 mg, 200/30 mg, 50 mg and 30 mg. In participants with AT/AU, the 95% CI
for the difference in proportion of responders based on SALT 10 at Week 24
between ritlecitinib and placebo excluded zero for ritlecitinib 200/50 mg and200/30 mg.
o The difference in the proportions of participants with PGI-C response at Week 24
between ritlecitinib and placebo was similar in participants with AT/AU andnon-AT/AU.
Secondary Endpoints
Exposure-Response of Ritlecitinib on the Regrowth of Scalp Hair
The results of this analysis demonstrated a positive relationship between dose and response
based on SALT ≤20 at Week 24, and a significant effect of loading dose. The treatment
effects of ritlecitinib estimated from this analysis were similar to those from the primary
analysis of SALT ≤20 at Week 24.
The results of this analysis also demonstrated a positive relationship between dose andresponse based on SALT ≤10 at Week 24. The treatment effects of ritlecitinib estimated fromthis analysis were similar to those from the primary analysis of SALT ≤10 at Week 24.
SALT ≤20/SALT ≤10/SALT75/EBA/ELA/PGI-C Responses up to Week 48
The proportion of participants with SALT ≤20/SALT ≤10/ SALT75/EBAa/ELA/PGI-C
response increased from Week 4 to Week 24 in ritlecitinib 200/50 mg, 200/30 mg, 50 mg,
and 30 mg; the increase was greater than in 10 mg and placebo. The proportion ofparticipants with a response continued to increase after Week 24.



At Week 24, the proportion of participants with SALT ≤20/SALT ≤10/ SALT75/EBA
response was larger in participants who had received a 200 mg loading dose for 4 weeks
than in participants treated for 24 weeks at a single dose level.
o By Week 48, the proportion of participants with SALT ≤20/SALT ≤10/ EBA/ELA/
PGI-C was similar between the participants who had received a 200 mg loading dosefor 4 weeks and those who were treated for 48 weeks without a loading dosea

EBA and ELA responses were evaluated in participants without normal EBA/ELA at BL.
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CLINICAL STUDY REPORT SYNOPSISAAPPO Scales up to Week 48
Up to Week 24, the proportion of participants reporting an improvement (achieving a scoreof 0 [no hair loss] or 1 [little hair loss]) on AAPPO hair loss items 1-4 (scalp, eyebrow,eyelash, body hair) increased in ritlecitinib 200/50 mg, 200/30 mg, 50 mg, and 30 mg; theincrease was greater than in 10 mg and placebo. In participants who had received placebo,
after transitioning to active treatment (pbo200/50 mg and pbo50 mg) the proportion ofparticipants with improvement on AAPPO items 1-4 increased from Week 24 to Week 48.
Mean BL scores of AAPPO Emotional Symptoms and Activity Limitations scores
corresponded to Emotional Symptoms that occurred 'never', ‘rarely’, or ‘sometimes’ andActivity Limitations that were ‘not at all’ or ‘a little’. Up to Week 24, the LSM CFB
indicated mean Emotional Symptoms scores improved modestly in all groups, including
placebo. There was no apparent difference between any active treatment group and placebo.
In ritlecitinib 200/50 mg, 200/30 mg, 50 mg, and 30 mg, the improvement in LSM CFB in
Emotional Symptoms score continued through Week 48.
Exploratory Endpoints
Response Based on SALT50/Absolute SALT Score/Improvement on PGI-C up to
Week 48

The proportion of responders (participants showing SALT50) consistently increased from
Week 4 to Week 24 in ritlecitinib 200/50 mg, 200/30 mg, 50 mg, and 30 mg, and was
greater than in 10 mg or placebo.
The proportion of participants reporting any improvement on PGI-C consistently
increased from Week 4 to Week 24 in ritlecitinib 200/50 mg, 200/30 mg, 50 mg, and30 mg, and was greater than in 10 mg or placebo.
Absolute SALT scores decreased (improved) consistently from Week 4 to Week 24 inritlecitinib 200/50 mg, 200/30 mg, 50 mg, and 30 mg compared with 10 mg and placebo.
These exploratory endpoints continued to show improvement in ritlecitinib 200/50 mg,
200/30 mg, 50 mg, and 30 mg after Week 24.

Number of Fingernails Affected by AA - Change from Baseline
At Week 24, the mean number of fingernails affected by AA decreased in all treatmentgroups, including placebo, with no dose-dependence. This decrease continued through Week
48.
CGI-AAThe CGI-AA is a single clinician-reported item developed to assess the clinical impression ofseverity of scalp hair loss. The rater is asked to rate the subject’s current hair loss on a scaleranging from ‘None (no hair loss)’ to ‘Very severe or complete hair loss’, with higher scoresindicating more severe hair loss. The proportion of participants with improvement in
CGI-AA (with a score ≥2 at BL) increased over time in active treatment groups;
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improvement was greater in ritlecitinib 200/50 mg, 200/30 mg, 50 mg, and 30 mg than in
10 mg or placebo. The proportion of participants with improvement in CGI-AA improved inall groups up to Week 48.
Patient-Reported OutcomesP-Sat: Up to Week 24, the proportion of participants showing improvement in all 3
aspects of P-Sat (amount of hair grown, overall hair grown back, and quality of new hair)
was greater in all active treatment groups than in placebo. From Week 24 to Week 48, theimprovement was maintained, however, there were only small additional changes in theinitial active groups. In the active treatment groups, improvement was seen as early as
Week 4; the largest increase in each aspect of P-Sat occurred between Week 4 andWeek 8.



EQ-5D-5L/EQ-VAS/EQ-5D-5Y: From Weeks 4 to 24, mean CFB indicated that mean
EQ-VAS (visual analogue scale) in both adults and adolescents, and EQ-5D-5L in adults
index scores did not change.



AARU: The proportion of participants with any HCP visits was similar across groups at
BL and through Week 48.



WPAI:AA: The mean percent work time missed, impairment while working, overall
work impairment, and activity impairment WPAI:AA scores at BL were similar acrosstreatment groups.



HADS:
o Mean depression and anxiety scores were consistent with normal depression/anxiety
scores (ie, no depression/no anxiety) at BL and at Week 24 for all groups. Overall,
LSM of CFB was similar between all ritlecitinib groups and placebo up to Week 24
and the LS mean CFB was similar among ritlecitinib groups up to Week 48.
o The proportion of participants with a BL subscale score indicative of depression/anxiety that indicated an improvement in depression/anxiety from BL was similar
between active ritlecitinib groups through Week 48; only a small subset ofparticipants reported scores indicative of depression/anxiety at BL.



SF36v2: BL normalized mean SF-36v2 scores for all 8 domains and physical (PCS) andmental (MCS) component scores were balanced across treatment groups andapproximated US population norms (mean=50, SD=10). From Weeks 4 to 24, normalized
mean scores were similar across groups; similar trends were observed for all groups from
Week 24 to 48.

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Pharmacokinetic and Pharmacodynamic Results
The mean plasma concentrations of ritlecitinib were similar between Weeks 4, 8, and 12 inparticipants who received the same dose throughout the Placebo-Controlled Period(ie, 50 mg, 30 mg, 10 mg). The difference in plasma concentration between groups was
proportional to the difference in dose. The mean plasma concentrations were higher at
Week 4 in participants who received a 200 mg loading dose for 4 weeks. At Weeks 8 and 12,
mean plasma concentrations were similar between all participants who received 50 mg(200/50 mg versus 50 mg) or 30 mg (200/30 mg versus 30 mg), independent of whether they
had received a loading dose during the first 4 weeks.
Safety Results
Adverse Events
The proportion of participants who experienced all-causality TEAEs was similar acrosstreatment groups up to Week 24 (Placebo-Controlled Period) and up to Week 48 (overall).
Up to Week 24: in active treatment groups, range 69.4% (10 mg) to 75.4% (50 mg)
compared with placebo (71.0%).

Up to Week 48: across treatment groups range 75.8% (10 mg) to 86.4% (pbo50 mg)(Table S4).

Up to Week 48, the incidence of TEAEs, SAEs, severe TEAEs, permanent discontinuations
and temporary drug discontinuations was not dose dependent across treatment groups.


No dose-dependent increase was observed in the number of participants with TEAEs in
active treatment groups.



14 participants experienced treatment-emergent SAEs, which were generally balanced
across treatment groups.



27 participants experienced severe TEAEs which were generally balanced acrosstreatment groups. (This excludes 1 TEAE of headache [severe, related] that was reported
erroneously.)

22 participants permanently discontinued from the study or study drug due to an TEAE.
o The TEAEs most frequently resulting in permanent discontinuation from the study or
study drug were urticaria, pregnancy, or headacheThere were no deaths.

There were an additional 6 TEAEs experienced by 4 participants not reported in summary
tables, all mild in severity, (1 TEAE each in 200/50 mg, 50 mg, and 10 mg; 3 TEAEs in 30

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CLINICAL STUDY REPORT SYNOPSISmg). None of these TEAEs were serious, related to study intervention, or resulted in a change
in study intervention or discontinuation from the study.

Table S4. Overall Summary of Treatment-Emergent Adverse Events (All
Causalities) up to Week 48 (SAS) (Protocol B7981015)
Ritlecitinib Ritlecitinib Ritlecitinib Ritlecitinib Ritlecitinib PlaceboPlacebo200/50 mg 200/30 mg 50 mg QD 30 mg QD 10 mg QD >Ritlecitinib >Ritlecitinib 50 mg
QD
QD
200/50 mg
QD
QD
Number (%) ofParticipants

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

Participantsevaluable foradverse events

131

129

130

132

62

65

66

Number ofadverse events

410

345

363

409

161

180

192

Participants withadverse events

108 (82.4)

105 (81.4)

110 (84.6)

106 (80.3)

47 (75.8)

54 (83.1)

57 (86.4)

Participants withserious adverse
events4 (3.1)2 (1.6)2 (1.5)1 (0.8)2 (3.2)0

3 (4.5)

Participants withsevere adverse
events5 (3.8)8 (6.2)2 (1.5)7 (5.3)2 (3.2)2 (3.1)2 (3.0)Participants
permanently
discontinued fromstudy due toadverse eventsa

4 (3.1)2 (1.6)4 (3.1)6 (4.5)2 (3.2)0

4 (6.1)

Participants withtemporary drug
discontinuation
due to adverse
events17 (13.0)

16 (12.4)

20 (15.4)

16 (12.1)

5 (8.1)

13 (20.0)

8 (12.1)

Included data up to Week 48 and follow-up period (if applicable).
Except for the Number of Adverse Events, participants are counted only once per treatment in each row.
Serious Adverse Events - according to the investigator's assessment.
a. Participants who have an AE record that indicates that the participant was discontinued from the study or study drug.
MedDRA v24.0 coding dictionary applied.
PFIZER CONFIDENTIAL SDTM Creation: 13JUL2021 (13:21) Source Data: adae Table Generation: 09AUG2021(17:54)(Database snapshot date : 12JUL2021) Output File: ./nda1_cdisc/B7981015/adae_s010c
Table 14.3.1.2.3.1 Ritlecitinib is for Pfizer internal use.

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Incidence of Adverse Events

The most frequently reported TEAEs (by preferred term [PT]) in any group during boththe Placebo-Controlled and Extension Periods included nasopharyngitis, headache, andupper respiratory tract infection.



The incidence of nasopharyngitis, dizziness, and urinary tract infection was higher inparticipants treated with ritlecitinib. For the 200/50 mg and 200/30 mg groups, incidence
was also higher for folliculitis, upper respiratory tract infection, and urticaria.



Most TEAEs were mild to moderate in severity.

Up to Week 24, 20 severe TEAEs were reported across all ritlecitinib treatment groups(excluding 1 TEAE of headache [severe, related] in ritlecitinib 30 mg that was reported
erroneously). The incidence of severe TEAEs was low in all treatment groups (range:
50 mg, 2 [1.5%] to 200/30 mg, 5 [3.9%]).
o Up to Week 48, an additional 7 severe TEAEs were reported. Overall, the incidenceof severe TEAEs ranged from 2 (1.5%) in 50 mg to 8 (6.2%) in 200/30 mg.



The most frequently reported severe TEAEs (n ≥1.6% of participants) were pruritus(2 [1.6%]), alopecia areata 2 [1.6%]), and blood creatine phosphokinase increased(2 [1.6%]) in 200/30 mg and vertigo positional (1 [1.6%]) and myalgia (2 [1.6%]) in
10 mg.

Serious Adverse Events
Treatment-emergent SAEs reported during the study were generally balanced acrosstreatment groups.


14 participants experienced 16 SAEs up to Week 48, 11 of which occurred in 10
participants during the Placebo-Controlled Period (up to Week 24).



No SAE was reported during the initial 4 weeks of treatment in participants receiving
200 mg loading dose.

All SAEs were considered by the investigator as unrelated to study drug, except in 3
participants (sepsis and empyema; breast cancer; and eczema). All SAEs were resolved
except for conversion disorder (resolved with sequelae), breast cancer (resolving) andinvasive lobular breast carcinoma (not resolved).
Other Safety Events of Interest
Overall, 4 (0.6%) participants experienced 5 TEAEs of serious infection. Of these, 4 TEAEs
in 3 participants occurred in the Placebo-Controlled Period (200/50 mg: sepsis and empyema[both severe], and appendicitis [moderate]; 30 mg: diverticulitis [moderate]), and 1 TEAE in
1 participant occurred in the Extension Period (200/30 mg: appendicitis [severe]). These
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SAEs were in the Infections and Infestations SOC; all TEAEs were recovered and 2 TEAEs(sepsis and empyema in 1 participant) were considered by the investigator as related to study
treatment.
There were no TEAEs adjudicated as opportunistic infections and no TEAEs oftuberculosis up to Week 48.
Up to Week 48, 8 (1.1%) participants experienced herpes zoster (7 coded to the PT herpes
zoster, 1 to varicella zoster virus infection); 4 of the TEAEs occurred up to Week 24. All
occurred in in ritlecitinib-treated participants (200/50 mg: 1 participant; 200/30 mg:
2 participants; 50 mg: 5 participants). Participants with TEAEs of herpes zoster ranged in age
from 28 to 65 years and most were female (6 participants). None of the TEAEs weredisseminated or multidermatomal, all were mild to moderate in severity, all participants
recovered, and no participant discontinued from the study due to these TEAEs. None of these
TEAEs were considered serious.
Up to Week 48, 21 (2.9%) participants experienced herpes simplex (18 coded to thepreferred term of herpes simplex, 1 to herpes simplex reactivation, 1 to herpes virus
infection, and 2 to oral herpes); 14 of the TEAEs occurred up to Week 24. Up to Week 48,
herpes simplex was reported across all treatment groups (range: 0.8% [200/50 mg] to 4.5%[30 mg and pbo50 mg]) with no dose-dependence; 3 of the TEAEs occurred in placebo.
Up to Week 48, there were no major adverse cardiovascular events.


There was 1 TEAE adjudicated by an external Cardiovascular Adjudication Committee tomeet criteria for a cardiovascular and thromboembolic event of pulmonary embolism.
The study drug was withdrawn and the participant (50 mg) was discontinued from thestudy as a result of the TEAE. The outcome of the TEAE was recovered/resolved.

Up to Week 48, there were 36 participants with TEAEs that were adjudicated to meet criteria
as neurosafety events of interest (EOI) by an external Neurosafety Event Adjudication
Committee; in 30 participants these TEAEs were adjudicated to meet criteria for neurological
EOI terms and in 6 participants these TEAEs were adjudicated to meet criteria for theaudiological EOI term sensorineural hearing loss.
The adjudicated neurological EOI were well distributed across treatment groups. A totalof 25 of these participants experienced TEAEs up to Week 24.



The TEAEs that were adjudicated to meet criteria for the audiological EOI term
sensorineural hearing loss were balanced across active treatment groups (2 each in 200/50
mg and 30 mg; 1 each in 200/30 mg and 50 mg), except for 10 mg and the groups
randomized to receive placebo during the first 24 weeks. All TEAEs adjudicated by theexternal NSEAC to meet criteria for the audiological EOI term sensorineural hearing loss
reflect only the outcome of the protocol-specified audiologic testing, as none of those

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TEAEs were spontaneously reported by study participants. None of the adjudicated
TEAEs met criteria for the EOI term central hearing disorder.
Up to Week 48, 2 participants each experienced 1 TEAE of malignancy. During thePlacebo-Controlled Period: (200/50 mg) SAE of invasive lobular breast carcinoma unrelated
to study treatment. During the Extension Period: (50 mg) SAE of breast cancer, related to
study treatment. Both of these malignancy TEAEs were severe and met adjudication criteria
as events of breast cancer.
o Up to Week 48, no TEAEs of squamous cell carcinoma or basal cell carcinoma werereported and there were no reports of adjudicated non-melanoma skin cancer.
Dermatological events were generally balanced across ritlecitinib and placebo treatmentgroups.
Up to Week 48, 229 (32.0%) participants experienced dermatological TEAEs (range:
27.4% [10 mg] to 37.2% [200/30 mg]).
The most common dermatological TEAEs (≥5%) across treatment groups were acne
(7.8%), folliculitis (6.6%), and urticaria (5.5%).

Rash was experienced more frequently in 50 mg (5.4% of participants) compared withother groups (0.0% to 3.8%).

Folliculitis, urticaria, and pruritus were reported more frequently in 200/50 mg(folliculitis, 8.4%; urticaria, 6.9%; pruritus, 3.1%) and 200/30 mg groups (folliculitis,
8.5%; urticaria, 7.0%; pruritus, 5.4%) compared with other groups, including placebo.

The proportion of participants that experienced TEAEs in the MedDRA HLT (high-levelterm) of Acne (including PTs of acne, acne cystic, dermatitis acneiform) ranged acrosstreatment groups from 6.1% (200/50 mg) to 13.6% (pbo50 mg).



There was 1 SAE among the dermatological TEAEs: 1 participant in the 10 mg groupexperienced an SAE of eczema on Study Day 147. The participant had a co-morbidity of
atopic dermatitis on arms and legs. The TEAE of eczema was assessed by theinvestigator as related to study treatment. Study drug was withdrawn and the participant
discontinued from the study. The outcome was recovered/resolved.



Up to Week 48, mild-to-moderate urticarias were reported in 41 participants (including 3
in the placebo arm).
o 25 participants received treatment.
o 3 participants (1 in 200/30 mg, and 2 in 50 mg) were permanently discontinued fromstudy or study drug due to TEAEs of urticaria.
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Exposure during pregnancy was reported for 4 participants up to Week 48. All TEAEs
were considered not related to study treatment; 3 participants (200/50 mg, 30 mg, andplacebo) had study drug withdrawn and were discontinued from the study. 1 participant hadcompleted study treatment by the time the site was made aware of the pregnancy.

COVID-19-related TEAEs were reported in 26 participants, including 13 participants with
TEAEs of COVID-19 or suspected COVID-19 up to Week 48. The number of participants
with of COVID-19 TEAEs ranged from 1 in 200/30 mg (0.8%) and pbo50 mg (1.5%) to
7 (5.4%) in 50 mg. All of these TEAEs were mild or moderate in severity, not consideredrelated to study drug, and all participants recovered. None of the TEAEs were SAEs and noparticipant was discontinued from the study due to the COVID-19-related TEAE.
DeathsNo deaths were reported
Laboratory Parameters
No SAEs related to laboratory abnormalities were reported.
Hematology: Treatment with ritlecitinib was associated with changes in hematologicalparameters, some of which were dose dependent.


There were slight, transient decreases in hemoglobin after initiation of treatment withritlecitinib . Hemoglobin levels were stable from Week 4 up to Week 48.

Small, early decreases in platelets were observed with ritlecitinib treatment; however,there was no dose dependence. Platelet levels remained stable at the lower level up to
Week 48.



There were small, variable changes in leukocytes from BL in the first weeks of the study,
which was more apparent in 200/30 mg. Leukocyte levels remained stable up to
Week 48.



There were small, variable changes in neutrophils early after initiation of treatment withritlecitinib. Neutrophil levels were stable from Week 4 up to Week 48.

Dose-dependent early decreases in absolute lymphocyte levels, CD3 (T lymphocytes) andT lymphocyte subsets (CD4 and CD8) were observed. After the initial decrease, thelevels partially recovered and remained stable up to Week 48.

There was no change in CD19 (B lymphocyte) cells in any treatment group.

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Final Clinical Study Report
Protocol B7981015

CLINICAL STUDY REPORT SYNOPSIS

There was a dose-dependent early decrease in CD16/56 (NK cells), which was the mostapparent in groups who had received a 200 mg loading dose (200/50 mg and 200/30 mg)
of ritlecitinib for 4 weeks.

Chemistry
Lipids: After initiation of treatment with ritlecitinib, there were small, transient increases intotal cholesterol, HDL cholesterol, and LDL cholesterol (relative to placebo), which weredose-dependent. There were no long-term changes across the groups in LDL cholesterol lipid
profile up to Week 24 or up to Week 48.
Liver Function: Overall, there were no clinically concerning effects of ritlecitinib on ALT,
AST, bilirubin, or alkaline phosphatase. Up to Week 48, the incidence of elevations inhepatic enzymes was low and not dose dependent, and there were no potential Hy’s law
cases.
Creatine Kinase: Up to Week 48, there were no clinically meaningful changes in CK acrosstreatment groups, and no cases of rhabdomyolysis were reported.
Vital Signs, ECG, and Physical Findings
Vital Signs: There were no clinically meaningful mean changes across treatment groups insystolic blood pressure, diastolic blood pressure, or pulse rate up to Week 48.
ECG: There were no clinically meaningful changes in QTcF across treatment groups during
the study up to Week 48, and no participant met the protocol-specified discontinuation
criteria of confirmed QTcF >500 milliseconds.
Physical Findings: There were no clinically meaningful mean changes across treatmentgroups in height or body weight up to Week 48 in adults. There were changes in height andbody weight up to Week 48 in adolescents; however, these changes were not consideredclinically meaningful given the age of these participants. The changes were consistent acrosstreatment groups.
CONCLUSIONS
Efficacy

Ritlecitinib 200/50 mg, 200/30 mg, 50 mg, and 30 mg were significantly superior toplacebo on clinician-assessed and patient-reported endpoints, including SALT ≤20,
SALT ≤10, and PGI-C responses.
o Overall efficacy was lower in participants with AT/AU compared with participants
with non-AT/AU.
o Overall efficacy was similar in adult and adolescent participants.

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Final Clinical Study Report
Protocol B7981015

CLINICAL STUDY REPORT SYNOPSIS

Exposure response modelling based on SALT ≤20 and SALT ≤10 response at Week 24
showed a positive relationship between dose and response. The effect of loading dose
was significant for the SALT ≤20 response; however, for the SALT ≤10 response, thep-value did not reach statistical significance.



Ritlecitinib 200/50 mg, 200/30 mg, 50 mg, and 30 mg produced significantly higher
response rates of scalp hair regrowth and were nominally superior to placebo at Week 24
in producing improvement in eyebrows and eyelashes.

Continued improvement in efficacy endpoints was seen between Week 24 and Week 48,
although this Extension Period was not placebo-controlled.



Although the Week 24 efficacy of dose regimens with a loading dose was higher thancorresponding dose regimens without a loading dose, the Week 48 efficacy of dose
regimens with or without a loading dose was comparable.

Safety

Ritlecitinib was safe and well-tolerated in participants treated with ritlecitinib for up to 48
weeks.

No deaths were reported.



There were no dose-dependent trends in SAEs, severe TEAEs, or TEAEs leading todiscontinuation.



There were few serious infections and no opportunistic infections. All TEAEs of herpes
zoster were mild to moderate and occurred in participants treated with ritlecitinib.



Dose regimens with a 200 mg loading dose had a higher incidence of some TEAEs(eg, folliculitis, urticaria, dizziness, influenza, upper respiratory tract infection, pruritus,
and urinary tract infection) compared to their respective maintenance dose (50 mg or
30 mg) and larger decreases in some hematological parameters (such as lymphocytes andlymphocyte subsets).



There were mild and mostly transient changes in hematological parameters and lipids,some of which were dose dependent. There were no clinically meaningful trends forhepatic laboratory parameters or CK.

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