Final Clinical Study Report
Protocol C3421015

CLINICAL STUDY REPORT SYNOPSIS
Sponsor: Pfizer, Inc
Investigational Product: Danuglipron (PF-06882961)
Clinical Study Report Synopsis: Protocol C3421015
Protocol Title: An 8-Week Phase 1, Randomized, Double-Blind, Sponsor-Open,
Placebo-Controlled, Parallel-Group Study to Evaluate the Safety, Tolerability,
Pharmacokinetics, and Pharmacodynamics of Twice Daily PF-06882961 Administration in
Japanese Adults With Type 2 Diabetes Mellitus
Investigators: Refer to Appendix 16.1.4.1 for a list of investigators involved in this study.
Study Centers: This study was conducted at 1 center in Japan. Refer to Appendix 16.1.4.1
for the details of site involved in this study.
Publications Based on the Study: None.
Study Initiation Date: 26 October 2020
Study Completion Date: 25 March 2021
Report Date: 12 November 2021
Previous Report Dates: Not Applicable.
Phase of Development: Phase 1
Primary and Secondary Study Objectives and Endpoints: The study objectives andendpoints are presented in Table S1.

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Table S1. Study Objectives and Endpoints
Types
Primary
SafetyObjectives

Endpoints

To evaluate the safety and tolerability ofmultiple, oral doses of danuglipron,
administered to adult Japanese participants
with T2DM

Incidence of treatment-emergent AEs (AEsand SAEs), clinical laboratory abnormalities,
vital signs, and ECG parameters during theentire study

SecondaryPK

To characterize plasma PK of danuglipron Danuglipron plasma PK parameters AUC24,
following Day 1 and following multiple,
Cmax, Tmax, t½ (as appropriate for the dosing
oral doses administered to adult Japaneseparadigm) following Day 1, and multiple doseparticipants with T2DM
administration, as data permitted
Abbreviations: AE=adverse event; AUC24=area under the plasma concentration-time profile from time 0
to 24 hours; Cmax=maximum plasma concentration observed from time 0 to 24 hours;
ECG=electrocardiogram; PK=pharmacokinetic; SAE=serious adverse event; t½=terminal half-life;
T2DM=Type 2 diabetes mellitus; Tmax=time for Cmax.

METHODS
Study Design: This was a Phase 1, randomized, double-blind (sponsor-open),placebo-controlled, 4-arm, parallel-group study of danuglipron in adult Japanese participants
with Type 2 diabetes mellitus (T2DM) inadequately controlled on diet and exercise alone.
The purpose of this study was to evaluate the safety, tolerability, and pharmacokinetic (PK)of multiple oral doses of danuglipron in adult Japanese participants with T2DM, who were
not receiving any background anti-hyperglycemic medication.
Participants received oral doses of danuglipron or placebo in this study. Approximately
9 participants were planned to be enrolled in each arm, for a total of 36 (4 arms) participants
to be randomized. The randomization ratio was 1:1:1:1 (1 of 3 active dosing regimens ofdanuglipron or placebo), and all 4 arms were enrolled in parallel. The study was conducted
at a single clinical site in Japan.
Target dose levels, achieved after completion of titration, for the 4 arms of the study wereplacebo and danuglipron doses of 40 mg twice a day (BID), 80 mg BID, and 120 mg BID.
Dose titration was incorporated to enhance tolerability to danuglipron. The titration wasplanned to start at danuglipron 10 mg BID (or matching placebo), then with increase in dose
every week to reach the targeted dose level of 40 mg BID at the start of Week 3 fordanuglipron 40, 80, and 120 mg BID dose groups, to reach the targeted dose level of 80 mg
BID at the start of Week 5 for danuglipron 80 and 120 mg BID dose groups, and to reach thetargeted dose level of 120 mg BID at the start of Week 7 for danuglipron 120 mg BID dosegroup. The maximum dose of danuglipron in this study did not exceed 120 mg BID.
Following the screening period to confirm eligibility (up to 4 weeks), the treatment period
was for approximately 8 weeks, followed by an approximate 4-week follow-up. The total
duration of participation in this study was approximately 12 weeks, after the screening
period. Dosing occurred with food BID, and up to 2 weeks (for target dose level:
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40 mg BID), 4 weeks (for target dose level: 80 mg BID) or 6 weeks (for target dose level:
120 mg BID) of the 8-week dosing duration was used for dose titration to maximize
tolerability of danuglipron.
Diagnosis and Main Criteria for Inclusion: Male and female participants of 20 to 70 yearsof age, inclusive, at the time of signing the informed consent document; with body massindex (BMI) of 22.5 to 45.4 kg/m2 and a total body weight >50 kg (110 lb) that had beenstable (<5% change) for 90 days prior to screening (Visit 1); hemoglobin A1c (HbA1c) ≥7%
and ≤10.5% at screening; who were being treated with diet and exercise but were not taking
antidiabetic medications for T2DM were included in the study.
Participants with evidence or history of clinically significant hematological, renal, endocrine,
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic
disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies
at the time of dosing), had a history of myocardial infarction, unstable angina, arterial
revascularization, stroke, New York Heart Association Functional Class II - IV heart failure,or transient ischemic attack within 6 months of screening, who had a diagnosis of type 1
diabetes mellitus or secondary forms of diabetes, or a history of ketoacidosis, had a personalor family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia
syndrome Type 2, or participants with suspected MTC per the investigator’s judgment, or
had a known intolerance or hypersensitivity to glucagon-like peptide-1 receptor (GLP-1R)
agonists, fasting blood glucose >270 mg/dL (15.0 mmol/L) at screening, or fingerstick blood
glucose on Day -2 of >270 mg/dL (15.0 mmol/L) were excluded from the study.
Study Treatment:
Danuglipron 10 mg, 40 mg, and 100 mg and matching placebo tablets were supplied
centrally by the sponsor to the site as packaged blister cards.
Participants took 3 tablets of danuglipron or matching placebo in the morning at
approximately 0800 hours with food and 3 tablets in the evening at approximately
1800 hours with food, approximately 10-12 hours apart and at approximately the same timeeach day. Participants took a total of 6 tablets of danuglipron or matching placebo daily.
The treatment period was for approximately 8 weeks.
Participants swallowed the study drug whole, and did not crush, chew, break, or dissolve thestudy drug prior to swallowing. Downward titration or dosing was not permitted during thestudy; participants who could not tolerate the titration scheme and/or assigned dose wererequired to discontinue dosing of the study drug.
Investigational product description is provided in Table S2.

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

Vendor Lot
NumberN/A
N/A
N/A

Pfizer Lot
Number18-003389
18-003390
18-003391

PF-06882961-82 10 mg oval white to off-white tablet
PF-06882961-82 40 mg oval white to off-white tablet
PF-06882961-82 100 mg oval white to off-whitetabletPlacebo oval tablet (2:1, MCC:lactose)
B1905319-002564
Abbreviations: MCC=microcrystalline cellulose; N/A=not applicable.

Strength/Potency
10 mg
40 mg
100 mgDosageForm
TabletTabletTablet0 mg

TabletEfficacy Evaluations: Not Applicable.
Pharmacokinetic Evaluations:
Blood samples of approximately 3 mL, to provide a minimum of 1 mL of plasma, werecollected into appropriately labeled tubes containing dipotassium ethylenediaminetetraacetic
acid for measurement of plasma concentrations of danuglipron at the following time points:
Day 1 (0 hour [predose] and at 1, 2, 4, 6, 8, 10, 12, and 14 hours [postdose]), Day 2 (24 hours
after AM dose on Day 1), Days 15, 29, and 43 (prior to AM dose and at 4 hours after AMdose), Day 50 (24 hours after AM dose on Day 49), Day 55 and Day 56 (0 hour [predose]and at 1, 2, 4, 6, 8, 10, 12, and 14 hours [postdose]), Day 57 (24 hours and 36 hours after AM
dose on Day 56), Day 58 (48 hours after AM dose on Day 56), and at early termination visit.
Samples collected for measurement of plasma concentrations of danuglipron were analyzed
using a validated analytical method.
The following danuglipron PK parameters: area under the plasma concentration-time profile
from time 0 to 24 hours (AUC24), maximum plasma concentration observed from time 0 to
24 hours (Cmax), time for Cmax (Tmax), and terminal half-life (t½) following Day 1, andmultiple dose administration, were calculated for each participant and treatment, using
non-compartmental analysis of plasma concentration-time data.
Safety Evaluations:
Safety assessments consisted of the collection of adverse events (AEs), serious adverse
events (SAEs), clinical laboratory abnormalities, vital signs (blood pressure [BP] and pulserate), and electrocardiogram (ECG) monitoring.
Safety was monitored at regular intervals throughout the study.
Statistical Methods:
Pharmacokinetic Analysis
The danuglipron PK concentration population was defined as all participants randomly
assigned to the study drug who took at least 1 dose of danuglipron and in whom at least
1 plasma PK concentration value of danuglipron was reported.
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The danuglipron PK parameter analysis population was defined as all participants randomly
assigned to the study drug who took at least 1 dose of danuglipron and who had at least 1 of
the PK parameters of interest for danuglipron calculated.
PK samples from placebo group were not analyzed.
The PK parameters (AUC24, Cmax, Tmax and t½) were summarized descriptively by treatment,dose and day (Day 1 and Day 56) for subjects in the PK parameter analysis set. Actual PK
sampling times were used in the derivation of PK parameters.
SafetyThe safety analysis set included all participants randomly assigned to study drug who took atleast 1 dose of study drug. Participants were analyzed according to the product they actually
received.
Safety data were summarized descriptively and reported in accordance with the sponsor
reporting standards.
RESULTS
Subject Disposition and Demography:
Of 65 participants screened for entry into the study, 37 participants were randomized andassigned to receive the study drug. Ten participants received danuglipron 40 mg BID and
9 participants each received danuglipron 80 mg BID, danuglipron 120 mg BID, or placebo.
All 37 randomized participants were included in the safety analysis set. All 28 participants
treated with danuglipron (in active treatment groups) were included in the PK concentration
and PK parameter analyses sets.
Of the 37 randomized participants, 8 participants discontinued the study drug and29 participants completed the dosing regimen. The disposition events summary is presented
in Table S3.
Of the 8 participants who discontinued the study drug, 6 participants (2, 3, and 1 participant
in danuglipron 40, 80, and 120 mg BID groups, respectively) permanently discontinued fromthe study drug due to treatment-emergent adverse events (TEAEs). One participant inplacebo group discontinued the study drug due to ‘lack of efficacy’. One participant indanuglipron 40 mg BID group discontinued the study drug as the participant no longer met
eligibility criteria.
Demographic characteristics were generally comparable across the treatment groups. The
37 treated participants consisted of 32 males (86.5%) and 5 females (13.5%). All
37 participants were Asian and Not Hispanic or Latino. The mean age of all participants was
55.8 years (range: 34 to 70 years).

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The mean weight and BMI were greater for all danuglipron dose groups compared toplacebo. The mean weight for all participants was 78.6 kg (range: 58.9 to 102.6 kg), and themean weight varied across treatment groups ranging from 73.3 kg to 81.5 kg. The mean
BMI for all participants was 27.8 kg/m2 (range: 22.9 to 36.8 kg/m2), and the mean BMI
varied across treatment groups ranging from 25.9 kg/m2 to 28.6 kg/m2.
The mean duration of diabetes for all participants was 5.748 years(range: 0.19 to 20.45 years). The mean duration of diabetes varied widely across treatmentgroups, ranging from 2.926 years to 9.107 years.

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Table S3. Disposition Events Summary - Safety Analysis Set (Protocol C3421015)
Placebo(N=9)

PF-06882961
40mg(N=10)

PF-06882961
80mg
(N=9)

PF-06882961 120mg
(N=9)

n (%)

n (%)

n (%)

n (%)

9
(100.0)10 (100.0)

9 (100.0)

9 (100.0)

0

0

0

0

Adverse Event

0

0

0

0

Lack of Efficacy

0

0

0

0

0

0

0

0

1 (11.1)

3 (30.0)

3 (33.3)

1 (11.1)

Adverse Event0

2 (20.0)

3 (33.3)

1 (11.1)

Lack of Efficacy

1 (11.1)

0

0

0

0

1 (10.0)00

8 (88.9)

7 (70.0)

6 (66.7)

8 (88.9)9(100.0)10 (100.0)

9 (100.0)

9 (100.0)

0

0

0

0

Adverse Event

0

0

0

0

Lack of Efficacy

0

0

0

0

0

0

0

0

9
(100.0)10 (100.0)

9 (100.0)

9 (100.0)

Number (%) of Subjects

Disposition phase: Blinded Treatment
Subjects Entered:
Discontinued from Study
Reason for discontinuation

No Longer Meets Eligibility
Criteria
Discontinued from Study Intervention
Reason for discontinuation

No Longer Meets Eligibility
Criteria
Completed
Disposition phase: Follow-Up
Subjects Entered:
Discontinued from Study
Reason for discontinuation

No Longer Meets Eligibility
Criteria
Completed

PFIZER CONFIDENTIAL SDTM Creation: 28APR2021 (01:41) Source Data: adds Table Generation: 09JUN2021(11:47)(Snapshot date : 19APR2021) Output File: ./csr6/C3421015/adds_s001
Table 14.1.1.2.2 PF-06882961 is for Pfizer internal use.

Efficacy Results: There were no efficacy evaluations done in this study.

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Pharmacokinetic Results:
Danuglipron Pharmacokinetics
Following single and multiple dosing of danuglipron in adult Japanese participants with
T2DM starting at a 10 mg BID dose on Day 1 and titrating up to 40 mg, 80 mg, and 120 mg
BID doses on Day 56, maximum plasma concentrations (Cmax, maximum plasma
concentration during the dosing interval tau1 [0 to 10 hours] [Cmax1] and maximum plasma
concentration during the dosing interval tau2 [10 to 24 hours] [Cmax2]) were observed within
a median Tmax, time for Cmax1 (Tmax1) and time for Cmax2 (Tmax2) of approximately 2 hours to
6 hours post each dose administered on Day 56.
Following multiple dosing, exposure appeared to increase in a dose-proportional manner for
doses titrated up to 40 mg, 80 mg, and 120 mg BID, with dose-proportional increases ingeometric mean AUC24, area under the plasma concentration-time profile from time 0 to time
tau1 (0 to 10 hours) (AUCtau1), area under the plasma concentration-time profile from time 0
to time tau2 (10 to 24 hours) (AUCtau2), Cmax, Cmax1 and Cmax2 values.
Lower median danuglipron concentrations were observed for the 120 mg BID dose groupcompared to the 80 mg BID dose group at the 24, 36, and 48 hours postdose on Day 56; thehigh inter-participant variability at these time points and the small number of participants percohort most likely contributed to this observation.
Mean t½ ranged from 5.300 hours to 6.373 hours across the doses administered.
Inter-participant variability for danuglipron exposure was based on geometric mean AUC24
and Cmax values, with percent coefficient of variation (%CV) values ranging between 58% to
73% for AUC24, 52% to 80% for Cmax, and 43% to 87% for Cmax1 on Day 1; and 45% to148% for AUC24, 54% to 153% for Cmax, and 51% to 153% for Cmax1 on Day 56 across alldose groups. The 120 mg BID dose group had the largest variability in exposure on Day 56,
with geometric %CVs of 148% for AUC24 and 153% for Cmax and Cmax1.
Safety Results:
Adverse Events
Incidence of all-causalities and treatment-related TEAEs are presented by system organ class(SOC) and preferred term (PT) in Table S4 and Table S5, respectively.
A total of 70 all-causalities TEAEs were reported by 28 participants (75.7%) in the study, of
which 54 (54/70: 77.14%) TEAEs reported by 24 participants (64.9%) were consideredtreatment-related. The number of participants with AEs (both all-causalities andtreatment-related) were observed to be higher in the active treatment groups compared withthe placebo group.

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The most frequently reported (in ≥10% of participants) all-causalities TEAEs by SOC were
Gastrointestinal Disorders (67.6%) and Nervous System Disorders (13.5%). The mostfrequently reported (in ≥10% of participants) treatment-related TEAE by SOC was
Gastrointestinal Disorders (64.9%).
The most frequently reported (in ≥10% of participants) all-causalities TEAEs by PT were
nausea (48.6%), vomiting (43.2%), abdominal discomfort (35.1%), diarrhea (10.8%), andheadache (10.8%). All TEAEs of nausea (48.6%), vomiting (43.2%), abdominal
discomfort (35.1%), and diarrhea (10.8%) were considered as treatment-related in all dosegroups. The incidence of all-causalities TEAEs in the Gastrointestinal Disorders SOC ineach danuglipron dose groups were higher than the incidence in the placebo group (11.1%).
All but one of all-causalities TEAEs were mild or moderate in severity. One TEAE wasreported as severe and was not considered treatment-related.

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Table S4. Treatment-Emergent Adverse Events by System Organ Class and Preferred Term (All Causalities) - Safety
Analysis Set (Protocol C3421015)
Number of Subjects Evaluable for AEs

Placebo(N=9)

PF-06882961 40mg
(N=10)

PF-06882961 80mg
(N=9)

PF-06882961 120mg
(N=9)

Total
(N=37)

Number (%) of Subjects:
by SYSTEM ORGAN CLASS
and Preferred Term

n (%)

n (%)

n (%)

n (%)

n (%)

With Any adverse event

3 (33.3)

7 (70.0)

9 (100.0)

9 (100.0)

28 (75.7)

GASTROINTESTINAL DISORDERS

1 (11.1)

7 (70.0)

9 (100)8 (88.9)25 (67.6)

04 (40.0)

4 (44.4)

5 (55.6)

13 (35.1)

Abdominal discomfort
Abdominal pain upper00

1 (11.1)0

1 (2.7)

Dental caries

1 (11.1)

00

1 (11.1)

2 (5.4)

Diarrhoea0

1 (10.0)

2 (22.2)

1 (11.1)

4 (10.8)

Nausea0

6 (60.0)

8 (88.9)

4 (44.4)

18 (48.6)

Stomatitis

00

1 (11.1)0

1 (2.7)

Vomiting

0

5 (50.0)

6 (66.7)

5 (55.6)

16 (43.2)

02 (20.0)0

1 (11.1)

3 (8.1)

Gastroenteritis

0

1 (10.0)00

1 (2.7)

Hordeolum0

1 (10.0)00

1 (2.7)

INFECTIONS AND INFESTATIONS

Influenza000

1 (11.1)

1 (2.7)

1 (11.1)

1 (10.0)00

2 (5.4)

Alanine aminotransferase increased0

1 (10.0)00

1 (2.7)

Aspartate aminotransferase increased0

1 (10.0)00

1 (2.7)INVESTIGATIONS

Lipase increased
METABOLISM AND NUTRITION DISORDERS
Decreased appetite

1 (11.1)000

1 (2.7)0

1 (10.0)

1 (11.1)

1 (11.1)

3 (8.1)00

1 (11.1)

1 (11.1)

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Table S4. Treatment-Emergent Adverse Events by System Organ Class and Preferred Term (All Causalities) - Safety
Analysis Set (Protocol C3421015)
Number of Subjects Evaluable for AEs
Number (%) of Subjects:
by SYSTEM ORGAN CLASS
and Preferred Term
Hypoglycaemia

Placebo(N=9)

PF-06882961 40mg
(N=10)

PF-06882961 80mg
(N=9)

PF-06882961 120mg
(N=9)

Total
(N=37)

n (%)

n (%)

n (%)

n (%)

n (%)

0

1 (10.0)00

1 (2.7)

1 (11.1)

2 (20.0)

1 (11.1)

1 (11.1)

5 (13.5)

Headache1 (11.1)

2 (20.0)

1 (11.1)

0

4 (10.8)

Presyncope

0

0

0

1 (11.1)

1 (2.7)00

1 (11.1)0

1 (2.7)00

1 (11.1)0

1 (2.7)NERVOUS SYSTEM DISORDERS

SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Dermatitis psoriasiform

Subjects are only counted once per treatment per event.
Totals for the No. of Subjects at a higher level are not necessarily the sum of those at the lower levels since a subject may report two or more different adverse events within thehigher level category.
Includes data up to lag days after last dose of study drug.
MedDRA v23.1 coding dictionary applied.
PFIZER CONFIDENTIAL SDTM Creation: 28APR2021 (05:21) Source Data: adae Table Generation: 09JUN2021 (11:47)(Snapshot date : 19APR2021) Output File: ./csr6/C3421015/adae_s0311
Table 14.3.1.2.4 PF-06882961 is for Pfizer internal use.

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Table S5. Treatment-Emergent Adverse Events by System Organ Class andPreferred Term (Treatment Related) - Safety Analysis Set (Protocol
C3421015)
Number of Subjects Evaluable for AEs Placebo(N=9)

PF-06882961
40mg(N=10)

PF-06882961
80mg
(N=9)

PF-06882961
120mg
(N=9)

Total
(N=37)

n (%)

n (%)

n (%)

n (%)

n (%)

With Any adverse event0

7 (70.0)

9 (100.0)

8 (88.9)24 (64.9)

GASTROINTESTINAL DISORDERS

Number (%) of Subjects:
by SYSTEM ORGAN CLASS
and Preferred Term

0

7 (70.0)

9 (100)8 (88.9)24 (64.9)

Abdominal discomfort

0

4 (40.0)

4 (44.4)

5 (55.6)

13 (35.1)

Diarrhoea0

1 (10.0)

2 (22.2)

1 (11.1)

4 (10.8)

Nausea0

6 (60.0)

8 (88.9)

4 (44.4)

18 (48.6)

Vomiting

0

5 (50.0)

6 (66.7)

5 (55.6)

16 (43.2)

0

1 (10.0)

1 (11.1)

1 (11.1)

3 (8.1)METABOLISM AND NUTRITIONDISORDERS
Decreased appetite00

1 (11.1)

1 (11.1)

2 (5.4)

Hypoglycaemia

0

1 (10.0)00

1 (2.7)

Subjects are only counted once per treatment per event.
Totals for the No. of Subjects at a higher level are not necessarily the sum of those at the lower levels since a subject mayreport two or more different adverse events within the higher level category.
Includes data up to lag days after last dose of study drug.
MedDRA v23.1 coding dictionary applied.
PFIZER CONFIDENTIAL SDTM Creation: 28APR2021 (05:21) Source Data: adae Table Generation: 09JUN2021(11:47)(Snapshot date : 19APR2021) Output File: ./csr6/C3421015/adae_s0311_1
Table 14.3.1.3.4 PF-06882961 is for Pfizer internal use.

There were no deaths, SAEs, or permanent discontinuations from the study due to TEAEs
reported in the study.
A total of 5 participants (13.5%) reported medication error events; none of which wereassociated with any AEs.
One participant (2.7%) experienced 1 severe TEAE of alanine aminotransferase increased(ALT) increased in the treatment period, which resolved on Day 36, and was not consideredtreatment-related; the study drug was temporarily interrupted due to this TEAE.
A total of 6 participants (16.2%) permanently discontinued from the study drug due to
TEAEs and were moved to the early termination visit after discontinuation; subsequently
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followed by, Follow-up Visit 1 and Follow-up Visit 2. All 6 participants discontinued due totreatment-related TEAEs of abdominal discomfort, nausea, and vomiting (2 participants[5.4%] each). All except 1 TEAE of abdominal discomfort were moderate in severity while
1 TEAE of abdominal discomfort was mild in severity. The outcome of all 6 TEAEs, which
resulted in discontinuations from study drug was reported as resolved.
Two participants (5.4%) temporarily discontinued the study drug due to TEAEs, of which
1 participant in 80 mg BID group discontinued the study drug due to treatment-related TEAE
of nausea and another participant in 40 mg BID group discontinued the study drug due to
TEAEs of ALT increased and aspartate aminotransferase increased (AST) increased, whichwere not considered to be treatment-related. The TEAEs of nausea and AST increased weremoderate in severity and the TEAE of ALT increased was severe. The outcome of all
3 TEAEs that resulted in temporary discontinuation of the study drug was reported as
resolved.
Hypoglycemic Adverse Events
One participant in the 40 mg BID dose group experienced a probable symptomatic
hypoglycemia (as the blood glucose was not measured) of mild severity, which wasconsidered treatment-related. The participant had symptoms of dizziness, light headedness,and sweats, but required no assistance; and the symptoms resolved on the same day of onset
when the participant was treated with oral carbohydrates.
Clinical Laboratory Evaluation
Without regard to baseline abnormality, 36 (97.3%) of the 37 participants evaluable forlaboratory tests experienced laboratory abnormalities. Overall, the most common laboratory
abnormality (in ≥50% of participants), without regard to baseline abnormality included,
glucose (mmol/L) >1.5 × ULN (24 [64.9%] participants),
urine glucose ≥1 (21 [56.8%] participants), triglycerides (mmol/L) >1.3 × upper limit of
normal (ULN) (20 [54.1%] participants), urine protein ≥1 (20 [54.1%] participants), granular
casts >1 (2 [100.0%] participants), and hyaline casts >1 (2 [100.0%] participants). Of note,the glucose values were included for fasting status only at scheduled visits. There were noapparent dose-related increases in the incidence of laboratory test abnormalities.
Vital Signs
Two participants met pre-specified criteria for categorical analysis of supine systolic BP
decrease ≥30 mm Hg, with 1 participant in the placebo group and 1 participant in thedanuglipron 120 mg BID group meeting this criterion. Ten participants met the pre-specified
criteria for categorical analysis of supine systolic BP increase ≥30 mm Hg, with
3 participants each in the placebo and danuglipron 80 mg BID dose groups and 2 participants
each in the 40 mg and 120 mg BID dose groups. Nine participants met the pre-specified
criteria for categorical analysis of supine diastolic BP increase ≥20 mm Hg, with
1 participant in the placebo group, 2 participants in the 40 mg BID group and 3 participants
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each in the 80 mg BID and 120 mg BID dose groups. None of the participants met the
pre-specified criteria for pulse rate with values of <40 bpm or >120 bpm.
On Day 1, there was increases in the mean time-matched double differences in systolic BP
over the course of the day for all the danuglipron BID dose groups, compared with placebo.
However, on Day 56, danuglipron 40 mg BID dose group had a decrease in meantime-matched double differences in systolic BP similar to placebo, while the danuglipron
80 mg and 120 mg BID dose groups had a trend for increases in time-matched double
differences in systolic BP over the course of the day. Mean systolic BP values for all dosegroups were generally in the normal range.
On Day 1, there was a trend for increases in the mean time-matched double differences indiastolic BP over the course of the day for all the danuglipron BID dose groups, comparedwith placebo. However, on Day 56, danuglipron 40 mg BID dose group had a decrease indiastolic BP similar to placebo, while the danuglipron 80 mg and 120 mg BID dose groups
had a trend for increases in time-matched double differences in diastolic BP over the courseof the day. Mean diastolic BP values for all dose groups were generally in the normal range.
On Day 1, mean time-matched double differences in pulse rate was similar for thedanuglipron BID dose groups, compared with placebo. However, on Day 56, all danuglipron
BID dose groups had a trend for increases in mean time-matched double differences in pulse
rate compared to placebo, over the course of the day. Also, the increase was greater indanuglipron 120 mg BID dose group compared with other groups. Mean pulse rate values
for all dose groups were generally in the normal range.
Electrocardiogram
A total of 3 (8.1%) participants reported post-baseline ECG data meeting pre-specified
categorical analysis criteria of corrected QT using Fridericia’s formula (QTcF) interval
450 and ≤480 msec, of which 1 (11.1%) participant each were in the placebo, danuglipron
80 mg, and danuglipron 120 mg groups. No data met the criteria of PR interval ≥300 msec
or QRS duration ≥140 msec. There were no apparent dose-related increases in the frequency
of ECG abnormalities by categorical analysis.
No apparent clinically adverse trends were noted for PR, QRS, QT, and QTcF intervals. The
mean time-matched double differences in ECG heart rate for the danuglipron 120 mg BID
dose group on Day 56 was higher than the placebo and danuglipron 40 mg and 80 mg dosegroups.

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Protocol C3421015

CLINICAL STUDY REPORT SYNOPSIS
Conclusions:
Safety

Ascending, multiple, oral doses of danuglipron were generally safe in adult Japaneseparticipants with T2DM. The most commonly reported all-causalities TEAEs were
nausea, vomiting, abdominal discomfort, diarrhea, and headache.



There were no apparent dose-related increases in the frequency of laboratory, vital
sign or ECG abnormalities by categorical analysis. A trend for increases intime-matched double differences in systolic and diastolic BP was observed on Day 56
with danuglipron doses of 80 mg and 120 mg BID, relative to placebo anddanuglipron 40 mg BID, with mean systolic and diastolic BP values in the normal
range.



Only 1 hypoglycemic adverse event of mild severity was reported as a probable
symptomatic hypoglycemia in the danuglipron 40 mg BID dose group.



Dose-proportional increases in danuglipron geometric mean AUC24, AUCtau1,
AUCtau2, Cmax, Cmax1 and Cmax2 values were observed on Day 56 following titration
up to 40, 80, or 120 mg BID.



Peak concentrations (Cmax, Cmax1 and Cmax2) were observed within a median Tmax,Tmax1
and Tmax2 of approximately 2 hours to 6 hours post each dose administered.

Mean t½ ranged from 5.300 hours to 6.373 hours across the doses administered.

PK

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