A Study of Ponsegromab in People With Heart Failure

Change From Baseline in KCCQ-23 CSS at Week 22: Cohort A

KCCQ is a self-reported 23-item questionnaire that assessed HRQL in participants with HF over the past 2 weeks. KCCQ quantifies 7 domains: physical limitations (6 items), symptom stability (1 item), symptom frequency (4 items), symptom burden (3 items), self-efficacy (2 items), quality of life (3 items) and social limitations (4 items). Scores were generated for each domain and scaled from 0 (worst status) to 100 (best possible status). KCCQ TSS: mean of domains- symptom frequency and symptom burden; and was transformed to a single score which ranged from 0 (worst) to 100 (best possible status). KCCQ-23-CSS: mean of the TSS and physical limitation domain score; and was transformed to a single score which ranged from 0 (worst) to 100 (best possible status), where higher KCCQ-23-CSS signified better health status.

Time frame: Baseline [the last measurement on study Day 1], Week 22

Change From Baseline in KCCQ-23-Overall Summary Score (OSS) at Week 22: Cohort A, Ponsegromab 300 mg Versus Placebo

KCCQ is a self-reported 23-item questionnaire that assessed HRQL in participants with HF over the past 2 weeks. KCCQ quantifies 7 domains: physical limitations (6 items), symptom stability (1 item), symptom frequency (4 items), symptom burden (3 items), self-efficacy (2 items), quality of life (3 items) and social limitations (4 items). Scores were generated for each domain and scaled from 0 (worst status) to 100 (best possible status). KCCQ-23-OSS: mean of domain scores- physical limitation, quality of life, social limitation and TSS (mean of symptom frequency and symptom burden); and was transformed to a single score which ranged from 0 (worst) to 100 (best possible status), where higher KCCQ-23-OSS signified better health status.

Time frame: Baseline [the last measurement on study Day 1], Week 22

Change From Baseline in KCCQ-23 OSS at Week 22: Cohort A

KCCQ is a self-reported 23-item questionnaire that assessed HRQL in participants with HF over the past 2 weeks. KCCQ quantifies 7 domains: physical limitations (6 items), symptom stability (1 item), symptom frequency (4 items), symptom burden (3 items), self-efficacy (2 items), quality of life (3 items) and social limitations (4 items). Scores were generated for each domain and scaled from 0 (worst status) to 100 (best possible status). KCCQ-23-OSS: mean of domain scores- physical limitation, quality of life, social limitation and TSS (mean of symptom frequency and symptom burden); and was transformed to a single score which ranged from 0 (worst) to 100 (best possible status), where higher KCCQ-23-OSS signified better health status.

Time frame: Baseline [the last measurement on study Day 1], Week 22

Change From Baseline in KCCQ-23-TSS at Week 22: Cohort A, Ponsegromab 300 mg Versus Placebo

KCCQ is a self-reported 23-item questionnaire that assessed HRQL in participants with HF over the past 2 weeks. KCCQ quantifies 7 domains: physical limitations (6 items), symptom stability (1 item), symptom frequency (4 items), symptom burden (3 items), self-efficacy (2 items), quality of life (3 items) and social limitations (4 items). Scores were generated for each domain and scaled from 0 (worst status) to 100 (best possible status). KCCQ-23-TSS: mean of domains- symptom frequency and symptom burden; and was transformed to a single score which ranged from 0 (worst) to 100 (best possible status), where higher KCCQ-23-TSS signified better health status.

Time frame: Baseline [the last measurement on study Day 1], Week 22

Change From Baseline in KCCQ-23 TSS at Week 22: Cohort A

KCCQ is a self-reported 23-item questionnaire that assessed HRQL in participants with HF over the past 2 weeks. KCCQ quantifies 7 domains: physical limitations (6 items), symptom stability (1 item), symptom frequency (4 items), symptom burden (3 items), self-efficacy (2 items), quality of life (3 items) and social limitations (4 items). Scores were generated for each domain and scaled from 0 (worst status) to 100 (best possible status). KCCQ-23-TSS: mean of domains- symptom frequency and symptom burden; and was transformed to a single score which ranged from 0 (worst) to 100 (best possible status), where higher KCCQ-23-TSS signified better health status.

Time frame: Baseline [the last measurement on study Day 1], Week 22

Change From Baseline in KCCQ-23 Physical Limitation Score at Week 22: Cohort A, Ponsegromab 300 mg Versus Placebo

KCCQ is a self-reported 23-item questionnaire that assessed HRQL in participants with HF over the past 2 weeks. KCCQ quantifies 7 domains: physical limitations (6 items), symptom stability (1 item), symptom frequency (4 items), symptom burden (3 items), self-efficacy (2 items), quality of life (3 items) and social limitations (4 items). Scores were generated for each domain and scaled from 0 (worst status) to 100 (best possible status). KCCQ-23 physical limitation score scaled from 0 (worst status) to 100 (best possible status), where higher scores signified better health status.

Time frame: Baseline [the last measurement on study Day 1], Week 22

Change From Baseline in KCCQ-23 Physical Limitation Score at Week 22: Cohort A

KCCQ is a self-reported 23-item questionnaire that assessed HRQL in participants with HF over the past 2 weeks. KCCQ quantifies 7 domains: physical limitations (6 items), symptom stability (1 item), symptom frequency (4 items), symptom burden (3 items), self-efficacy (2 items), quality of life (3 items) and social limitations (4 items). Scores were generated for each domain and scaled from 0 (worst status) to 100 (best possible status). KCCQ-23 physical limitation score scaled from 0 (worst status) to 100 (best possible status), where higher scores signified better health status.

Time frame: Baseline [the last measurement on study Day 1], Week 22

Percentage of Participants With >= 5-Point Increase From Baseline in KCCQ-23-CSS at Week 22: Cohort A, Ponsegromab 300 mg Versus Placebo

KCCQ is a self-reported 23-item questionnaire that assessed HRQL in participants with HF over the past 2 weeks. KCCQ quantifies 7 domains: physical limitations (6 items), symptom stability (1 item), symptom frequency (4 items), symptom burden (3 items), self-efficacy (2 items), quality of life (3 items) and social limitations (4 items). Scores were generated for each domain and scaled from 0 (worst status) to 100 (best possible status). KCCQ TSS: mean of domains- symptom frequency and symptom burden; and was transformed to a single score which ranged from 0 (worst) to 100 (best possible status). KCCQ-23-CSS: mean of the TSS and physical limitation domain score; and was transformed to a single score which ranged from 0 (worst) to 100 (best possible status), where higher KCCQ-23-CSS signified better health status.

Time frame: Week 22

Percentage of Participants With >= 5-Point Increase From Baseline in KCCQ-23 CSS Score at Week 22: Cohort A

KCCQ is a self-reported 23-item questionnaire that assessed HRQL in participants with HF over the past 2 weeks. KCCQ quantifies 7 domains: physical limitations (6 items), symptom stability (1 item), symptom frequency (4 items), symptom burden (3 items), self-efficacy (2 items), quality of life (3 items) and social limitations (4 items). Scores were generated for each domain and scaled from 0 (worst status) to 100 (best possible status). KCCQ TSS: mean of domains- symptom frequency and symptom burden; and was transformed to a single score which ranged from 0 (worst) to 100 (best possible status). KCCQ-23-CSS: mean of the TSS and physical limitation domain score; and was transformed to a single score which ranged from 0 (worst) to 100 (best possible status), where higher KCCQ-23-CSS signified better health status.

Time frame: Week 22

Percentage of Participants With >= 5-Point Increase From Baseline in KCCQ-23 OSS Score at Week 22: Cohort A, Ponsegromab 300 mg Versus Placebo

KCCQ is a self-reported 23-item questionnaire that assessed HRQL in participants with HF over the past 2 weeks. KCCQ quantifies 7 domains: physical limitations (6 items), symptom stability (1 item), symptom frequency (4 items), symptom burden (3 items), self-efficacy (2 items), quality of life (3 items) and social limitations (4 items). Scores were generated for each domain and scaled from 0 (worst status) to 100 (best possible status). KCCQ-23-OSS: mean of domain scores- physical limitation, quality of life, social limitation and TSS (mean of symptom frequency and symptom burden); and was transformed to a single score which ranged from 0 (worst) to 100 (best possible status), where higher KCCQ-23-OSS signified better health status.

Time frame: Week 22

Percentage of Participants With >= 5-Point Increase From Baseline in KCCQ-23 OSS Score at Week 22: Cohort A

KCCQ is a self-reported 23-item questionnaire that assessed HRQL in participants with HF over the past 2 weeks. KCCQ quantifies 7 domains: physical limitations (6 items), symptom stability (1 item), symptom frequency (4 items), symptom burden (3 items), self-efficacy (2 items), quality of life (3 items) and social limitations (4 items). Scores were generated for each domain and scaled from 0 (worst status) to 100 (best possible status). KCCQ-23-OSS: mean of domain scores- physical limitation, quality of life, social limitation and TSS (mean of symptom frequency and symptom burden); and was transformed to a single score which ranged from 0 (worst) to 100 (best possible status), where higher KCCQ-23-OSS signified better health status.

Time frame: Week 22

Percentage of Participants With >= 5-Point Increase From Baseline in KCCQ-23 TSS Score at Week 22: Cohort A, Ponsegromab 300 mg Versus Placebo

KCCQ is a self-reported 23-item questionnaire that assessed HRQL in participants with HF over the past 2 weeks. KCCQ quantifies 7 domains: physical limitations (6 items), symptom stability (1 item), symptom frequency (4 items), symptom burden (3 items), self-efficacy (2 items), quality of life (3 items) and social limitations (4 items). Scores were generated for each domain and scaled from 0 (worst status) to 100 (best possible status). KCCQ-23-TSS: mean of domains- symptom frequency and symptom burden; and was transformed to a single score which ranged from 0 (worst) to 100 (best possible status), where higher KCCQ-23-TSS signified better health status.

Time frame: Week 22

Percentage of Participants With >= 5-Point Increase From Baseline in KCCQ-23 TSS Score at Week 22: Cohort A

KCCQ is a self-reported 23-item questionnaire that assessed HRQL in participants with HF over the past 2 weeks. KCCQ quantifies 7 domains: physical limitations (6 items), symptom stability (1 item), symptom frequency (4 items), symptom burden (3 items), self-efficacy (2 items), quality of life (3 items) and social limitations (4 items). Scores were generated for each domain and scaled from 0 (worst status) to 100 (best possible status). KCCQ-23-TSS: mean of domains- symptom frequency and symptom burden; and was transformed to a single score which ranged from 0 (worst) to 100 (best possible status), where higher KCCQ-23-TSS signified better health status.

Time frame: Week 22

Percentage of Participants With >= 5-Point Increase From Baseline in KCCQ-23 PL Score at Week 22: Cohort A, Ponsegromab 300 mg Versus Placebo

KCCQ is a self-reported 23-item questionnaire that assessed HRQL in participants with HF over the past 2 weeks. KCCQ quantifies 7 domains: physical limitations (6 items), symptom stability (1 item), symptom frequency (4 items), symptom burden (3 items), self-efficacy (2 items), quality of life (3 items) and social limitations (4 items). Scores were generated for each domain and scaled from 0 (worst status) to 100 (best possible status). KCCQ-23 physical limitation score scaled from 0 (worst status) to 100 (best possible status), where higher scores signified better health status.

Time frame: Week 22

Percentage of Participants With >= 5-Point Increase From Baseline in KCCQ-23 PL Score at Week 22: Cohort A

KCCQ is a self-reported 23-item questionnaire that assessed HRQL in participants with HF over the past 2 weeks. KCCQ quantifies 7 domains: physical limitations (6 items), symptom stability (1 item), symptom frequency (4 items), symptom burden (3 items), self-efficacy (2 items), quality of life (3 items) and social limitations (4 items). Scores were generated for each domain and scaled from 0 (worst status) to 100 (best possible status). KCCQ-23 physical limitation score scaled from 0 (worst status) to 100 (best possible status), where higher scores signified better health status.

Time frame: Week 22

Change From Baseline in 6-Minute Walk Distance (6MWD) at Week 22: Cohort A, Ponsegromab 300 mg Versus Placebo

The 6-minute walk test (6MWT) is a submaximal exercise test that entails measurement of distance walked over a span of 6 minutes. The 6MWD (distance travelled in meters) provides a measure for integrated global response of multiple cardiopulmonary and musculoskeletal systems involved in exercise.

Time frame: Baseline [the last measurement on study Day 1], Week 22

Change From Baseline in 6MWD at Week 22: Cohort A

The 6MWT is a submaximal exercise test that entails measurement of distance walked over a span of 6 minutes. The 6MWD (distance travelled in meters) provides a measure for integrated global response of multiple cardiopulmonary and musculoskeletal systems involved in exercise.

Time frame: Baseline [the last measurement on study Day 1], Week 22

Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue (Version 7a) at Week 22: Cohort A, Ponsegromab 300 mg Versus Placebo

The PROMIS Fatigue 7a is a self-reported measure that assessed a range of symptoms in the past 7 days from mild subjective feelings of tiredness to an overwhelming, debilitating, and sustained sense of exhaustion that likely decreases one's ability to execute daily activities and function normally in family or social roles. The short form (SF) 7A consisted of 7 items that study participants rated from 1: "Never" to 5: "Always". A global raw score ranged from 7 to 35 was calculated and translated into a T-score with minimum of 29.4 and maximum of 83.2 (mean = 50, a standard deviation \[SD\] = 10) using the applicable score conversion provided in the PROMIS user's manual. Higher scores indicated more fatigue.

Time frame: Baseline [the last measurement on study Day 1], Week 22

Change From Baseline in PROMIS Fatigue (Version 7a) at Week 22: Cohort A

The PROMIS Fatigue 7a is a self-reported measure that assessed a range of symptoms in the past 7 days from mild subjective feelings of tiredness to an overwhelming, debilitating, and sustained sense of exhaustion that likely decreases one's ability to execute daily activities and function normally in family or social roles. The short form (SF) 7A consisted of 7 items that study participants rated from 1: "Never" to 5: "Always". A global raw score ranged from 7 to 35 was calculated and translated into a T-score (mean = 50, a standard deviation \[SD\] = 10) using the applicable score conversion provided in the PROMIS user's manual. Higher scores indicated more fatigue.

Time frame: Baseline [the last measurement on study Day 1], Week 22

Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs): Cohort A

An adverse event (AE) was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE was considered a TEAE if the event started during the effective duration of treatment. TESAE was a TEAE which met the definition of serious adverse event (SAE) viz. any untoward medical occurrence at any dose that resulted in death; was life-threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was considered an important medical event. AEs included SAEs and all other AEs (non-SAEs).

Time frame: From first dose of study treatment (Day 1) maximum up to 10 weeks post Week 22 (maximum up to approximately 32 weeks)

Number of Participants With Any Abnormalities in Laboratory Test Parameters: Cohort A

Laboratory parameters included were: hematology (hemoglobin, hematocrit, red blood cells \[RBC\] count, platelet count, white blood cells \[WBC\] count) and chemistry (urea and creatinine, estimated glomerular filtration rate \[eGFR\], cystatin C \[at baseline only\], sodium, potassium, aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\], total bilirubin, alkaline phosphatase \[ALP\], total protein, glucose \[non-fasting\] and lipid panel, total cholesterol, high-density lipoprotein \[HDL\] cholesterol, Non HDL cholesterol, calculated low-density lipoprotein \[LDL\] cholesterol and triglycerides. Number of participants with any abnormalities in laboratory test parameters as judged by investigator were reported.

Time frame: From first dose of study treatment (Day 1) up to Week 22

Number of Participants With Abnormalities in Vital Signs: Cohort A

Vital signs abnormalities criteria included: supine systolic blood pressure (SBP) \<90 millimeters of mercury (mmHg), increase and decrease in change of \>= 30mmHg; supine diastolic blood pressure (DBP) \<50 mmHg, increase and decrease in change of \>=20mmHg; and pulse rate (PR) \<40 beats per minute (bpm) and \>120 bpm.

Time frame: From first dose of study treatment (Day 1) maximum up to 10 weeks post Week 22 (maximum up to approximately 32 weeks)

Number of Participants With TEAEs and TEASAEs: Cohort B

An AE was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE was considered a TEAE if the event started during the effective duration of treatment. TESAE was a TEAE which met the definition of SAE viz. any untoward medical occurrence at any dose that resulted in death; was life-threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was considered an important medical event. AEs included SAEs and all other AEs (non-SAEs).

Time frame: From first dose of study treatment (Day 1) maximum up to 10 weeks post Week 12 (maximum up to approximately 22 weeks)

Number of Participants With Any Abnormalities in Laboratory Test Parameters: Cohort B

Laboratory parameters included were: hematology (hemoglobin, hematocrit, RBC count, platelet count, WBC count) and chemistry (urea and creatinine, eGFR, cystatin C \[at baseline only\], sodium, potassium, AST, ALT, total bilirubin, ALP, total protein, glucose \[non-fasting\] and lipid panel, total cholesterol, HDL cholesterol, Non HDL cholesterol, calculated LDL cholesterol and triglycerides. Number of participants with any abnormalities in laboratory test parameters as judged by investigator were reported.

Time frame: From first dose of study treatment (Day 1) maximum up to 4 weeks post Week 12 (maximum up to approximately 16 weeks)

Number of Participants With Abnormalities in Vital Signs: Cohort B

Vital signs criteria included: supine SBP \<90 mmHg, increase and decrease in change of \>= 30mmHg; supine DBP \<50 mmHg, increase and decrease in change of \>=20mmHg; and PR \<40 bpm to \>120 bpm.

Time frame: From start of study drug on Day 1 maximum up to 4weeks post last dose on Week 12 (maximum up to approximately Week 16)