Trial Outcomes & Findings for A Study of Sotatercept in Participants With PAH WHO FC III or FC IV at High Risk of Mortality (MK-7962-006/ZENITH) (NCT NCT04896008)

Last Updated: 2025-08-22

Results Overview

Morbidity or mortality events were defined as all-cause death, lung transplantation, or PAH worsening-related hospitalization of ≥24 hours. All events were adjudicated by a blinded, independent committee of clinical experts. Only adjudication-confirmed lung transplantation and PAH worsening-related hospitalization of ≥24 hours were included in the primary analysis. All deaths that are a first event for a participant were included regardless of adjudication. The time from randomization to the first confirmed morbidity or mortality event, calculated using the non-parametric Kaplan-Meier method, is presented.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

173 participants

Primary outcome timeframe

Up to approximately 26 months

Results posted on

2025-08-22

Participant Flow

Of 255 screened participants, 173 were randomized. One participant was randomized in error and did not receive study treatment. This participant was discontinued from the study and no data was collected. As pre-specified in the statistical analysis plan (SAP), this participant was excluded from all study analyses. Therefore, analyses are presented for 172 participants.

Protocol-specified final analysis of all outcome measures is reported here. At the time of the primary completion data cutoff, 108 participants were ongoing in the study for safety and survival follow-up. Per protocol, participants completing this study may have been eligible to enroll in an open-label, long-term follow-up study (MK-7962-004; NCT04796337).

Participant milestones

Participant milestones
Measure	Sotatercept Participants on background pulmonary arterial hypertension (PAH) therapy were administered sotatercept by subcutaneous (SC) injection at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, every 21 days for up to approximately 26 months.	Placebo Participants on background PAH therapy were administered placebo by SC injection every 21 days for up to approximately 26 months.
Overall Study STARTED	86	86
Overall Study COMPLETED	4	30
Overall Study NOT COMPLETED	82	56

Reasons for withdrawal

Reasons for withdrawal
Measure	Sotatercept Participants on background pulmonary arterial hypertension (PAH) therapy were administered sotatercept by subcutaneous (SC) injection at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, every 21 days for up to approximately 26 months.	Placebo Participants on background PAH therapy were administered placebo by SC injection every 21 days for up to approximately 26 months.
Overall Study Ongoing	70	38
Overall Study Adverse Event	0	2
Overall Study Death	5	10
Overall Study More Than 3 Dose Delays Required Per Dose Adjustment Guidelines	1	0
Overall Study Fridericia's Corrected QT Interval Above 500 ms	0	1
Overall Study Unwillingness Or Inability To Comply With Protocol	1	0
Overall Study Withdrawal by Subject	1	4
Overall Study Investigator Decision	2	0
Overall Study Transitioned to Commercial Sotatercept	2	1

Baseline Characteristics

A Study of Sotatercept in Participants With PAH WHO FC III or FC IV at High Risk of Mortality (MK-7962-006/ZENITH)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Sotatercept n=86 Participants Participants on background PAH therapy were administered sotatercept by subcutaneous (SC) injection at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, every 21 days for up to approximately 26 months.	Placebo n=86 Participants Participants on background PAH therapy were administered placebo by SC injection every 21 days for up to approximately 26 months.	Total n=172 Participants Total of all reporting groups
Age, Continuous	55.3 Years STANDARD_DEVIATION 14.3 • n=5 Participants	53.5 Years STANDARD_DEVIATION 14.3 • n=7 Participants	54.4 Years STANDARD_DEVIATION 14.3 • n=5 Participants
Sex: Female, Male Female	61 Participants n=5 Participants	71 Participants n=7 Participants	132 Participants n=5 Participants
Sex: Female, Male Male	25 Participants n=5 Participants	15 Participants n=7 Participants	40 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	6 Participants n=5 Participants	12 Participants n=7 Participants	18 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	78 Participants n=5 Participants	73 Participants n=7 Participants	151 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Asian	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	5 Participants n=5 Participants	4 Participants n=7 Participants	9 Participants n=5 Participants
Race/Ethnicity, Customized White	73 Participants n=5 Participants	76 Participants n=7 Participants	149 Participants n=5 Participants
Race/Ethnicity, Customized West Indian	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized More than one race	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Unknown or Not Reported	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) Lite 2.0 Score <9	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants
Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) Lite 2.0 Score 9 to 10	59 Participants n=5 Participants	57 Participants n=7 Participants	116 Participants n=5 Participants
Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) Lite 2.0 Score ≥11	26 Participants n=5 Participants	26 Participants n=7 Participants	52 Participants n=5 Participants
PAH Subtype Idiopathic PAH	42 Participants n=5 Participants	44 Participants n=7 Participants	86 Participants n=5 Participants
PAH Subtype Heritable PAH	11 Participants n=5 Participants	7 Participants n=7 Participants	18 Participants n=5 Participants
PAH Subtype Drug or toxin-induced PAH	6 Participants n=5 Participants	5 Participants n=7 Participants	11 Participants n=5 Participants
PAH Subtype PAH associated with connective tissue disease	22 Participants n=5 Participants	26 Participants n=7 Participants	48 Participants n=5 Participants
PAH Subtype PAH associated with simple, congenital systemic-to-pulmonary shunts >1 year following shunt repair	5 Participants n=5 Participants	4 Participants n=7 Participants	9 Participants n=5 Participants

PRIMARY outcome

Timeframe: Up to approximately 26 months

Population: All randomized participants who received at least one dose of study treatment.

Outcome measures

Outcome measures
Measure	Sotatercept n=86 Participants Participants on background PAH therapy were administered sotatercept by subcutaneous (SC) injection at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, every 21 days for up to approximately 26 months.	Placebo n=86 Participants Participants on background PAH therapy were administered placebo by SC injection every 21 days for up to approximately 26 months.
Time to First Confirmed Morbidity or Mortality Event	NA Months NA = Median, upper limit, and lower limit not reached at time of data cut-off due to insufficient number of participants with an event.	9.6 Months Interval 6.2 to 14.8

SECONDARY outcome

Timeframe: Up to approximately 26 months

Population: All randomized participants who received at least one dose of study treatment.

OS was defined as the time from randomization to death due to any cause. As pre-specified in the SAP, all deaths up to data cutoff, including among participants who completed or discontinued the study, were included except for those that occurred after enrollment in the long-term follow-up study (MK-7962-004) or after lung transplantation. The OS for participants, calculated using the non-parametric Kaplan-Meier method, is reported.

Outcome measures

Outcome measures
Measure	Sotatercept n=86 Participants Participants on background PAH therapy were administered sotatercept by subcutaneous (SC) injection at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, every 21 days for up to approximately 26 months.	Placebo n=86 Participants Participants on background PAH therapy were administered placebo by SC injection every 21 days for up to approximately 26 months.
Overall Survival (OS)	NA Months NA = Median, upper limit, and lower limit not reached at time of data cut-off due to insufficient number of participants with an event.	NA Months NA = Median, upper limit, and lower limit not reached at time of data cut-off due to insufficient number of participants with an event.

SECONDARY outcome

Timeframe: Up to approximately 26 months

Population: All randomized participants who received at least one dose of study treatment.

Transplant-free survival was defined as the time from randomization to the first lung transplantation or death due to any cause. As pre-specified in the SAP, all deaths up to data cutoff, including among participants who completed or discontinued the study, were included except for those that occurred after enrollment in the long-term follow-up study (MK-7962-004) or after lung transplantation. Transplant-free survival for participants, calculated using the non-parametric Kaplan-Meier method, is reported.

Outcome measures

Outcome measures
Measure	Sotatercept n=86 Participants Participants on background PAH therapy were administered sotatercept by subcutaneous (SC) injection at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, every 21 days for up to approximately 26 months.	Placebo n=86 Participants Participants on background PAH therapy were administered placebo by SC injection every 21 days for up to approximately 26 months.
Transplant-free Survival	NA Months NA = Median, upper limit, and lower limit not reached at time of data cut-off due to insufficient number of participants with an event.	NA Months Interval 8.8 to NA = Median and upper limit not reached at time of data cut-off due to insufficient number of participants with an event.

SECONDARY outcome

Timeframe: Up to approximately 26 months

Population: All randomized participants who received at least one dose of study treatment.

Mortality events were defined as death due to any cause throughout the study. As pre-specified in the SAP, all deaths up to data cutoff, including among participants who completed or discontinued the study, were included except for those that occurred after enrollment in the long-term follow-up study (MK-7962-004) or after lung transplantation. The percent of participants who experienced a mortality event is reported.

Outcome measures

Outcome measures
Measure	Sotatercept n=86 Participants Participants on background PAH therapy were administered sotatercept by subcutaneous (SC) injection at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, every 21 days for up to approximately 26 months.	Placebo n=86 Participants Participants on background PAH therapy were administered placebo by SC injection every 21 days for up to approximately 26 months.
Percentage of Participants Who Experienced a Mortality Event	8.1 Percentage of Participants	15.1 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: All randomized participants who received at least one dose of study treatment and who were randomized more than 24 weeks prior to the data cutoff.

REVEAL Lite 2.0 risk scoring is used to guide PAH treatment decisions. Total score uses 6 variables with each assessed based on contribution to mortality risk. Variables and sub-score ranges: eGFR (0, +1), WHO FC (-1, 0, +1, +2), SBP (0, +1), heart rate (0, +1), 6MWD (-2, -1, 0, +1), and NT-proBNP (-2, 0, +2). Sub-scores are added to a base score of +6 and a total score of 1 to 14 is obtained (≤5=low risk; 6,7=intermediate risk; ≥8=high risk). A higher score = higher risk. Per SAP, multiple imputation was used to impute the missing data at Week 24 for reasons other than death or a non-fatal clinical worsening event. Range was based on the minimum and maximum of median scores across the imputed dataset (100 repetitions). Thus, median change from baseline and range could be the same or show minimal variability. Comparisons with other REVEAL analyses may not be possible due to Week 24 data imputation. The change from baseline in REVEAL Lite 2.0 risk score at Week 24 is reported.

Outcome measures

Outcome measures
Measure	Sotatercept n=77 Participants Participants on background PAH therapy were administered sotatercept by subcutaneous (SC) injection at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, every 21 days for up to approximately 26 months.	Placebo n=78 Participants Participants on background PAH therapy were administered placebo by SC injection every 21 days for up to approximately 26 months.
Change From Baseline in REVEAL Lite 2.0 Risk Score at Week 24	-3.0 Scores on a scale Interval -3.0 to -2.0	0.0 Scores on a scale Interval 0.0 to 0.0

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: All randomized participants who received at least one dose of study treatment, who were randomized more than 24 weeks prior to the data cutoff, and who had a REVEAL Lite 2.0 risk score \>7 at baseline.

REVEAL Lite 2.0 risk scoring is used to guide PAH treatment decisions. Total score uses 6 variables with each assessed based on contribution to mortality risk. Variables and sub-score ranges: eGFR (0, +1), WHO FC (-1, 0, +1, +2), SBP (0, +1), heart rate (0, +1), 6MWD (-2, -1, 0, +1), and NT-proBNP (-2, 0, +2). Sub-scores are added to a base score of +6 and a total score of 1 to 14 is obtained (≤5=low risk; 6,7=intermediate risk; ≥8=high risk). A higher score = higher risk. Per SAP, participants who did not have a REVEAL risk score at Week 24 were considered as non-responders and multiple imputation was not conducted for this endpoint. Comparisons between this analysis reporting non-imputed data should not be made to other REVEAL analyses which included imputation of missing Week 24 data. The percentage of participants who achieved a low or intermediate REVEAL Lite 2.0 score at Week 24 is reported.

Outcome measures

Outcome measures
Measure	Sotatercept n=69 Participants Participants on background PAH therapy were administered sotatercept by subcutaneous (SC) injection at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, every 21 days for up to approximately 26 months.	Placebo n=72 Participants Participants on background PAH therapy were administered placebo by SC injection every 21 days for up to approximately 26 months.
Percentage of Participants Achieving a Low or Intermediate (≤7) REVEAL Lite 2 Risk Score at Week 24	49.3 Percentage of Participants	15.3 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: All randomized participants who received at least one dose of study treatment and who were randomized more than 24 weeks prior to the data cutoff.

NT-proBNP is secreted by cardiomyocytes in response to ventricular stretch and is an established noninvasive marker of ventricular dysfunction in patients with PAH. Blood samples were collected at baseline and at Week 24 to measure NT-proBNP levels. Per SAP, multiple imputation was used to impute the missing data at Week 24 for reasons other than death or a non-fatal clinical worsening event. Range was based on the minimum and maximum of median scores across the imputed dataset (100 repetitions). Thus, median change from baseline and range could be the same or show minimal variability. The change from baseline in NT-proBNP levels at Week 24 is reported.

Outcome measures

Outcome measures
Measure	Sotatercept n=77 Participants Participants on background PAH therapy were administered sotatercept by subcutaneous (SC) injection at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, every 21 days for up to approximately 26 months.	Placebo n=78 Participants Participants on background PAH therapy were administered placebo by SC injection every 21 days for up to approximately 26 months.
Change From Baseline in NT-proBNP Levels at Week 24	-1233.0 pg/mL Interval -1233.0 to -1233.0	255.4 pg/mL Interval 211.0 to 263.0

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: All randomized participants who received at least one dose of study treatment and who were randomized more than 24 weeks prior to the data cutoff.

mPAP is a prognostic hemodynamic parameter measured at baseline and at Week 24 by right heart catheterization (RHC). Per SAP, multiple imputation was used to impute the missing data at Week 24 for reasons other than death or a non-fatal clinical worsening event. Range was based on the minimum and maximum of median scores across the imputed dataset (100 repetitions). Thus, median change from baseline and range could be the same or show minimal variability. The change from baseline in mPAP at Week 24 is reported.

Outcome measures

Outcome measures
Measure	Sotatercept n=77 Participants Participants on background PAH therapy were administered sotatercept by subcutaneous (SC) injection at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, every 21 days for up to approximately 26 months.	Placebo n=78 Participants Participants on background PAH therapy were administered placebo by SC injection every 21 days for up to approximately 26 months.
Change From Baseline in Mean Pulmonary Artery Pressure (mPAP) at Week 24	-13.6 mmHg Interval -14.0 to -13.0	5.5 mmHg Interval 5.0 to 6.0

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: All randomized participants who received at least one dose of study treatment and who were randomized more than 24 weeks prior to the data cutoff.

PVR is a prognostic hemodynamic variable of pulmonary circulation and was measured at baseline and at Week 24 by right heart catheterization (RHC). Per SAP, multiple imputation was used to impute the missing data at Week 24 for reasons other than death or a non-fatal clinical worsening event. Range was based on the minimum and maximum of median scores across the imputed dataset (100 repetitions). Thus, median change from baseline and range could be the same or show minimal variability. The change from baseline in PVR at Week 24 is reported.

Outcome measures

Outcome measures
Measure	Sotatercept n=77 Participants Participants on background PAH therapy were administered sotatercept by subcutaneous (SC) injection at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, every 21 days for up to approximately 26 months.	Placebo n=78 Participants Participants on background PAH therapy were administered placebo by SC injection every 21 days for up to approximately 26 months.
Change From Baseline in Pulmonary Vascular Resistance (PVR)	-156.6 Dynes*sec/cm^5 Interval -160.0 to -152.0	46.6 Dynes*sec/cm^5 Interval 36.0 to 104.0

SECONDARY outcome

Timeframe: Baseline and up to approximately 26 months

Population: All randomized participants who received at least one dose of study treatment.

The severity of a participant's PAH symptoms was graded using the WHO FC system. WHO functional classification for PAH ranges from Class I (no limitation in physical activity, no dyspnea with normal activity), Class II (slight limitation of physical activity), Class III (marked limitation of physical activity), and Class IV (cannot perform a physical activity without any symptoms, dyspnea at rest). Participants who improve in WHO FC were classified into "Improved", "No change", or "Worsened" (Improved = reduction in FC; Worsened = increase in FC; No change = no change in FC). The percentage of participants who had improvement from baseline in WHO FC at the end of the treatment period is reported.

Outcome measures

Outcome measures
Measure	Sotatercept n=86 Participants Participants on background PAH therapy were administered sotatercept by subcutaneous (SC) injection at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, every 21 days for up to approximately 26 months.	Placebo n=86 Participants Participants on background PAH therapy were administered placebo by SC injection every 21 days for up to approximately 26 months.
Percentage of Participants Who Improve in WHO FC	55.8 Percentage of Participants	27.9 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: All randomized participants who received at least one dose of study treatment and who were randomized more than 24 weeks prior to the data cutoff.

6MWD was measured using the 6-Minute Walk Test (6MWT). The 6MWT measures the distance covered in 6 minutes and is intended to measure changes in functional exercise capacity. Each participant's 6MWD was measured at baseline and at 24 weeks. An increase in the distance walked during the 6MWT indicated improvement in functional exercise capacity. Per SAP, multiple imputation was used to impute the missing data at Week 24 for reasons other than death or a non-fatal clinical worsening event. Range was based on the minimum and maximum of median scores across the imputed dataset (100 repetitions). Thus, median change from baseline and range could be the same or show minimal variability. The change from baseline in 6MWD at Week 24 is reported.

Outcome measures

Outcome measures
Measure	Sotatercept n=77 Participants Participants on background PAH therapy were administered sotatercept by subcutaneous (SC) injection at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, every 21 days for up to approximately 26 months.	Placebo n=78 Participants Participants on background PAH therapy were administered placebo by SC injection every 21 days for up to approximately 26 months.
Change From Baseline in 6MWD at Week 24	45.39 Meters Interval 45.0 to 46.0	-5.36 Meters Interval -9.5 to -1.0

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: All randomized participants who received at least one dose of study treatment and who were randomized more than 24 weeks prior to the data cutoff.

CO is a prognostic hemodynamic parameter measured at baseline and at Week 24 by RHC. Per SAP, multiple imputation was used to impute the missing data at Week 24 for reasons other than death or a non-fatal clinical worsening event. Range was based on the minimum and maximum of median scores across the imputed dataset (100 repetitions). Thus, median change from baseline and range could be the same or show minimal variability. The change from baseline in CO at Week 24 is reported.

Outcome measures

Outcome measures
Measure	Sotatercept n=77 Participants Participants on background PAH therapy were administered sotatercept by subcutaneous (SC) injection at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, every 21 days for up to approximately 26 months.	Placebo n=78 Participants Participants on background PAH therapy were administered placebo by SC injection every 21 days for up to approximately 26 months.
Change From Baseline in Cardiac Output (CO) at Week 24	-0.1 Liters/minute Interval -0.1 to -0.1	-0.38 Liters/minute Interval -0.42 to -0.35

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: All randomized participants who received at least one dose of study treatment, who were randomized more than 24 weeks prior to the data cutoff, and who had data available from at least one baseline and post-baseline PRO assessment.

EQ-5D-5L is a standardized measure of health status, consisting of 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each assessed on a 5-point scale (1=no problem, 2=slight problems, 3=moderate problems, 4=severe problems, 5=extreme problems). Participants score each dimension based on their health that day and their responses are used to generate a health index score. Index scores could range from \<0 (a health state equivalent to dead with negative values representing a state worse than dead) to 1 (full health). Higher scores indicated better health and a positive change in score indicated improved overall health. Per SAP, multiple imputation was used to impute missing data at Week 24 for reasons other than death or a non-fatal clinical worsening event. Range was based on the minimum and maximum of median scores across the imputed dataset (100 repetitions). The change from baseline to Week 24 in EQ-5D-5L index score is reported.

Outcome measures

Outcome measures
Measure	Sotatercept n=41 Participants Participants on background PAH therapy were administered sotatercept by subcutaneous (SC) injection at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, every 21 days for up to approximately 26 months.	Placebo n=36 Participants Participants on background PAH therapy were administered placebo by SC injection every 21 days for up to approximately 26 months.
Change From Baseline in European Quality of Life (EuroQoL)-5 Dimensions-5 Levels (EQ-5D-5L) Index Score at Week 24	0.060 Scores on a Scale Interval -1.02 to 0.512	0.007 Scores on a Scale Interval -0.358 to 0.74

Adverse Events

Sotatercept

Serious events: 46 serious events

Other events: 79 other events

Deaths: 8 deaths

Placebo

Serious events: 55 serious events

Other events: 74 other events

Deaths: 18 deaths

Serious adverse events

Other adverse events

Additional Information

Senior Vice President, Global Clinical Development

Merck Sharp & Dohme LLC

Phone: 1-800-672-6372

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee No publication or disclosure of study results will be permitted except as specified in a separate, written agreement between the Sponsor and the investigator. The Sponsor will comply with the requirements for publication of study results. In accordance with standard editorial and ethical practice, the Sponsor will generally support publication.
Publication restrictions are in place

Restriction type: OTHER