Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following data reflect exposure to WINREVAIR in the STELLAR trial. Adult PAH patients with WHO FC II or III (n=323) were randomized in a 1:1 ratio to receive WINREVAIR or placebo in combination with background standard of care therapies. Patients received a starting dose of 0.3 mg/kg via SC injection and the dose was increased to the target dose of 0.7 mg/kg administered once every 3 weeks for 24 weeks. After completing the primary 24-week treatment phase, patients continued into a long-term double-blind (LTDB) treatment period, maintaining their randomized treatment assignment, until all patients completed the primary treatment period. The median duration of treatment was 273 days in the placebo group and 313 days in the WINREVAIR group

The most common adverse reactions occurring in STELLAR (≥10% for WINREVAIR and at least 5% more than placebo) are shown in

Increases in Hgb were managed by dose delays (10%), dose reductions (6%), or both (5%). Shifts in Hgb from normal to above normal levels occurred in 87 (53%) patients receiving WINREVAIR and in 23 (14%) patients receiving placebo.

Decreases in platelets were managed by dose delays (2%), dose reductions (2%), or both (2%). Shifts in platelet count from normal to below normal occurred in 40 (25%) patients receiving WINREVAIR and in 26 (16%) patients receiving placebo.

In patients exposed to WINREVAIR who experienced telangiectasia, the median time to onset was 36.1 weeks.

In patients taking WINREVAIR, mean systolic/diastolic blood pressure increased from baseline by 2.2/4.9 mmHg at 24 weeks. In patients taking placebo, the change from baseline in mean blood pressure was -1.6/-0.6 mmHg.

The incidences of treatment discontinuations due to an adverse reaction were 4% in the WINREVAIR group and 7% in the placebo group. No specific adverse reactions causing treatment discontinuations occurred with a frequency greater than 1% and more often in the WINREVAIR group.

The following data reflect exposure to WINREVAIR in the ZENITH trial. Adult PAH patients with WHO FC III or IV at high risk of mortality (n=172) were randomized in a 1:1 ratio to treatment with WINREVAIR or placebo in combination with background standard of care therapies. Patients who did not experience a primary endpoint event remained in the Double-Blind Placebo-Controlled (DBPC) Treatment Period, while patients who experienced an event of PAH worsening-related hospitalization of ≥24 hours were eligible to enroll into the open-label, long-term follow-up (LTFU) study SOTERIA. The median duration of exposure was longer in the WINREVAIR group (435 days) than in the placebo group (268 days)

The overall incidences of adverse reactions in both arms were higher in the ZENITH trial than in the STELLAR trial. Severe reduction in platelet count <50,000/mm

The most common adverse reactions occurring in ZENITH (≥10% for WINREVAIR and at least 5% more than placebo) are shown in

The following data reflect exposure to WINREVAIR in the HYPERION trial. Newly diagnosed adult PAH patients in WHO FC II or III at intermediate or high risk of disease progression (n=320) were randomized in a 1:1 ratio to treatment with WINREVAIR or placebo in combination with background standard of care therapies. The median duration of exposure was longer in the WINREVAIR group (443 days) than in the placebo group (350 days)

The adverse reactions observed in the HYPERION trial were generally consistent with those observed in the STELLAR trial. No severe reductions in platelet count <50,000/mm

The most common adverse reactions occurring in HYPERION (≥10% for WINREVAIR and at least 5% more than placebo) are shown in

Gastrointestinal disorders: In a pooled analysis of STELLAR, ZENITH, and HYPERION, gastrointestinal bleeding was observed in 7% of patients in the sotatercept group compared with 2% in the placebo group. Colonic angioectasia was reported in 2% of patients in the sotatercept group compared with 0.2% in the placebo group.

Pooled long-term safety data are available from 431 patients who participated in multicenter phase 2 (PULSAR, SPECTRA) and phase 3 (STELLAR) clinical trials. A majority of these patients continued in SOTERIA, an ongoing, open-label follow-up study of the long-term safety and efficacy of WINREVAIR. The safety profile with long-term exposure was generally similar to that observed in the STELLAR study. The mean duration of exposure to WINREVAIR was 173 weeks with a maximum exposure of 335 weeks.

Skin hypopigmentation: In the pooled long-term safety population (n=431), skin hypopigmentation was reported in 5% of patients. Reported manifestations included white or hypochromic spots and hypopigmented macules affecting the extremities or trunk. No events required dose reduction or treatment interruption.

Intrapulmonary right-to-left shunting: In SOTERIA, right-to-left intrapulmonary shunting has been reported in 3 participants (<0.7%) who developed worsening hypoxemia despite improved PAH hemodynamics. Post-marketing cases have also been reported. Partial to complete improvement in oxygenation has been observed following discontinuation of WINREVAIR.

The following adverse reaction has been reported during post-approval use of WINREVAIR. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.