Winrevair
(Sotatercept-Csrk)Dosage & Administration
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WINREVAIR Prescribing Information
Indications and Usage (WINREVAIR™ is indicated for the treatment of adults with pulmonary arterial hypertension (PAH, Group 1 pulmonary hypertension) to improve exercise capacity and World Health Organization (WHO) functional class (FC), and reduce the risk of clinical worsening events including hospitalization for PAH, lung transplantation and death [see Clinical Studies (14.1)] .WINREVAIR is an activin signaling inhibitor indicated for the treatment of adults with pulmonary arterial hypertension (PAH, WHO Group 1 pulmonary hypertension) to improve exercise capacity and WHO functional class (FC), and reduce the risk of clinical worsening events, including hospitalization for PAH, lung transplantation and death. | 10/2025 |
The efficacy of WINREVAIR was evaluated in adult patients with PAH in the STELLAR trial (NCT04576988). STELLAR was a global, double-blind, placebo-controlled, multicenter, parallel-group clinical trial in which 323 patients with PAH (WHO Group 1, FC II or III) were randomized 1:1 to WINREVAIR (target dose 0.7 mg/kg) (n=163) or placebo (n=160) administered subcutaneously once every 3 weeks.
Participants were: 79% female; had a median age of 48 years (range: 18 to 82 years), and median body weight of 68 kg (range 38 to 141 kg); and 89% White, 2% Black/African American, 2% Asian, 0.3% American Indian or Alaska Native, 0.3% Native Hawaiian or Other Pacific Islander, 6% Missing/Other races. The most common PAH etiologies were idiopathic PAH (59%), heritable PAH (18%), and PAH associated with connective tissue diseases (CTD) (15%). STELLAR excluded patients with human immunodeficiency virus (HIV)-associated PAH, PAH associated with portal hypertension, schistosomiasis-associated PAH, and pulmonary veno occlusive disease. The mean time from PAH diagnosis to screening was 8.8 years. Most participants were receiving either three (61%) or two (35%) background drugs for PAH, and 40% were receiving prostacyclin infusions. Patients had a WHO FC II (49%) or III (51%) at baseline.
The primary efficacy endpoint was the change from baseline at Week 24 in 6-Minute Walk Distance (6 MWD). In the WINREVAIR group, the placebo-adjusted median increase in 6 MWD was 41 meters (95% CI: 28, 54; p<0.001). Figure 1 displays placebo-adjusted changes in 6 MWD at Week 24 in relevant subgroups.
| *Hodges-Lehmann location shift from placebo estimate (median of all paired differences). ASE = asymptomatic standard error. Change from baseline in 6 MWD at Week 24 for subjects who died was imputed to -2000 meters to receive the worst rank. Change from baseline in 6 MWD at Week 24 for subjects who had missing data due to a non-fatal clinical worsening event was imputed to -1000 meters to receive the next-worst rank. |
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Treatment with WINREVAIR led to an improvement from baseline by at least 1 WHO FC at Week 24 in 29% of patients compared to 14% of patients treated with placebo (p<0.001).
Treatment with WINREVAIR resulted in an 84% reduction in the occurrence of death from any cause or PAH clinical worsening events compared to placebo (see Table 5and Figure 2). These outcomes were captured until the last patient completed the Week 24 visit (data up to the data cutoff; median duration of exposure 33.6 weeks).
| WINREVAIR (N=163) n (%) | Placebo (N=160) n (%) | Hazard Ratio (95% CI) | |
|---|---|---|---|
| N = number of subjects in the category. 6 MWT = 6-Minute Walking Test | |||
| Number of subjects who experienced death or at least one clinical worsening event | 9 (5.5) | 42 (26.3) | 0.16 (0.08, 0.35) p<0.001 |
| Assessment of clinical worsening eventsA subject can have more than one assessment recorded for their clinical worsening. | |||
| Death | 2 (1.2) | 7 (4.4) | |
| Worsening-related listing for lung and/or heart transplant | 1 (0.6) | 2 (1.3) | |
| Need to initiate rescue therapy with an approved PAH therapy or the need to increase the dose of infusion prostacyclin by 10% or more | 2 (1.2) | 17 (10.6) | |
| Need for atrial septostomyThere were no events of atrial septostomy. | 0 (0.0) | 0 (0.0) | |
| PAH-specific hospitalization (≥24 hours) | 0 (0.0) | 8 (5.0) | |
| Deterioration of PAHDeterioration of PAH is defined by both of the following events occurring at any time, even if they began at different times, as compared to their baseline values: (a) Worsened WHO functional class (II to III, III to IV, II to IV, etc.); and (b) Decrease in 6 MWD by ≥15% (confirmed by two 6 MWTs at least 4 hours apart but no more than one week). | 4 (2.5) | 15 (9.4) | |
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The efficacy of WINREVAIR was evaluated in adult PAH patients with WHO FC III or IV at high risk of mortality in the ZENITH trial (NCT04896008). ZENITH was a global, double-blind, placebo-controlled, multicenter, parallel-group clinical trial in which 172 patients were randomized 1:1 to WINREVAIR (target dose 0.7 mg/kg) (n=86) or placebo (n=86) administered subcutaneously once every 3 weeks. Efficacy was evaluated at the pre-specified interim analysis which occurred when 61 patients experienced a primary endpoint event and median patient time on study was 273 days.
The demographic and baseline clinical characteristics were similar between the WINREVAIR and placebo groups. Participants were: 77% female; had a median age of 58 years (range: 18 to 75 years); and 87% White, 5% Black/African American, 4% Asian, 1% American Indian or Alaska Native, 3% Missing/Other race, 74% were FC III and 26% were FC IV. The most common PAH etiologies were idiopathic PAH (50%), PAH associated with connective tissue diseases (CTD) (28%), and heritable PAH (11%). The mean time since PAH diagnosis to screening was 8 years. Participants were on background PAH treatment, 72% on triple therapy, 28% on double therapy, and 59% on prostacyclin infusion therapy. The REVEAL Lite 2 risk score was <9 for 2% of participants, 9 to 10 for 67% of participants, and ≥11 for 30% of participants. The ZENITH trial excluded patients diagnosed with human immunodeficiency virus (HIV)-associated PAH, PAH associated with portal hypertension, pulmonary veno-occlusive disease, or pulmonary capillary hemangiomatosis or overt signs of capillary and/or venous involvement.
The primary efficacy endpoint was time to first event of all-cause death, lung transplantation, or PAH worsening-related hospitalization of ≥24 hours. In the WINREVAIR treatment group, the risk of a first event of all-cause death, lung transplantation, or PAH worsening-related hospitalization of ≥24 hours was 76% lower compared with the placebo group (HR: 0.24; 95% CI: 0.13, 0.43; p<0.0001) (see Table 6). Fewer participants in the WINREVAIR group (15 [17%]) than in the placebo group (47 [55%]) had a primary endpoint event as of the data cutoff. Based on the primary endpoint result, the study was stopped for favorable efficacy at the interim analysis.
The treatment effect of WINREVAIR was consistent across the prespecified subgroups (see Figure 4).
| WINREVAIR (N=86) n (%) | Placebo (N=86) n (%) | Hazard Ratio (95% CI) p-value | |
|---|---|---|---|
| Number of participants with at least 1 primary eventThe primary composite endpoint analysis includes the first occurrence of an adjudicated morbidity-mortality event up to the data cutoff. All deaths up to the data cutoff are included, regardless of adjudication and regardless of whether they occurred during or post-ZENITH, except for those occurring after lung transplantation or enrollment in SOTERIA. | 15 (17.4) | 47 (54.7) | 0.24 (0.13, 0.43) <0.0001 |
| Components of primary endpointShows each component of the composite primary endpoint as a standalone outcome. A participant is included in more than one row if multiple events meeting primary endpoint definition were observed. | |||
| All-cause death | 7 (8.1) | 13 (15.1) | |
| Lung transplantation | 1 (1.2) | 6 (7.0) | |
| PAH worsening-related to hospitalization (≥24 hours) | 8 (9.3) | 43 (50.0) | |
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| Subgroup analyses were not displayed if the number of participants in subgroup category was less than 10% of FAS. For participants with REVEAL Lite 2.0 risk score <9 at screening, they were grouped under “9 to 10” for the analyses. |
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The secondary endpoint of overall survival (OS) included all deaths up to the data cutoff, except for those occurring after lung transplantation or enrollment in a long-term follow-up study. Twenty OS events were observed (7 deaths in the WINREVAIR treatment group and 13 deaths in the placebo group). The point estimate for the OS HR favored the WINREVAIR treatment group over the placebo group.
Subsequent secondary endpoints were not eligible to be tested due to the hierarchical testing strategy.
- The recommended starting dose is 0.3 mg/kg by subcutaneous injection. ()
2.1 Recommended Starting DosageWINREVAIR is administered once every 3 weeks by subcutaneous injection according to patient body weight. The starting dose of WINREVAIR is 0.3 mg/kg.
Obtain hemoglobin (Hgb) and platelet count prior to the first dose of WINREVAIR. Do not initiate treatment if platelet count is <50,000/mm3(<50 x 109/L)
[see Dosage and Administration (2.3)].Injection volume for starting dose is calculated based on patient weight as follows:
Injection Volume (mL)=Weight (kg) x 0.3 mg/kg50 mg/mLInjection volume should be rounded to the nearest 0.1 mL.
For example: (70 kg x 0.3 mg/kg) ÷ 50 mg/mL = 0.42 mL, rounds to 0.4 mL
See Table 1for selecting the appropriate kit based on calculated injection volume for starting dose.
Table 1: Kit Type Based on Injection Volume for Dose of 0.3 mg/kg Injection Volume (mL) Kit Type 0.2 to 0.9 45 mg kit (containing 1 x 45 mg vial) 1 to 1.1 60 mg kit (containing 1 x 60 mg vial) - The recommended target dose is 0.7 mg/kg every 3 weeks by subcutaneous injection. ()
2.2 Recommended Target DosageAfter verifying acceptable Hgb and platelet count, increase to the target dose of 0.7 mg/kg. Continue treatment at 0.7 mg/kg every 3 weeks unless dosage adjustments are required
[see Dosage and Administration (2.3)].Injection volume for target dose is calculated based on patient weight as follows:
Injection Volume (mL)=Weight (kg) x 0.7 mg/kg50 mg/mLInjection volume should be rounded to the nearest 0.1 mL.
For example: (70 kg x 0.7 mg/kg) ÷ 50 mg/mL = 0.98 mL, rounds to 1 mL
See Table 2for selecting the appropriate kit based on calculated injection volume for target dose.
Table 2: Kit Type Based on Injection Volume for Dose of 0.7 mg/kg Injection Volume (mL) Kit Type 0.4 to 0.9 45 mg kit (containing 1 x 45 mg vial) 1 to 1.2 60 mg kit (containing 1 x 60 mg vial) 1.3 to 1.8 90 mg kit (containing 2 x 45 mg vials) 1.9 to 2.4 120 mg kit (containing 2 x 60 mg vials) Missed Dose, Overdose, and UnderdoseIf a dose of WINREVAIR is missed, administer as soon as possible. If the missed dose of WINREVAIR is not administered within 3 days of the scheduled date, adjust the schedule to maintain 3-week dosing intervals. In case of an overdose, monitor for erythrocytosis
[see Overdosage (10)]. - Dosage modifications due to increased hemoglobin (Hgb) and decreased platelets may be necessary. Check Hgb and platelets before each dose for the first 5 doses, or longer if values are unstable, and monitor periodically thereafter. ()
2.3 Dosage Modifications Due to Hemoglobin Increase or Platelet Count DecreaseCheck Hgb and platelet count before each dose for the first 5 doses, or longer if values are unstable. Thereafter, monitor Hgb and platelet count periodically
[see Warnings and Precautions (5.1, 5.2)].Delay treatment for at least 3 weeks if any of the following occur:
- Hgb increases >2.0 g/dL from the previous dose and is above ULN.
- Hgb increases >4.0 g/dL from baseline.
- Hgb increases >2.0 g/dL above ULN.
- Platelet count decreases to <50,000/mm3(<50 x 109/L).
Recheck Hgb and platelet count before reinitiating treatment. For treatment delays lasting >9 weeks, restart treatment at 0.3 mg/kg, and escalate to 0.7 mg/kg after verifying acceptable Hgb and platelet count.
- See full prescribing information for preparation and administration instructions. ()
2.4 Preparation and AdministrationAdministration is subject to monitoring of hemoglobin and platelet count
[see Dosage and Administration (2.3), Warnings and Precautions (5.1, 5.2)].WINREVAIR is intended for use under the guidance of a healthcare professional. Patients and caregivers may administer WINREVAIR when considered appropriate and when they receive training and follow-up from the healthcare provider (HCP) on how to reconstitute, prepare, measure, and inject WINREVAIR
[see Patient Counseling Information (17)].Confirm at subsequent visits that the patient and/or caregiver can correctly prepare and administer WINREVAIR, particularly if the dose changes or the patient requires a different kit
[see Warnings and Precautions (5.1)].Refer to the Instructions for Use (IFU) for detailed instructions on the proper preparation and administration of WINREVAIR.
Selecting the Appropriate Product KitIf a patient’s body weight requires the use of two 45 mg vials or two 60 mg vials of lyophilized product, use a 2-vial kit instead of two individual 1-vial kits. A 2-vial kit includes instructions to combine the contents of two vials, which aids in measuring the proper dosage and eliminates the need for multiple injections
[see How Supplied/Storage and Handling (16.1)].Reconstitution Instructions- Remove the injection kit from the refrigerator and wait 15 minutes to allow the prefilled syringe(s) and drug product to come to room temperature prior to preparation.
- Attach the vial adapter to the vial.
- Visually inspect the pre-filled syringe for any damage or leaks and the Sterile Water for Injection inside to ensure there are no visible particles.
- Snap off the cap of the pre-filled syringe and attach the syringe to the vial adapter.
- Inject all of the Sterile Water for Injection from the attached syringe into the vial containing the lyophilized powder. This will provide a final concentration of 50 mg/mL.
- Gently swirl the vial to reconstitute the drug product. DO NOT shake or vigorously agitate.
- Allow the vial to stand for up to 3 minutes to allow bubbles to disappear.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- When properly mixed, WINREVAIR should be clear to opalescent and colorless to slightly brownish-yellow and does not have clumps or powder.
- If prescribed a 2-vial presentation, repeat the steps within this section to prepare the second vial.
- Use the reconstituted solution as soon as possible, but no later than 4 hours after reconstitution. Discard unused reconstituted solution.
Syringe Preparation- Turn the syringe and vial upside-down and withdraw the appropriate volume for injection, based on the patient’s weight.
- If the dose amount requires the use of two vials, withdraw the entire contents of the first vial and slowly transfer full contents into the second vial.
- Turn the syringe and vial upside-down and withdraw the required amount of drug product.
- If necessary, remove excess drug product.
- If necessary, remove excess air from the syringe.
Administration InstructionsWINREVAIR is for subcutaneous injection.
- Select the injection site on the abdomen (at least 2 inches away from navel), upper thigh, or upper arm, and swab with an alcohol wipe. Select a new site for each injection that is not scarred, tender, or bruised.
- For administration by the patient or caregiver, use only the abdomen and upper thigh (see IFU).
- Perform subcutaneous injection.
- For injection: 45 mg white to off-white lyophilized cake or powder appearance in a single-dose vial.
- For injection: 60 mg white to off-white lyophilized cake or powder appearance in a single-dose vial.
Lactation: Breastfeeding not recommended. (
There are no data on the presence of sotatercept-csrk in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise patients that breastfeeding is not recommended during treatment with WINREVAIR, and for 4 months after the final dose.
None.