Winrevair Drug Information
Generic name: SOTATERCEPT-CSRK
Uses of Winrevair
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 . 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.
Dosage & Administration of Winrevair
Side Effects of Winrevair
Clinical Trials Experience
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. STELLAR 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 Table 3. Table 3: Adverse Reactions ≥10% in Patients Receiving WINREVAIR and at least 5% More Than Placebo in STELLAR Double-blind placebo-controlled period + Long-term double-blind period of STELLAR Adverse reaction WINREVAIR N=163 Placebo N=160 Headache 40 28 Epistaxis 36 3 Rash 33 13 Telangiectasia 27 7 Diarrhea 25 16 Dizziness 24 10 Erythema 22 5 Increased Hemoglobin 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. Thrombocytopenia 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. Telangiectasia In patients exposed to WINREVAIR who experienced telangiectasia, the median time to onset was 36.1 weeks.
Increased Blood Pressure 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. Treatment Discontinuation 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. ZENITH 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 3 (<50.0 x 10 9 /L) occurred in 6% of patients taking WINREVAIR. In the WINREVAIR group, 1 patient (1%) discontinued study intervention due to an adverse event, compared with 4 patients (5%) in the placebo group. Table 4: Adverse Reactions ≥10% in Patients Receiving WINREVAIR and at least 5% More Than Placebo in ZENITH Adverse reaction WINREVAIR N=86 Placebo N=86 Infections 58 38 Epistaxis 39 8 Diarrhea 22 15 Telangiectasia 22 3 Increased hemoglobin 13 1 Rash 9 4 Erythema 9 3 Gingival bleeding 9 2 Uncontrolled Long-term Safety Data PULSAR was a multicenter, randomized, double-blind, phase 2 trial that included a 24-week placebo-controlled treatment period, followed by an 18-month active-drug extension period.
The safety profile in the long-term uncontrolled extension period of the PULSAR study was generally similar to that observed in the STELLAR study. Patients were treated with WINREVAIR 0.3 mg/kg or 0.7 mg/kg (n=104) and had a mean duration of exposure of 151 weeks (maximum 218 weeks). Intrapulmonary Right-to-Left Shunting: Cases of intrapulmonary right-to-left shunting have been reported in a clinical trial with WINREVAIR. In SOTERIA, an ongoing open-label study of the long-term safety and efficacy of WINREVAIR, right-to-left intrapulmonary shunting has been reported in 2 participants (<0.5%) 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.
Post-marketing Experience
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. Cardiac disorders: pericardial effusion
Warnings & Cautions for Winrevair
Erythrocytosis
WINREVAIR may increase hemoglobin. Severe erythrocytosis may increase the risk of thromboembolic events or hyperviscosity syndrome. In clinical studies, moderate elevations in Hgb (>2 g/dL above ULN) occurred in 15% of patients taking WINREVAIR while no elevations ≥4 g/dL above ULN were observed.
Monitor Hgb before each dose for the first 5 doses, or longer if values are unstable, and periodically thereafter, to determine if dose adjustments are required .
Severe Thrombocytopenia
WINREVAIR may decrease platelet count. Severe thrombocytopenia may increase the risk of bleeding. In clinical studies, severe thrombocytopenia (platelet count <50,000/mm 3 ) occurred in 3% to 6% of patients taking WINREVAIR. Thrombocytopenia occurred more frequently in patients also receiving prostacyclin infusion.
Do not initiate treatment if platelet count is <50,000/mm 3 . Monitor platelets before each dose for the first 5 doses, or longer if values are unstable, and periodically thereafter to determine whether dose adjustments are required. .
Serious Bleeding
In clinical studies, serious bleeding (e.g., gastrointestinal, intracranial hemorrhage) was reported in 4% vs 1% (STELLAR) and 7% vs 5% (ZENITH) of patients taking WINREVAIR vs placebo, respectively . Patients with serious bleeding were more likely to be on prostacyclin background therapy and/or antithrombotic agents, or have low platelet counts. Advise patients about signs and symptoms of blood loss. Evaluate and treat bleeding accordingly.
Do not administer WINREVAIR if the patient is experiencing serious bleeding .
Embryo-Fetal Toxicity
Based on findings in animal reproduction studies, WINREVAIR may cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of WINREVAIR to pregnant rats and rabbits during organogenesis resulted in adverse developmental outcomes, including increased embryo-fetal mortality, alterations to growth, and structural variations at exposures 4-fold and 0.6-fold (based on area under the curve ) those occurring at the maximum recommended human dose (MRHD), respectively. Advise pregnant women of the potential risk to a fetus.
Advise females of reproductive potential to use an effective method of contraception during treatment with WINREVAIR and for at least 4 months after the final dose .
Impaired Fertility
Based on findings in animals, WINREVAIR may impair female and male fertility. Advise patients on the potential effects on fertility.
Pregnancy Safety for Winrevair
Pregnancy Risk Summary Based on findings in animal reproduction studies, WINREVAIR may cause fetal harm when administered to a pregnant woman. There are risks to the mother and the fetus associated with pulmonary arterial hypertension in pregnancy (see Clinical Considerations ). There are no available data on WINREVAIR use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, administration of WINREVAIR to pregnant rats and rabbits during the period of organogenesis resulted in adverse developmental outcomes, including embryo-fetal mortality, alterations to growth, and structural variations at exposures 4-fold and 0.6-fold (based on area under the curve ) above those occurring at the maximum recommended human dose (MRHD), respectively (see Data ). Advise pregnant women of the potential risk to a fetus . The background risk of major birth defects and miscarriage for the indicated population is not known.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Report exposure during pregnancy or lactation to the Merck Sharp & Dohme, LLC Adverse Event reporting line at 1-877-888-4231. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk In patients with pulmonary arterial hypertension, pregnancy is associated with an increased rate of maternal and fetal morbidity and mortality, including spontaneous abortion, intrauterine growth restriction, and premature labor.
Data Animal Data In embryo-fetal developmental toxicity studies, pregnant animals were dosed subcutaneously with sotatercept-csrk during the period of organogenesis. Sotatercept-csrk was administered to rats on gestation days 6 and 13 at doses of 5, 15, or 50 mg/kg and to rabbits on gestation days 7 and 14 at doses of 0.5, 1.5, or 5 mg/kg. Effects in both species included reductions in numbers of live fetuses and fetal body weights, delays in ossification, and increases in resorptions and post-implantation losses.
In rats and rabbits, these effects were observed at exposures (based on area under the curve ) approximately 4-fold and 0.6-fold the maximum recommended human dose (MRHD), respectively. In rats only, skeletal variations (increased number of supernumerary ribs and changes in the number of thoracic or lumbar vertebrae) occurred at an exposure 15-fold the human exposure at the MRHD. In a prenatal and postnatal development study in rats, sotatercept-csrk was administered subcutaneously at doses of 1.5 and 5 mg/kg on gestation days 6 and 13, or at dosages of 1.5, 5, or 10 mg/kg during lactation on days 1, 8, and 15. There were no adverse effects in first filial generation (F1) pups from dams dosed during gestation at estimated exposures up to 2-fold the MRHD. In F1 pups from dams dosed during lactation, decreases in pup weight correlated with delays in sexual maturation at estimated exposures (based on AUC) ≥2-fold the MRHD.
Pediatric Use of Winrevair
Pediatric Use The safety and effectiveness of WINREVAIR have not been established in patients less than 18 years of age.
Overdosage Information for Winrevair
In healthy volunteers, WINREVAIR dosed at 1 mg/kg resulted in increases in Hgb associated with hypertension; both improved with phlebotomy. In the event of overdose, monitor closely for increases in Hgb and blood pressure, and provide supportive care as appropriate. WINREVAIR is not dialyzable.
Clinical Studies of Winrevair
Pulmonary Arterial Hypertension
STELLAR 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. Figure 1: Change from Baseline in 6-Minute Walk Distance (meters) at Week 24 in Subgroups in STELLAR * Hodges-Lehmann location shift from placebo estimate (median of all paired differences). ASE = asymptotic 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. 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 5 and 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). Table 5: Death from Any Cause or PAH Clinical Worsening Events in STELLAR 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 42 0.16 p<0.001 Assessment of clinical worsening events A subject can have more than one assessment recorded for their clinical worsening. Death 2 7 Worsening-related listing for lung and/or heart transplant 1 2 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 17 Need for atrial septostomy There were no events of atrial septostomy. 0 0 PAH-specific hospitalization (≥24 hours) 0 8 Deterioration of PAH Deterioration 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 15 Figure 2: Time to Death from Any Cause or First Occurrence of PAH Clinical Worsening Event Kaplan-Meier Plot in STELLAR ZENITH 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 than in the placebo group 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 ). Table 6: Primary Endpoint Results in ZENITH WINREVAIR (N=86) n (%) Placebo (N=86) n (%) Hazard Ratio (95% CI) p-value Number of participants with at least 1 primary event The 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 47 0.24 <0.0001 Components of primary endpoint Shows 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 13 Lung transplantation 1 6 PAH worsening-related to hospitalization (≥24 hours) 8 43 Figure 3: Time to First Event in ZENITH of All-cause Death, Lung Transplantation, or PAH Worsening-related Hospitalization of ≥ 24 Hours Kaplan-Meier Plot Figure 4: Hazard Ratio for the Primary Endpoint in Subgroups in ZENITH 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. 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. Figure 1 Figure 2 Figure 138 Figure 139
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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