Sotatercept-Csrk

1 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. ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended starting dose is 0.3 mg/kg by subcutaneous injection. ( 2.1 ) The recommended target dose is 0.7 mg/kg every 3 weeks by subcutaneous injection. ( 2.2 ) 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 ) See full prescribing information for preparation and administration instructions. ( 2.4 ) 2.1 Recommended Starting Dosage WINREVAIR 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/mm 3 (<50 x 10 9 /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/kg 50 mg/mL Injection 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 1 for 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) 2.2 Recommended Target Dosage After 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/kg 50 mg/mL Injection 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 2 for 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 Underdose If 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) ] . 2.3 Dosage Modifications Due to Hemoglobin Increase or Platelet Count Decrease Check 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/mm 3 (<50 x 10 9 /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. 2.4 Preparation and Administration Administration 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 Kit If 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 Instructions WINREVAIR 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.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Erythrocytosis [see Warnings and Precautions (5.1) ] Severe Thrombocytopenia [see Warnings and Precautions (5.2) ] Serious Bleeding [see Warnings and Precautions (5.3) ] Embryo-Fetal Toxicity [see Warnings and Precautions (5.4) ] Impaired Fertility [see Warnings and Precautions (5.5) ] The most common (≥10% in patients receiving WINREVAIR and 5% more than placebo) adverse reactions were infections, epistaxis, telangiectasia, diarrhea, headache, rash, increased hemoglobin, dizziness, erythema, and gingival bleeding. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 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 [see Clinical Studies (14.1) ]. 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 (24.5) 28 (17.5) Epistaxis 36 (22.1) 3 (1.9) Rash 33 (20.2) 13 (8.1) Telangiectasia 27 (16.6) 7 (4.4) Diarrhea 25 (15.3) 16 (10.0) Dizziness 24 (14.7) 10 (6.3) Erythema 22 (13.5) 5 (3.1) 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) [see Clinical Studies (14.1) ]. 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 (67.4) 38 (44.2) Epistaxis 39 (45.3) 8 (9.3) Diarrhea 22 (25.6) 15 (17.4) Telangiectasia 22 (25.6) 3 (3.5) Increased hemoglobin 13 (15.1) 1 (1.2) Rash 9 (10.5) 4 (4.7) Erythema 9 (10.5) 3 (3.5) Gingival bleeding 9 (10.5) 2 (2.3) 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. 6.2 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

12.3 Pharmacokinetics Following subcutaneous administration of 0.7 mg/kg WINREVAIR every three weeks to PAH patients (PULSAR, SPECTRA, and STELLAR), the steady state geometric mean (%CV) area under the time concentration curve (AUC) is 171.3 mcg×d/mL (34.2%), and peak concentration (C max ) is 9.7 mcg/mL (30%). Sotatercept-csrk AUC and C max increased proportionally with dose. Steady state is achieved after approximately 15 weeks following initiation of multiple dosing. The accumulation ratio of sotatercept-csrk AUC is approximately 2.2. Sotatercept-csrk pharmacokinetics were similar in PAH participants in ZENITH. Absorption Following subcutaneous administration, the absolute bioavailability of sotatercept-csrk is approximately 66%. The sotatercept-csrk median time to peak drug concentration (T max ) is approximately 7 days (range from 2 to 8 days) following multiple SC administration every 4 weeks. Distribution The population PK model estimated volume of distribution (%CV) of sotatercept-csrk at steady state is approximately 5.3 L (27.3%) in patients with PAH. Elimination The sotatercept-csrk effective half-life is approximately 24 days and its clearance is approximately 0.18 L/day. Metabolism Sotatercept-csrk is expected to be metabolized into small peptides by catabolic pathways. Specific Populations No clinically significant differences in sotatercept-csrk pharmacokinetics (PK) were observed based on age (18 to 81 years of age), sex, race, mild to moderate (eGFR ranging from 30 to 89 mL/min) renal impairment (PAH patients), or end-stage kidney disease (eGFR <15 mL/min) with dialysis. Based on limited data, severe renal impairment (eGFR ranging from 15 to 30 mL/min, n=3) had no impact on the PK of sotatercept-csrk. Sotatercept-csrk is not dialyzable. The effect of hepatic impairment on the PK of sotatercept-csrk has not been studied. Body Weight The clearance (CL) and central volume of distribution (Vc) increase with increase in body weight. This effect is not clinically significant when sotatercept-csrk is administered using weight-based dosing as recommended.