Methods of treating pulmonary arterial hypertension with activin receptor type IIA (ACTRIIA) protein and / or variants thereof

Abstract

The present invention relates to therapies useful for treating pulmonary arterial hypertension. In particular, the present invention relates to a method of treating pulmonary arterial hypertension comprising administering to a patient in need thereof an ActRIIA-Fc fusion protein or a variant thereof using the dosage regimen specified herein.

Description

Cross-reference to related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 607,422, filed December 7, 2023. The aforementioned application is incorporated herein by reference. Reference to the sequence listing submitted electronically

[0002] The contents of the electronic sequence list (1848179-0002-173-WO1_SL.xml; size: 36,788 bytes; and creation date: December 5, 2024) are incorporated herein by reference in their entirety. Technical Field

[0003] This invention relates to therapies that can be used to treat pulmonary hypertension. In particular, this invention relates to a method for treating pulmonary hypertension, the method comprising administering ActRIIA-Fc fusion protein or a variant thereof to a patient in need using a dosage regimen specified herein. Background Technology

[0004] Pulmonary arterial hypertension (PAH) is a debilitating disease characterized by elevated blood pressure in the pulmonary arteries, leading to progressive heart failure and shortened life expectancy. Dysregulation of signal transduction involving transforming growth factor β (TGF-β) superfamily members (including bone morphogenetic protein receptor type II (BMPR-II), activin receptor type IIA (ActRIIA), and ActRIIA ligands activin A, activin B, growth differentiation factor 8 (GDF8), and GDF11) is implicated in the pathogenesis of the underlying disease. An imbalance between BMPR-II-mediated antiproliferative signals and ActRIIA and its ligands-mediated proproliferative signals leads to pulmonary artery vascular remodeling.

[0005] Sotatercept, an activin receptor type IIA-Fc fusion protein, resolves the imbalance between activin / growth differentiation factor and bone morphogenetic protein signaling. Sotatercept captures activin A to improve cardiopulmonary function in patients with PAH and has been shown to reverse pulmonary artery wall and right ventricular remodeling. The phase 3 randomized controlled trial STELLAR (NCT04576988) demonstrated the clinical benefit of sotatercept as adjunctive therapy to patients with stable PAH backgrounds, with an increase of 40.8 meters in 6-minute walk distance (6MWD) and an 84% reduction in time to clinical deterioration (hazard ratio [HR] 0.16, 95% CI 0.08–0.35). Background therapy is defined as standard care for PAH during STELLAR, including monotherapy, dual therapy, or triple therapy in certain combinations of endothelin receptor antagonists (ERAs), phosphodiesterase type 5 (PDE-5) inhibitors, soluble guanylate cyclase (sGC) stimulators, prostaglandin I2 (PGI2) analogs, and PGI2 agonists.

[0006] Throughout the STELLAR study, sotecavir was administered based on individual patient weight (weight-based dosing). Patients were given an initial dose of 0.3 mg / kg and a second or maintenance dose of 0.7 mg / kg. Using a weight-based dosing regimen places a burden on healthcare professionals who need to calculate the dose before administration. Furthermore, sotecavir is provided in lyophilized vials containing 45 mg or 65 mg; therefore, unused sotecavir is wasted if the patient does not require the total dose prepared by the healthcare professional.

[0007] Therefore, there is a desire to shift from weight-based dosing to weight-zone dosing (based on comparing the patient's weight to a pre-selected dose within a predetermined weight zone, rather than dosing based on each individual's specific weight). This method of dosing will maintain safety and efficacy while providing greater convenience for patients and healthcare professionals by simplifying administration, saving time, and eliminating the chance of error. Furthermore, weight-zone dosing helps reduce drug waste and lower the demand for drug supplies. In addition, weight-zone dosing can facilitate further patient improvements, such as the use of auto-injectors administered by healthcare professionals or for self-administration. Summary of the Invention

[0008] This disclosure provides a therapy that can be used to treat pulmonary hypertension. In particular, the present invention relates to a method for treating pulmonary hypertension, the method comprising administering ActRIIA-Fc fusion protein or a variant thereof to a patient in need using a dosage regimen specified herein. In one aspect, this disclosure provides a method for treating pulmonary hypertension in a patient with this need, the method comprising administering to the patient an initial dose of a human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking a C-terminal lysine (e.g., SEQ ID NO: 41), wherein the initial dose is 15 mg or a multiple of 15 mg, and the dose administered to the patient is determined by comparing the patient's weight with a list of predetermined weight intervals and selecting a pre-selected dose for a weight interval corresponding to the patient's weight as the initial dose.

[0009] In some embodiments, the initial dose is 15 mg, 30 mg, or 45 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine, such as a variant consisting of SEQ ID NO: 41.

[0010] In some embodiments of the dosing regimens described herein, the body weight range is selected from the following: <50 kg, [50-75) kg, [75-100) kg, [100-125) kg, and >125 kg, wherein the initial dose of the ActRIIA-Fc fusion protein or a variant of the ActRIIA-Fc fusion protein is selected from one of the following: (a) For patients weighing less than 50 kg, 15 mg, (b) For patients weighing between 50 kg and 75 kg but excluding 75 kg, 15 mg, (c) For patients weighing between 75 kg and 100 kg but not exceeding 100 kg, 30 mg, (d) For patients weighing between 100 kg and 125 kg but excluding 125 kg, 30 mg, or (e) For patients weighing 125 kg or more, 45 mg.

[0011] In another aspect, this disclosure provides a method for treating pulmonary hypertension in a patient with this need, wherein the initial dose is as described above, and wherein the method further comprises administering to the patient a maintenance dose of a human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41, wherein the maintenance dose is a multiple of 15, and the dose administered to the patient is determined based on which weight range the patient's weight falls into.

[0012] In some embodiments, the maintenance dose is 30 mg, 45 mg, 60 mg, 75 mg, or 90 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine, such as a variant consisting of SEQ ID NO: 41.

[0013] In certain embodiments of the dosing regimens described herein, the body weight range is selected from the following: <50 kg, [50-75) kg, [75-100) kg, [100-125) kg, [125-150) kg, or >150 kg, wherein the maintenance dose of the ActRIIA-Fc fusion protein or a variant of the ActRIIA-Fc fusion protein is selected from one of the following: (a) For patients weighing less than 50 kg, 30 mg, (b) For patients weighing between 50 kg and 75 kg but excluding 75 kg, 45 mg, (c) For patients weighing between 75 kg and 100 kg but not exceeding 100 kg, 60 mg, (d) For patients weighing between 100 kg and 125 kg but excluding 125 kg, 75 mg, or (e) For patients weighing 125 kg or more, 90 mg.

[0014] In some embodiments of the dosing regimen described herein, a maintenance dose is administered to the patient every 3 weeks, wherein the first maintenance dose is administered 3 weeks after the initial dose.

[0015] In another aspect, this disclosure provides a method for treating pulmonary hypertension in patients with this need, the method comprising administering to the patient an initial dose of 10-50 mg of human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine (e.g., human ActRIIA-Fc fusion protein comprising SEQ ID NO: 41) if the patient weighs less than 150 kg.

[0016] In some embodiments, the patient is given an initial dose of 15-45 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41), and the patient weighs less than 150 kg.

[0017] In some embodiments, the patient is given an initial dose of 10-20 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41), and the patient weighs less than 75 kg.

[0018] In some embodiments, the patient is given an initial dose of 20-30 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41), and the patient weighs less than 125 kg.

[0019] In some implementations, the patient is given an initial dose of 30-50 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41), and the patient weighs less than 150 kg.

[0020] In some embodiments, the patient is given an initial dose of 15 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41), and the patient weighs less than 75 kg.

[0021] In some embodiments, the patient is given an initial dose of 15 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41), and the patient weighs less than 50 kg.

[0022] In some embodiments, the patient is given an initial dose of 30 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41), and the patient's weight is between 75-100 kg.

[0023] In some embodiments, the patient is given an initial dose of 30 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41), and the patient's weight is between 100-125 kg.

[0024] In some embodiments, the patient is given an initial dose of 45 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41), and the patient's weight is between [125-150) kg.

[0025] In another aspect, this disclosure provides a method for treating pulmonary hypertension in a patient with this need, the method comprising administering to the patient, if the patient weighs less than 150 kg, a maintenance dose of 20-100 mg of a human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking a C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41).

[0026] In some embodiments, a maintenance dose of 20-40 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41) is administered to the patient, and the patient weighs less than 50 kg.

[0027] In some implementations, a maintenance dose of 40-50 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41) is administered to the patient, and the patient weighs less than 75 kg.

[0028] In some embodiments, a maintenance dose of 50-70 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41) is administered to the patient, and the patient weighs less than 100 kg.

[0029] In some embodiments, a maintenance dose of 70-80 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41) is administered to the patient, and the patient weighs less than 125 kg.

[0030] In some embodiments, a maintenance dose of 80-90 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41) is administered to the patient, and the patient weighs less than 150 kg.

[0031] In some embodiments, a maintenance dose of 30 mg of human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41) is administered to the patient, and the patient weighs less than 50 kg.

[0032] In some embodiments, a maintenance dose of 45 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41) is administered to the patient, and the patient's weight is between 50-75 kg.

[0033] In some embodiments, a maintenance dose of 60 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41) is administered to the patient, and the patient's weight is between [75-100) kg.

[0034] In some embodiments, a maintenance dose of 75 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41) is administered to the patient, and the patient's weight is between [100-125) kg.

[0035] In some embodiments, the patient is given a maintenance dose of 75 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41), and the patient's weight is between [125-150) kg.

[0036] In another aspect, this disclosure provides a method for treating pulmonary hypertension in patients with this need, the method comprising administering to the patient an initial dose of 40-50 mg of human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41) if the patient weighs 125 kg or more.

[0037] In some embodiments, the patient is given an initial dose of 40-50 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41), and the patient weighs ≥150 kg.

[0038] In some embodiments, the patient is given an initial dose of 45 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41), and the patient weighs ≥125 kg.

[0039] In some embodiments, the patient is given an initial dose of 45 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41), and the patient weighs ≥150 kg.

[0040] In some implementations, if the patient weighs 125 kg or more, a maintenance dose of 50-100 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41) is administered to the patient.

[0041] In some embodiments, a maintenance dose of 75-100 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41) is administered to the patient, and the patient weighs ≥125 kg.

[0042] In some embodiments, a maintenance dose of 90 mg of human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking the C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41) is administered to the patient, and the patient weighs ≥150 kg.

[0043] In some embodiments, an initial dose of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41) is administered to the patient on day 1, and a maintenance dose of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41) is administered every three weeks from day 1.

[0044] In another aspect, this disclosure provides a method for treating pulmonary hypertension in patients with this need, the method comprising, on day 1, administering an initial dose of 15 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41) to the patient if the patient weighs less than 50 kg; and, on day 1, administering a maintenance dose of 30 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of SEQ ID NO: 32 lacking C-terminal lysine (e.g., a variant consisting of SEQ ID NO: 41) to the patient every three weeks.

[0045] In another aspect, this disclosure provides a method for treating pulmonary hypertension in a patient with this need, the method comprising administering an initial dose of 15 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant ActRIIA-Fc fusion protein containing SEQ ID NO: 41 to the patient on day 1 if the patient's weight is between [50-75) kg; and administering a maintenance dose of 45 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant ActRIIA-Fc fusion protein containing SEQ ID NO: 41 to the patient every three weeks starting from day 1 if the patient's weight is between [50-75) kg.

[0046] In another aspect, this disclosure provides a method for treating pulmonary hypertension in a patient with this need, the method comprising administering an initial dose of 30 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant ActRIIA-Fc fusion protein containing SEQ ID NO: 41 to the patient on day 1 if the patient weighs 75 kg or more; and administering a maintenance dose of 50-100 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant ActRIIA-Fc fusion protein containing SEQ ID NO: 41 to the patient every three weeks starting from day 1 if the patient weighs 75 kg or more.

[0047] In another aspect, this disclosure provides a method for treating pulmonary hypertension in a patient with this need, the method comprising administering an initial dose of 30 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant ActRIIA-Fc fusion protein containing SEQ ID NO: 41 to the patient on day 1 if the patient's weight is between [75-100) kg; and administering a maintenance dose of 60 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant ActRIIA-Fc fusion protein containing SEQ ID NO: 41 to the patient every three weeks starting from day 1 if the patient's weight is between [75-100) kg.

[0048] In another aspect, this disclosure provides a method for treating pulmonary hypertension in a patient with this need, the method comprising administering an initial dose of 30 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant ActRIIA-Fc fusion protein containing SEQ ID NO: 41 to the patient on day 1 if the patient's weight is between [100-125) kg; and administering a maintenance dose of 75 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant ActRIIA-Fc fusion protein containing SEQ ID NO: 41 to the patient every three weeks starting from day 1 if the patient's weight is between [100-125) kg.

[0049] In another aspect, this disclosure provides a method for treating pulmonary hypertension in a patient with this need, the method comprising administering an initial dose of 45 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant ActRIIA-Fc fusion protein containing SEQ ID NO: 41 to the patient on day 1 if the patient weighs 125 kg or more; and administering a maintenance dose of 90 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant ActRIIA-Fc fusion protein containing SEQ ID NO: 41 to the patient every three weeks starting from day 1 if the patient weighs 125 kg or more.

[0050] In another aspect, this disclosure provides a method for treating pulmonary hypertension in a patient with this need, the method comprising administering to the patient an initial dose of human ActRIIA-Fc fusion protein (which contains the amino acid sequence shown in SEQ ID NO: 32) or a variant of human ActRIIA-Fc fusion protein (which contains the amino acid sequence shown in SEQ ID NO: 41), wherein the initial dose is 15 mg or a multiple of 15 mg, and the initial dose is determined by comparing the patient's weight with a list of predetermined weight intervals and selecting a pre-selected dose for a weight interval corresponding to the patient's weight as the initial dose.

[0051] In some implementations, the initial dose is selected from one of the following predetermined weight ranges:

[0052] (a) For patients weighing less than 50 kg, 15 mg,

[0053] (b) For patients weighing between 50 kg and 75 kg but excluding 75 kg, 15 mg,

[0054] (c) For patients weighing between 75 kg and 100 kg but not exceeding 100 kg, 30 mg,

[0055] (d) For patients weighing between 100 kg and 125 kg but excluding 125 kg, 30 mg, or

[0056] (e) For patients weighing 125 kg or more, 45 mg.

[0057] In another aspect, this disclosure provides a method for treating pulmonary hypertension in a patient with this need, the method further comprising administering to the patient a maintenance dose of a human ActRIIA-Fc fusion protein (which comprises the amino acid sequence shown in SEQ ID NO: 32) or a variant of the human ActRIIA-Fc fusion protein (which comprises the amino acid sequence shown in SEQ ID NO: 41), wherein the maintenance dose is a multiple of 15 mg, and the maintenance dose is determined by comparing the patient's weight with a list of predetermined weight intervals and selecting a pre-selected dose for a weight interval corresponding to the patient's weight as the maintenance dose, wherein the maintenance dose is administered to the patient approximately 3 weeks after the initial dose.

[0058] In some implementations, the maintenance dose is selected from one of the following predetermined weight ranges:

[0059] (a) For patients weighing less than 50 kg, 30 mg,

[0060] (b) For patients weighing between 50 kg and 75 kg but excluding 75 kg, 45 mg,

[0061] (c) For patients weighing between 75 kg and 100 kg but not exceeding 100 kg, 60 mg,

[0062] (d) For patients weighing between 100 kg and 125 kg but excluding 125 kg, 75 mg, or

[0063] (e) For patients weighing 125 kg or more, 90 mg.

[0064] In some implementations, a maintenance dose is administered to the patient every 3 weeks.

[0065] In some implementations, the initial and / or maintenance doses of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein are administered to the patient via subcutaneous injection.

[0066] In some implementations, the initial and / or maintenance doses of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein are administered to the patient using an autoinjector.

[0067] In some implementations, a maintenance dose of human ActRIIA-Fc fusion protein or a variant of human ActRIIA-Fc fusion protein is administered to the patient using an autoinjector.

[0068] In some implementations, an initial dose of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient using an autoinjector.

[0069] In some implementations, the maintenance dose is administered via a single injection.

[0070] In some implementations, the patient weighs 125 kg or more, and the maintenance dose is 90 mg, which is administered to the patient in a single injection.

[0071] In some implementations, the patient weighs 125 kg or more, and the maintenance dose is 90 mg, which is administered to the patient in two or more injections.

[0072] In some implementations, a maintenance dose is administered to the patient every 3 weeks for 72 weeks or less.

[0073] In some implementations, patients are further treated with one or more additional PAH therapies. Additional PAH therapies include, but are not limited to: phosphodiesterase-5 inhibitors (PDE-5i), soluble guanylate cyclase stimulators (sGCS), endothelin receptor antagonists (ERA), and prostacyclin therapies (prostacyclin = PCY).

[0074] In another aspect, this disclosure provides a method for treating pulmonary hypertension in a patient with this need, the method comprising administering to the patient an initial dose of sotexip or a sotexip variant lacking a C-terminal lysine, wherein the initial dose is selected from the group consisting of:

[0075] (a) For patients weighing less than 50 kg, 15 mg,

[0076] (b) For patients weighing between 50 kg and 75 kg but excluding 75 kg, 15 mg,

[0077] (c) For patients weighing between 75 kg and 100 kg but not exceeding 100 kg, 30 mg,

[0078] (d) For patients weighing between 100 kg and 125 kg but excluding 125 kg, 30 mg, and

[0079] (e) For patients weighing 125 kg or more, 45 mg.

[0080] In another aspect, this disclosure provides a method for treating pulmonary hypertension in a patient with this need, the method further comprising administering a maintenance dose of sotexip or a sotexip variant lacking a C-terminal lysine to the patient approximately 3 weeks after an initial dose, wherein the maintenance dose is selected from the group consisting of:

[0081] (a) For patients weighing less than 50 kg, 30 mg,

[0082] (b) For patients weighing between 50 kg and 75 kg but excluding 75 kg, 45 mg,

[0083] (c) For patients weighing between 75 kg and 100 kg but not exceeding 100 kg, 60 mg,

[0084] (d) For patients weighing between 100 kg and 125 kg but excluding 125 kg, 75 mg, and

[0085] (e) For patients weighing 125 kg or more, 90 mg.

[0086] In some implementations, patients are given two or more maintenance doses of sotexip, with approximately three weeks between each dose.

[0087] In some implementations, the initial and / or maintenance doses of sotexip are administered to the patient via subcutaneous injection.

[0088] In some implementations, the initial and / or maintenance doses of sotexip are administered to the patient using an autoinjector.

[0089] In another aspect, this disclosure provides a method for treating pulmonary hypertension in a patient with this need, the method comprising administering to the patient an initial dose of 10-50 mg of human ActRIIA-Fc fusion protein (which contains the amino acid sequence shown in SEQ ID NO: 32) or a variant of human ActRIIA-Fc fusion protein (which contains the amino acid sequence shown in SEQ ID NO: 41), wherein the patient weighs less than 150 kg.

[0090] In some implementations, patients are given an initial dose of 15-45 mg of human ActRIIA-Fc fusion protein or a variant of human ActRIIA-Fc fusion protein.

[0091] In some implementations, an initial dose of 10-20 mg of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to a patient who weighs less than 75 kg.

[0092] In some implementations, an initial dose of 20-30 mg of human ActRIIA-Fc fusion protein or a variant of human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs less than 125 kg.

[0093] In some implementations, an initial dose of 30-50 mg of human ActRIIA-Fc fusion protein or a variant of human ActRIIA-Fc fusion protein is administered to the patient, where the patient weighs less than 150 kg.

[0094] In some implementations, a patient is given an initial dose of 15 mg of human ActRIIA-Fc fusion protein or a variant of human ActRIIA-Fc fusion protein, wherein the patient weighs less than 75 kg.

[0095] In some implementations, a patient is given an initial dose of 15 mg of human ActRIIA-Fc fusion protein or a variant of human ActRIIA-Fc fusion protein, wherein the patient weighs less than 50 kg.

[0096] In some implementations, a patient is given an initial dose of 30 mg of human ActRIIA-Fc fusion protein or a variant of human ActRIIA-Fc fusion protein, wherein the patient weighs between 75 kg and 100 kg (but not 100 kg).

[0097] In some implementations, a patient is given an initial dose of 30 mg of human ActRIIA-Fc fusion protein or a variant of human ActRIIA-Fc fusion protein, wherein the patient weighs between 100 kg and 125 kg (but not including 125 kg).

[0098] In some implementations, a patient is given an initial dose of 45 mg of human ActRIIA-Fc fusion protein or a variant of human ActRIIA-Fc fusion protein, wherein the patient weighs between 125 kg and 150 kg (but not including 150 kg).

[0099] In another aspect, this disclosure provides a method for treating pulmonary hypertension in patients with this need, the method comprising administering to the patient a maintenance dose of 20-100 mg of human ActRIIA-Fc fusion protein or a variant of human ActRIIA-Fc fusion protein, wherein the patient weighs less than 150 kg.

[0100] In some implementations, a maintenance dose of 20-40 mg of human ActRIIA-Fc fusion protein or a variant of human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs less than 50 kg.

[0101] In some implementations, a maintenance dose of 40-50 mg of human ActRIIA-Fc fusion protein or a variant of human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs less than 75 kg.

[0102] In some implementations, a maintenance dose of 50-70 mg of human ActRIIA-Fc fusion protein or a variant of human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs less than 100 kg.

[0103] In some implementations, a maintenance dose of 70-80 mg of human ActRIIA-Fc fusion protein or a variant of human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs less than 125 kg.

[0104] In some implementations, a maintenance dose of 80-90 mg of human ActRIIA-Fc fusion protein or a variant of human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs less than 150 kg.

[0105] In some implementations, a maintenance dose of 30 mg of human ActRIIA-Fc fusion protein or a variant of human ActRIIA-Fc fusion protein is administered to a patient who weighs less than 50 kg.

[0106] In some implementations, a maintenance dose of 45 mg of human ActRIIA-Fc fusion protein or a variant of human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs between 50 kg and 75 kg (but not including 75 kg).

[0107] In some implementations, a maintenance dose of 60 mg of human ActRIIA-Fc fusion protein or a variant of human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs between 75 kg and 100 kg (but not 100 kg).

[0108] In some implementations, a maintenance dose of 75 mg of human ActRIIA-Fc fusion protein or a variant of human ActRIIA-Fc fusion protein is administered to a patient who weighs between 100 kg and 125 kg (but not 125 kg).

[0109] In some implementations, a maintenance dose of 75 mg of human ActRIIA-Fc fusion protein or a variant of human ActRIIA-Fc fusion protein is administered to a patient who weighs between 125 kg and 150 kg (but not 150 kg).

[0110] In another aspect, this disclosure provides a method for treating pulmonary hypertension in a patient with this need, the method comprising administering an initial dose of 40-50 mg of human ActRIIA-Fc fusion protein (which contains the amino acid sequence shown in SEQ ID NO: 32) or a variant of human ActRIIA-Fc fusion protein (which contains the amino acid sequence shown in SEQ ID NO: 41) to the patient, wherein the patient weighs ≥125 kg.

[0111] In some implementations, an initial dose of 40-50 mg of human ActRIIA-Fc fusion protein or a variant of human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs 150 kg or more.

[0112] In some implementations, a patient is given an initial dose of 45 mg of human ActRIIA-Fc fusion protein or a variant of human ActRIIA-Fc fusion protein, wherein the patient weighs 125 kg or more.

[0113] In some implementations, a patient is given an initial dose of 45 mg of human ActRIIA-Fc fusion protein or a variant of human ActRIIA-Fc fusion protein, wherein the patient weighs 150 kg or more.

[0114] In another aspect, this disclosure provides a method for treating pulmonary hypertension in a patient, the method further comprising administering a maintenance dose of 50-100 mg of human ActRIIA-Fc fusion protein or a variant of human ActRIIA-Fc fusion protein to the patient, wherein the patient weighs ≥125 kg.

[0115] In some implementations, a maintenance dose of 75-100 mg of human ActRIIA-Fc fusion protein or a variant of human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs ≥125 kg.

[0116] In some implementations, a maintenance dose of 90 mg of human ActRIIA-Fc fusion protein or a variant of human ActRIIA-Fc fusion protein is administered to a patient whose weight is greater than or equal to 150 kg.

[0117] In some implementations, an initial dose of human ActRIIA-Fc fusion protein or a variant of human ActRIIA-Fc fusion protein is administered to the patient, followed by a maintenance dose of human ActRIIA-Fc fusion protein or a variant of human ActRIIA-Fc fusion protein, wherein the maintenance dose is administered to the patient approximately 3 weeks after the initial dose.

[0118] In another aspect, this disclosure provides a method for treating pulmonary hypertension in patients with this need, the method comprising administering an initial dose of 15 mg of human ActRIIA-Fc fusion protein (containing the amino acid sequence shown in SEQ ID NO: 32) or a variant of human ActRIIA-Fc fusion protein (containing the amino acid sequence shown in SEQ ID NO: 41) to the patient on day 1; and administering a maintenance dose of 30 mg of human ActRIIA-Fc fusion protein (containing the amino acid sequence shown in SEQ ID NO: 32) or a variant of human ActRIIA-Fc fusion protein (containing the amino acid sequence shown in SEQ ID NO: 41) to the patient every three weeks starting from day 1, wherein the patient weighs less than 50 kg.

[0119] In another aspect, this disclosure provides a method for treating pulmonary hypertension in a patient with this need, the method comprising administering an initial dose of 15 mg of human ActRIIA-Fc fusion protein (containing the amino acid sequence shown in SEQ ID NO: 32) or a variant of human ActRIIA-Fc fusion protein (containing the amino acid sequence shown in SEQ ID NO: 41) to the patient on day 1; and administering a maintenance dose of 45 mg of human ActRIIA-Fc fusion protein (containing the amino acid sequence shown in SEQ ID NO: 32) or a variant of human ActRIIA-Fc fusion protein (containing the amino acid sequence shown in SEQ ID NO: 41) to the patient every three weeks starting from day 1, wherein the patient weighs [50-75) kg.

[0120] In another aspect, this disclosure provides a method for treating pulmonary hypertension in patients with this need, the method comprising administering an initial dose of 30 mg of human ActRIIA-Fc fusion protein (containing the amino acid sequence shown in SEQ ID NO: 32) or a variant of human ActRIIA-Fc fusion protein (containing the amino acid sequence shown in SEQ ID NO: 41) to the patient on day 1; and administering a maintenance dose of 50-100 mg of human ActRIIA-Fc fusion protein (containing the amino acid sequence shown in SEQ ID NO: 32) or a variant of human ActRIIA-Fc fusion protein (containing the amino acid sequence shown in SEQ ID NO: 41) to the patient every three weeks starting from day 1, wherein the patient weighs ≥75 kg.

[0121] In another aspect, this disclosure provides a method for treating pulmonary hypertension in a patient with this need, the method comprising administering an initial dose of 30 mg of human ActRIIA-Fc fusion protein (containing the amino acid sequence shown in SEQ ID NO: 32) or a variant of human ActRIIA-Fc fusion protein (containing the amino acid sequence shown in SEQ ID NO: 41) to the patient on day 1; and administering a maintenance dose of 60 mg of human ActRIIA-Fc fusion protein (containing the amino acid sequence shown in SEQ ID NO: 32) or a variant of human ActRIIA-Fc fusion protein (containing the amino acid sequence shown in SEQ ID NO: 41) to the patient every three weeks starting from day 1, wherein the patient's weight is between [75-100) kg.

[0122] In another aspect, this disclosure provides a method for treating pulmonary hypertension in a patient with this need, the method comprising administering an initial dose of 30 mg of human ActRIIA-Fc fusion protein (containing the amino acid sequence shown in SEQ ID NO: 32) or a variant of human ActRIIA-Fc fusion protein (containing the amino acid sequence shown in SEQ ID NO: 41) to the patient on day 1; and administering a maintenance dose of 75 mg of human ActRIIA-Fc fusion protein (containing the amino acid sequence shown in SEQ ID NO: 32) or a variant of human ActRIIA-Fc fusion protein (containing the amino acid sequence shown in SEQ ID NO: 41) to the patient every three weeks starting from day 1, wherein the patient's weight is between [100-125) kg.

[0123] In another aspect, this disclosure provides a method for treating pulmonary hypertension in patients with this need, the method comprising administering an initial dose of 45 mg of human ActRIIA-Fc fusion protein (containing the amino acid sequence shown in SEQ ID NO: 32) or a variant of human ActRIIA-Fc fusion protein (containing the amino acid sequence shown in SEQ ID NO: 41) to the patient on day 1; and administering a maintenance dose of 90 mg of human ActRIIA-Fc fusion protein (containing the amino acid sequence shown in SEQ ID NO: 32) or a variant of human ActRIIA-Fc fusion protein (containing the amino acid sequence shown in SEQ ID NO: 41) to the patient every three weeks starting from day 1, wherein the patient weighs ≥125 kg.

[0124] In some embodiments, an initial dose and / or maintenance dose of human ActRIIA-Fc fusion protein (which contains the amino acid sequence shown in SEQ ID NO: 32) or a variant of human ActRIIA-Fc fusion protein (which contains the amino acid sequence shown in SEQ ID NO: 41) is administered to the patient via subcutaneous injection.

[0125] In some embodiments, an initial dose and / or maintenance dose of human ActRIIA-Fc fusion protein (which contains the amino acid sequence shown in SEQ ID NO: 32) or a variant of human ActRIIA-Fc fusion protein (which contains the amino acid sequence shown in SEQ ID NO: 41) is administered to the patient using an autoinjector.

[0126] In some embodiments, a maintenance dose of human ActRIIA-Fc fusion protein (which contains the amino acid sequence shown in SEQ ID NO: 32) or a variant of human ActRIIA-Fc fusion protein (which contains the amino acid sequence shown in SEQ ID NO: 41) is administered to the patient using an autoinjector.

[0127] In some embodiments, an initial dose of human ActRIIA-Fc fusion protein (which contains the amino acid sequence shown in SEQ ID NO: 32) or a variant of human ActRIIA-Fc fusion protein (which contains the amino acid sequence shown in SEQ ID NO: 41) is administered to the patient using an autoinjector.

[0128] In some implementations, the maintenance dose is administered via a single injection.

[0129] The overview of the technology described above is non-limiting, and other features and advantages of the technology will become clear from the following detailed description and the claims. Attached Figure Description

[0130] Figure 1 This study shows multiple sequence alignments of the extracellular domain of human ActRIIA with various ActRIIA orthologs.

[0131] Figure 2 The predicted steady-state Cavg is shown after administering doses based on body weight range and doses based on body weight (0.7 mg / kg).

[0132] Figure 3 The predicted Cavg (weeks 1 through 3) after administration of doses based on body weight range and doses based on body weight (0.3 mg / kg) are shown. Detailed Implementation

[0133] This disclosure relates to therapies that can be used to treat pulmonary hypertension. In particular, the present invention relates to a method for treating pulmonary hypertension, the method comprising administering ActRIIA-Fc fusion protein or a variant thereof to a patient in need, based on the patient's weight range. definition

[0134] The following lists the definitions of various terms used herein. Unless otherwise limited in specific circumstances, these definitions apply to terms used throughout this specification and claims, individually or as part of a larger group.

[0135] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein, as well as laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry, are those well-known and commonly used in the art.

[0136] As used herein, the articles “a” and “an” refer to one or more (i.e., at least one) grammatical objects of the articles. For example, “an element” means one or more elements. Furthermore, the use of the term “including” and other forms such as “including,” “included,” and “included” is not restrictive.

[0137] As used in this article, the term “about” in quantitative terms refers to ±10% of the value it modifies (rounded to the nearest integer if the value is not subdividable, such as the number of molecules or nucleotides).

[0138] Certain ranges in this document are enclosed in square brackets or parentheses. Ranges or numbers enclosed in square brackets or a single square bracket are included within the range. Ranges or numbers enclosed in parentheses or a single parenthesis are not included within the range. Ranges not enclosed in square brackets or parentheses include the listed endpoints and can be combined independently (e.g., a range “from 50 mg to 500 mg” includes the endpoints 50 mg and 500 mg, as well as all intermediate values). The endpoints and any values ​​of the ranges disclosed herein are not limited to precise ranges or values; they are sufficiently imprecise to include values ​​that approximate these ranges and / or values.

[0139] As used herein, the term “comprising” can include embodiments of “consisting of” and “substantially composed of”. As used herein, the terms “comprising,” “including,” “having,” “has,” “may,” “contains,” and variations thereof are intended to be open-ended transitional phrases, terms, or words that require the presence of the referred ingredient / step and allow for the presence of other ingredients / steps. However, such descriptions should be construed as also describing the composition or method as “consisting of” and “substantially composed of” the components listed, which allows for the presence of only the referred component or compound and any acceptable carrier or fluid, and excludes other components or compounds.

[0140] As used herein, a “weight range” refers to a weight range within a series. In some embodiments, the weight ranges used herein begin at 50 kg and are established in increments of 25 kg. For example, some weight ranges used herein are [50–75) kg, [75–100) kg, and [100–125) kg. Additionally, weight ranges may include <50 kg, >125 kg, and >150 kg.

[0141] As used herein, "patient" refers to a mammal capable of developing pulmonary arterial hypertension (PAH). In a preferred embodiment, the patient is a human. Treatment may be administered to reduce the severity or clinical effect of PAH. Those patients "in need of treatment" include those who have been diagnosed with PAH, are suspected of having PAH, or have clinical symptoms of PAH. Activin receptor type IIA-Fc fusion protein

[0142] ActRIIA protein

[0143] In some embodiments, this disclosure relates to ActRIIA proteins. As used herein, the term "ActRIIA" refers to the activin receptor type IIA (ActRIIA) protein family from any species, as well as variants derived from such ActRIIA proteins through mutagenesis or other modifications. References to ActRIIA herein should be understood as references to any of the currently identified forms. ActRIIA family members are typically transmembrane proteins consisting of a ligand-binding extracellular domain containing a cysteine-rich region, a transmembrane domain, and a cytoplasmic domain having predicted serine / threonine kinase activity.

[0144] The term "ActRIIA protein" includes any naturally occurring protein comprising a member of the ActRIIA family, as well as any variants (including mutants, fragments, fusions, and peptide-like forms) that retain useful activity. Examples of such variant ActRIIA proteins are provided in the full text of this disclosure and in International Patent Application Publications WO 2006 / 012627 and WO 2007 / 062188 (which are incorporated herein by reference in their entirety). Unless otherwise specified, the amino acid numbers of all ActRIIA-related proteins described herein are based on the sequence number of the human ActRIIA precursor protein (SEQ ID NO: 9) provided below.

[0145] The standard human ActRIIA precursor protein sequence is as follows:

[0146] Signal peptides are composed of single underscore Indications: Extracellular domains are indicated in bold; and potential endogenous N-linked glycosylation sites are indicated by... Marking.

[0147] The processed (mature) extracellular human ActRIIA protein sequence is as follows: ILGRSETQECLFFNANWEKDRTNQTGVEPCYGDKDKRRHCFATWKNISGSIEIVKQGCWLDDINCYDRTDCVEKKDSPEVYFCCCEGNMCNEKFSYFPEM EVTQPTSNPVTPKPP (SEQ ID NO: 10)

[0148] The C-terminal "tail" of the extracellular domain is composed of single underscore The sequence with the missing "tail" (Δ15 sequence) is shown below: ILGRSETQECLFFNANWEKDRTNQTGVEPCYGDKDKRRHCFATWKNISGSIEIVKQGCWLDDINCYDRTDCVEKKDSPEVYFCCCEGNMCNEKFSYFPEM (SEQ ID NO: 11)

[0149] The nucleic acid sequence encoding the human ActRIIA precursor protein is shown below (SEQ ID NO: 12), specifically nucleotides 159-1700 of the Genbank reference sequence NM_001616.4 shown below. The signal sequence is... underlined . 1 atgggagctg ctgcaaagtt ggcgtttgcc gtctttctta tctcctgttc 51 ttcaggtgct atacttggta gatcagaaac tcaggagtgt cttttcttta 101 atgctaattg ggaaaaagac agaaccaatc aaactggtgt tgaaccgtgt 151 tatggtgaca aagataaacg gcggcattgt tttgctacct ggaagaatat 201 ttctggttcc attgaaatag tgaaacaagg ttgttggctg gatgatatca 251 actgctatga caggactgat tgtgtagaaa aaaaagacag ccctgaagta 301 tatttttgtt gctgtgaggg caatatgtgt aatgaaaagt tttcttattt 351 tccggagatg gaagtcacac agcccacttc aaatccagtt acacctaagc 401 caccctatta caacatcctg ctctattcct tggtgccact tatgttaatt 451 gcggggattg tcatttgtgc attttgggtg tacaggcatc acaagatggc 501 ctaccctcct gtacttgttc caactcaaga cccaggacca cccccacctt 551 ctccattact aggtttgaaa ccactgcagt tattagaagt gaaagcaagg 601 ggaagatttg gttgtgtctg gaaagcccag ttgcttaacg aatatgtggc 651 tgtcaaaata tttccaatac aggacaaaca gtcatggcaa aatgaatacg 701 aagtctacag tttgcctgga atgaagcatg agaacatatt acagttcatt 751 ggtgcagaaa aacgaggcac cagtgttgat gtggatcttt ggctgatcac 801 agcatttcat gaaaagggtt cactatcaga ctttcttaag gctaatgtgg 851 tctcttggaa tgaactgtgt catattgcag aaaccatggc tagaggattg 901 gcatatttac atgaggatat acctggccta aaagatggcc acaaacctgc 951 catatctcac agggacatca aaagtaaaaa tgtgctgttg aaaaacaacc 1001 tgacagcttg cattgctgac tttgggttgg ccttaaaatt tgaggctggc 1051 aagtctgcag gcgataccca tggacaggtt ggtacccgga ggtacatggc 1101 tccagaggta ttagagggtg ctataaactt ccaaagggat gcatttttga 1151 ggatagatat gtatgccatg ggattagtcc tatgggaact ggcttctcgc 1201 tgtactgctg cagatggacc tgtagatgaa tacatgttgc catttgagga 1251 ggaaattggc cagcatccat ctcttgaaga catgcaggaa gttgttgtgc 1301 ataaaaaaaa gaggcctgtt ttaagagatt attggcagaa acatgctgga 1351 atggcaatgc tctgtgaaac cattgaagaa tgttgggatc acgacgcaga 1401 agccaggtta tcagctggat gtgtaggtga aagaattacc cagatgcaga 1451 gactaacaaa tattattacc acagaggaca ttgtaacagt ggtcacaatg 1501 gtgacaaatg ttgactttcc tcccaaagaa tctagtcta (SEQ ID NO: 12)

[0150] The nucleic acid sequence encoding the processed soluble (extracellular) human ActRIIA protein is as follows: 1 atacttggta gatcagaaac tcaggagtgt cttttcttta atgctaattg 51 ggaaaaagac agaaccaatc aaactggtgt tgaaccgtgt tatggtgaca 101 aagataaacg gcggcattgt tttgctacct ggaagaatat ttctggttcc 151 attgaaatag tgaaacaagg ttgttggctg gatgatatca actgctatga 201 caggactgat tgtgtagaaa aaaaagacag ccctgaagta tatttttgtt 251 gctgtgaggg caatatgtgt aatgaaaagt tttcttattt tccggagatg 301 gaagtcacac agcccacttc aaatccagtt acacctaagc caccc (SEQ ID NO:13)

[0151] ActRIIA is highly conserved in vertebrates, with large segments of its extracellular domains being completely conserved. For example, Figure 1 Multiple sequence alignments were performed to depict the extracellular domains of human ActRIIA and various ActRIIA orthologs. Many ActRIIA-binding ligands are also highly conserved. Therefore, from these alignments, key amino acid positions within the ligand-binding domain that are important for normal ActRIIA-ligand binding activity can be predicted, as well as amino acid positions that may tolerate substitutions without significantly altering normal ActRIIA-ligand binding activity. Therefore, active human ActRIIA variant proteins that can be used according to the methods of this disclosure may include one or more amino acids at corresponding positions from sequences of ActRIIA from another vertebrate, or may include residues similar to residues in human or other vertebrate sequences.

[0152] This is not intended to be limiting; the following examples illustrate this method of defining active ActRIIA variants. For example... Figure 1 As shown, F13 in the extracellular domain of human cells is present in sheep (SEQ ID NO: 62) and red junglefowl (…). Gallus In the ActRIIA of the human extracellular domain (SEQ ID NO: 65), domestic cattle (SEQ ID NO: 66), barn owl (SEQ ID NO: 67), and David's mouse-eared bat (SEQ ID NO: 68), the position is Y, indicating that this position is tolerant to aromatic residues, including F, W, and Y. Q24 in the human extracellular domain is R in the domestic cattle ActRIIA, indicating that this position is tolerant to charged residues, including D, R, K, H, and E. S95 in the human extracellular domain is R in the domestic chicken (SEQ ID NO: 68). Gallus gallus The E52 in the human extracellular domain is F in sheep ActRIIA, indicating that this site is likely tolerant to a wide variety of variations, including polar residues such as E, D, K, R, H, S, T, P, G, and Y, as well as possible hydrophobic residues such as L, I, or F. The E52 in the human extracellular domain is D in sheep ActRIIA, indicating that this position is tolerant to acidic residues, including D and E. P29 in the human extracellular domain is relatively poorly conserved, appearing as S in sheep ActRIIA and L in David's mouse-eared bat ActRIIA, therefore this position should essentially be tolerant to any amino acid.

[0153] Furthermore, as mentioned above, ActRII proteins have been characterized in the art based on their structural / functional features, particularly regarding ligand binding (Attisano et al.). .(1992) Cell 68(1):97-108; Greenwald et al. . (1999) Nature Structural Biology 6(1): 18-22; Allendorph et al. . (2006) PNAS 103(20): 7643-7648; Thompson et al. (2003) The EMBO Journal 22(7): 1555-1566; and U.S. Patent Nos. 7,709,605, 7,612,041, and 7,842,663). In addition to the teachings herein, these references provide ample guidance on how to generate ActRII variants that retain one or more desired activities, such as ligand-binding activity.

[0154] For example, a defined structural motif known as the three-finger toxin fold is important for ligand binding of both type I and type II receptors and is formed by conserved cysteine ​​residues located at different positions within the extracellular domain of each monomeric receptor (Greenwald et al. (1999) Nat Struct Biol 6:18-22; and Hinck (2012) FEBS Lett 586:1860-1870). Thus, as defined by the outermost of these conserved cysteine ​​residues, the core ligand-binding domain of human ActRIIA corresponds to positions 30-110 of SEQ ID NO: 9 (ActRIIA precursor). Therefore, the lower-ordered amino acids flanking these cysteine-bound core sequences can be truncated by approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 residues at the N-terminus and by approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 residues at the C-terminus without necessarily altering ligand binding. Exemplary ActRIIA extracellular domain truncations include SEQ ID NO: 10 and 11.

[0155] Therefore, the general formula for the active portion of ActRIIA (e.g., ligand binding) is a protein comprising, substantially composed of, or consisting of amino acids 30-110 of SEQ ID NO: 9. Thus, an ActRIIA protein may, for example, comprise, substantially composed of, or consist of: a residue starting at any amino acid corresponding to amino acids 21-30 of SEQ ID NO: 9 (e.g., starting at any amino acid 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) and ending at any amino acid corresponding to amino acids 110-135 of SEQ ID NO: 9 (e.g., starting at any amino acid 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) and ending at any amino acid corresponding to amino acids 110-135 of SEQ ID NO: 9 (e.g., starting at any amino acid 110-135). ，The ActRIIA portion of the amino acid sequence ending at any one of amino acids 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, or 135 is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical. Other examples include positions starting at SEQ ID NO: 21-30 (e.g., starting at any amino acid 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30), 22-30 (e.g., starting at any amino acid 22, 23, 24, 25, 26, 27, 28, 29, or 30), 23-30 (e.g., starting at any amino acid 23, 24, 25, 26, 27, 28, 29, or 30), and 24-30 (e.g., starting at any amino acid 24, 25, 26, 27, 28, 29, or 30), and ending at positions selected from SEQ ID NO: 9 at 111-135 (e.g., ending at any amino acid among 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, or 135), 112-135 (e.g., ending at any amino acid among 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, or 135), 113-135 (e.g.) For example, ending at any amino acid among amino acids 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, or 135; 120-135 (e.g., ending at any amino acid among amino acids 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, or 135); 130-135 (e.g., ending at any amino acid among amino acids 130, 131, 132, 133, 134, or 135); 111-134 (e.g.,Ending at any amino acid among amino acids 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, or 134), 111-133 (e.g., ending at any amino acid among amino acids 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, or 133), 1 A construct ending at positions 11-132 (e.g., ending at any one of amino acids 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, or 132) or 111-131 (e.g., ending at any one of amino acids 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, or 131).

[0156] Variants within these ranges are also considered, particularly those comprising, substantially comprising, or consisting of: an amino acid sequence having at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the corresponding portion of SEQ ID NO: 9 or SEQ ID NO: 10. Therefore, in some embodiments, the ActRIIA protein may comprise, substantially comprising, or consisting of: a protein having at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with amino acids 30-110 of SEQ ID NO: 9 or SEQ ID NO: 10. Optionally, the ActRIIA protein comprises at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to amino acids 30-110 of SEQ ID NO: 9, and contains no more than 1, 2, 5, 10, or 15 conserved amino acid variations in the ligand-binding pocket. Optionally, the ActRIIA protein comprises at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to amino acids 30-110 of SEQ ID NO: 10, and contains no more than 1, 2, 5, 10, or 15 conserved amino acid variations in the ligand-binding pocket.

[0157] In some embodiments, the ActRIIA protein described herein is soluble (e.g., the extracellular domain of ActRIIA). In some embodiments, the ActRIIA protein inhibits one or more GDF / BMP ligands (e.g., GDF11, GDF8, activins (activin A, activin B, activin AB, activin C, activin E), BMP6, GDF3, BMP15, and / or BMP10) (e.g., Smad signaling). In some embodiments, the ActRIIA protein binds to one or more GDF / BMP ligands (e.g., GDF11, GDF8, activins (activin A, activin B, activin AB, activin C, activin E), BMP6, GDF3, BMP15, and / or BMP10).

[0158] In some embodiments, the ActRIIA protein is a fusion protein comprising the ActRIIA domain and one or more protein domains heterologous to ActRIIA. In some embodiments, the ActRIIA protein is a fusion protein comprising the Fc domain of an immunoglobulin. In some embodiments, the Fc domain of the immunoglobulin is the Fc domain of IgG1 immunoglobulin.

[0159] Examples of native amino acid sequences that can be used for the Fc portion (G1Fc) of human IgG1 are shown below (SEQ ID NO:1). Dashed underlines indicate hinge regions, and solid underlines indicate locations of naturally occurring variants. In part, this disclosure provides polypeptides comprising, substantially comprising, or consisting of amino acid sequences having 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with SEQ ID NO:1. According to the numbering system used in SEQ ID NO:1 (see Uniprot P01857), naturally occurring variants in G1Fc include E134D and M136L.

[0160] Optionally, the IgG1 Fc domain has one or more mutations at residues such as Asp-265, lysine 322, and Asn-434. In some cases, the mutant IgG1 Fc domain having one or more of these mutations (e.g., the Asp-265 mutation) has a reduced ability to bind to the Fcγ receptor compared to the wild-type Fc domain. In other cases, the mutant Fc domain having one or more of these mutations (e.g., the Asn-434 mutation) has an increased ability to bind to the MHC class I-associated Fc receptor (FcRN) compared to the wild-type IgG1 Fc domain.

[0161] An example of a natural amino acid sequence that can be used for the Fc portion (G2Fc) of human IgG2 is shown below (SEQ ID NO:6). Dashed underlines indicate hinge regions, and double underlines indicate locations in the sequence where database conflicts exist (according to UniProt P01859). In part, this disclosure provides polypeptides comprising, substantially consisting of, or composed of: amino acid sequences having 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with SEQ ID NO:6.

[0162] Two examples of amino acid sequences that can be used for the Fc portion (G3Fc) of human IgG3 are shown below. The hinge region in G3Fc can be up to four times longer than in other Fc chains and contains three identical 15-residue segments preceding a similar 17-residue segment. The first G3Fc sequence shown below (SEQ ID NO: 3) contains a short hinge region consisting of a single 15-residue segment, while the second G3Fc sequence (SEQ ID NO: 4) contains a full-length hinge region. In each case, the dashed underline indicates the hinge region, and the solid underline indicates the location of a naturally occurring variant according to UniProt P01859. In part, this disclosure provides polypeptides comprising, substantially consisting of, or composed of amino acid sequences having 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with SEQ ID NO: 3 and 4.

[0163] Naturally occurring variants of G3Fc (e.g., see Uniprot P01860) include E68Q, P76L, E79Q, Y81F, D97N, N100D, T124A, S169N, S169del, and F221Y (when converted to the numbering system used in SEQ ID NO: 3), and this disclosure provides fusion proteins comprising a G3Fc domain containing one or more of these variants. Furthermore, the human immunoglobulin IgG3 gene ( IGHG3 The variant exhibits structural polymorphism characterized by varying hinge lengths [see Uniprot P01859]. Specifically, variant WIS lacks most of the V region and all of the CH1 region. In addition to the 11 interchain disulfide bonds typically present in the hinge region, it has an additional interchain disulfide bond at position 7. Variant ZUC lacks most of the V region, all of the CH1 region, and part of the hinge. Variant OMM may represent an allelic form or another γ-chain subclass. This disclosure provides additional fusion proteins comprising one or more of these variants' G3Fc domains.

[0164] Examples of natural amino acid sequences that can be used for the Fc portion (G4Fc) of human IgG4 are shown below (SEQ ID NO:5). The dashed underline indicates the hinge region. In part, this disclosure provides polypeptides comprising, substantially consisting of, or composed of: amino acid sequences having 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with SEQ ID NO:5.

[0165] Various methods are known in the art to improve the desired pairing of Fc-containing fusion polypeptide chains in a single cell line to produce preferred asymmetric fusion proteins in acceptable yields [Klein et al. (2012) mAbs 4:653-663; and Spiess et al. (2015) Molecular Immunology 67(2A): 95-106]. Methods for obtaining desired pairings containing Fc chains include, but are not limited to, charge-based pairing (electrostatic redirection), "mortar and pestle" spatial pairing, SEEDbody pairing, and leucine zipper-based pairing [Ridgway et al. (1996) Protein Eng 9:617-621; Merchant et al. (1998) NatBiotech 16:677-681; Davis et al. (2010) Protein Eng Des Sel 23:195-202; Gunasekaran et al. (2010); 285:19637-19646; Wranik et al. (2012) J Biol Chem 287:43331-43339; US5932448; WO 1993 / 011162; WO 2009 / 089004 and WO 2011 / 034605].

[0166] It should be understood that the different elements of a fusion protein (e.g., an immunoglobulin Fc fusion protein) can be arranged in any manner consistent with the desired function. For example, the ActRIIA peptide domain can be positioned at the C-terminus of the heterologous domain, or alternatively, the heterologous domain can be positioned at the C-terminus of the ActRII peptide domain. The ActRIIA peptide domain and the heterologous domain need not be adjacent in the fusion protein, and additional domains or amino acid sequences may be included at the C-terminus or N-terminus of either domain or between the domains.

[0167] In some embodiments, the ActRIIA fusion protein further includes a linker domain located between the ActRIIA protein domain and one or more heterologous domains (e.g., Fc immunoglobulin domains). In other embodiments, the fusion protein further includes a linker domain located between the protein domain and the Fc domain of an immunoglobulin. In some embodiments, the linker domain is a polyglycine linker. In some embodiments, the protein is glycosylated. In some embodiments, the linker domain is selected from: TGGG (SEQ ID NO: 23), TGGGG (SEQ ID NO: 21), SGGGG (SEQ ID NO: 22), GGGGS (SEQ ID NO: 25), GGG (SEQ ID NO: 19), GGGG (SEQ ID NO: 20), and SGGG (SEQ ID NO: 24).

[0168] In some embodiments, the ActRIIA fusion protein comprises an ActRIIA protein linked to the Fc region via a linker domain. In some embodiments, the ActRIIA fusion protein comprises the ActRIIA protein containing SEQ ID NO: 10, which is linked to the Fc region of SEQ ID NO: 1 via the linker domain of SEQ ID NO: 23, wherein the linked Fc region and the linker are connected at the C-terminus of the ActRIIA protein.

[0169] In some embodiments, the ActRIIA protein comprises at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical amino acid sequence to the amino acid sequence of SEQ ID NO: 32. In some embodiments, the ActRIIA protein comprises the amino acid sequence of SEQ ID NO: 32. In some embodiments, the ActRIIA protein consists of the amino acid sequence of SEQ ID NO: 32. SEQ ID NO: 32 is also known as sotsip. In some embodiments, the ActRIIA protein is part of a homodimeric protein complex. In some embodiments, the ActRIIA protein is glycosylated. In some embodiments, the ActRIIA protein has a glycosylation pattern obtainable by expression in Chinese hamster ovary cells.

[0170] In some alternative embodiments, the ActRII protein (e.g., SEQ ID NO: 32) lacks a C-terminal lysine. In some embodiments, the ActRII protein lacking a C-terminal lysine is SEQ ID NO: 41. In some embodiments, the formulation comprises a mixture of SEQ ID NO: 32 and SEQ ID NO: 41.

[0171] In some embodiments, the ActRIIA protein comprises, consists of, or is substantially composed of the following: an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID NO: 9, 10, 11, 32, 36, 39, and 41. Dosing regimen

[0172] Currently, sotexip (SEQ ID NO: 32) is administered based on the patient's individual weight. The initial dose of 0.3 mg / kg is given to each patient according to the table below: Table 1

[0173] Following the initial dose, a maintenance dose of 0.7 mg / kg should be administered to the patient every three weeks according to the table below: Table 2

[0174] This invention eliminates the need for healthcare professionals to calculate the amount of ActRIIA fusion protein or its variants (e.g., sotexip) to be administered to a patient based on the patient's individual weight, and reduces waste by allowing the use of the full dose rather than just a portion of the current 45 mg and 60 mg vials.

[0175] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering an initial dose to the patient on day 1 of either the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41, wherein the amount of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 administered to the patient as an initial dose is a multiple of 15. In some embodiments, the amount of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 administered to the patient as an initial dose is 15 mg, 30 mg, or 45 mg.

[0176] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering an initial dose of either the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 to the patient on day 1, and administering a maintenance dose at least every three weeks thereafter, wherein the amount of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 administered to the patient as a maintenance dose is a multiple of 15. In some embodiments, the amount of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 administered to the patient as an initial dose is 15 mg, 30 mg, or 45 mg. In some embodiments, the amount of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 administered to the patient as a maintenance dose is 30 mg, 45 mg, 60 mg, 75 mg or 90 mg.

[0177] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering an initial dose to the patient of a human ActRIIA-Fc fusion protein (which contains the amino acid sequence shown in SEQ ID NO: 32) or a variant of the human ActRIIA-Fc fusion protein (which contains the amino acid sequence shown in SEQ ID NO: 41), wherein the initial dose is 15 mg or a multiple of 15 mg, and the initial dose is determined by comparing the patient’s weight with a list of predetermined weight intervals and selecting a pre-selected dose corresponding to the patient’s weight interval as the initial dose.

[0178] In some implementations, the initial dose is selected from one of the following predetermined weight ranges:

[0179] (a) For patients weighing less than 50 kg, 15 mg,

[0180] (b) For patients weighing between 50 kg and 75 kg but excluding 75 kg, 15 mg,

[0181] (c) For patients weighing between 75 kg and 100 kg but not exceeding 100 kg, 30 mg,

[0182] (d) For patients weighing between 100 kg and 125 kg but excluding 125 kg, 30 mg, or

[0183] (e) For patients weighing 125 kg or more, 45 mg.

[0184] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering an initial dose of sotexip or a sotexip variant lacking a C-terminal lysine, wherein the initial dose is selected from:

[0185] (a) For patients weighing less than 50 kg, 15 mg,

[0186] (b) For patients weighing between 50 kg and 75 kg but excluding 75 kg, 15 mg,

[0187] (c) For patients weighing between 75 kg and 100 kg but not exceeding 100 kg, 30 mg,

[0188] (d) For patients weighing between 100 kg and 125 kg but excluding 125 kg, 30 mg, and

[0189] (e) For patients weighing 125 kg or more, 45 mg.

[0190] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering an initial dose of sotexip or a sotexip variant lacking a C-terminal lysine, wherein the initial dose is selected from:

[0191] (a) For patients weighing less than 50 kg, 15 mg,

[0192] (b) For patients weighing between 50 kg and 75 kg but excluding 75 kg, 15 mg,

[0193] (c) For patients weighing between 75 kg and 100 kg but not exceeding 100 kg, 30 mg,

[0194] (d) For patients weighing between 100 kg and 125 kg but excluding 125 kg, 30 mg, and

[0195] (e) For patients weighing 125 kg or more, 45 mg.

[0196] This article describes a method for treating pulmonary hypertension in patients with this need, the method further comprising administering a maintenance dose of sotexip or a sotexip variant lacking a C-terminal lysine to the patient approximately 3 weeks after the initial dose, wherein the maintenance dose is selected from:

[0197] (a) For patients weighing less than 50 kg, 30 mg,

[0198] (b) For patients weighing between 50 kg and 75 kg but excluding 75 kg, 45 mg,

[0199] (c) For patients weighing between 75 kg and 100 kg but not exceeding 100 kg, 60 mg,

[0200] (d) For patients weighing between 100 kg and 125 kg but excluding 125 kg, 75 mg, and

[0201] (e) For patients weighing 125 kg or more, 90 mg.

[0202] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering an initial dose to the patient on day 1 of either the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41, wherein the amount of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 administered to the patient as an initial dose is a multiple of 12. In some embodiments, the amount of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 administered to the patient as an initial dose is 12 mg, 24 mg, or 36 mg.

[0203] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering an initial dose of either the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 to the patient on day 1, and administering a maintenance dose at least every three weeks thereafter, wherein the amount of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 administered to the patient as a maintenance dose is a multiple of 12. In some embodiments, the amount of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 administered to the patient as a maintenance dose is 12 mg, 24 mg, 36 mg, 48 mg, 60 mg, 72 mg, 84 mg, or 96 mg.

[0204] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering an initial dose to the patient on day 1 of either the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or a variant of the ActRIIA-Fc fusion protein comprising SEQ ID NO: 41, wherein the amount of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the variant comprising SEQ ID NO: 32 lacking a C-terminal lysine administered to the patient as an initial dose is a multiple of 10. In some embodiments, the amount of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the variant of the ActRIIA-Fc fusion protein comprising SEQ ID NO: 41 administered to the patient as an initial dose is 10 mg, 20 mg, or 30 mg.

[0205] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering an initial dose of either the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 to the patient on day 1, and administering a maintenance dose at least every three weeks thereafter, wherein the amount of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 administered to the patient as a maintenance dose is a multiple of 10. In some embodiments, the amount of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 administered to the patient as a maintenance dose is 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, or 90 mg.

[0206] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering an initial dose of 10-50 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or an ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 to the patient if the patient weighs less than 150 kg. In some embodiments, if the patient weighs less than 150 kg, administering an initial dose of 15-45 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or an ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 to the patient. In some embodiments, if the patient weighs less than 150 kg, administering an initial dose of 10 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or an ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 to the patient. In some embodiments, if the patient weighs less than 150 kg, an initial dose of 12 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO:32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO:41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, an initial dose of 15 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO:32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO:41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, an initial dose of 20 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO:32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO:41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, an initial dose of 24 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, an initial dose of 25 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, an initial dose of 30 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient.In some embodiments, if the patient weighs less than 150 kg, an initial dose of 35 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, an initial dose of 36 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, an initial dose of 40 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, an initial dose of 45 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, an initial dose of 48 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, an initial dose of 50 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient.

[0207] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering an initial dose of 10-20 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32, or a variant of ActRIIA-Fc fusion protein containing SEQ ID NO: 41, to the patient if the patient weighs less than (but not including) 75 kg. In some embodiments, if the patient weighs less than (but not including) 75 kg, administering an initial dose of 10 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32, or a variant of ActRIIA-Fc fusion protein containing SEQ ID NO: 41, to the patient. In some embodiments, if the patient weighs less than (but not including) 75 kg, administering an initial dose of 12 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32, or a variant of ActRIIA-Fc fusion protein containing SEQ ID NO: 41, to the patient. In some embodiments, if the patient weighs less than (but not including) 75 kg, an initial dose of 15 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs between 50 and 75 kg, an initial dose of 15 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient.

[0208] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering an initial dose of 10-20 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32, or a variant of ActRIIA-Fc fusion protein containing SEQ ID NO: 41, to the patient if the patient weighs less than (but not including) 50 kg. In some embodiments, if the patient weighs less than (but not including) 50 kg, administering an initial dose of 10 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32, or a variant of ActRIIA-Fc fusion protein containing SEQ ID NO: 41, to the patient. In some embodiments, if the patient weighs less than (but not including) 50 kg, administering an initial dose of 12 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32, or a variant of ActRIIA-Fc fusion protein containing SEQ ID NO: 41, to the patient. In some embodiments, if the patient weighs less than (but not including) 50 kg, an initial dose of 15 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs between 35 and 50 kg, an initial dose of 15 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient.

[0209] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering an initial dose of 20-40 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO:41, to the patient if the patient's weight is less than (but not including) 125 kg. In some embodiments, if the patient's weight is less than (but not including) 125 kg, an initial dose of 20 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO:41, is administered to the patient. In some embodiments, if the patient's weight is less than (but not including) 125 kg, an initial dose of 24 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO:41, is administered to the patient. In some embodiments, if the patient weighs less than (but not including) 125 kg, an initial dose of 25 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than (but not including) 125 kg, an initial dose of 30 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than (but not including) 125 kg, an initial dose of 35 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient's weight is less than (but not including) 125 kg, an initial dose of 36 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient's weight is between 100 and 125 kg, an initial dose of 30 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient.

[0210] This document describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering an initial dose of 20-40 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO:41, to the patient if the patient's weight is less than (but not including) 100 kg. In some embodiments, if the patient's weight is less than (but not including) 100 kg, administering an initial dose of 20 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO:41, to the patient. In some embodiments, if the patient's weight is less than (but not including) 100 kg, administering an initial dose of 24 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO:41, to the patient. In some embodiments, if the patient weighs less than (but not including) 100 kg, an initial dose of 25 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than (but not including) 100 kg, an initial dose of 30 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than (but not including) 100 kg, an initial dose of 35 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than (but not including) 100 kg, an initial dose of 36 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs between 75 and 100 kg, an initial dose of 30 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient.

[0211] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering an initial dose of 30-50 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO:41, to the patient if the patient weighs less than (but not including) 150 kg. In some embodiments, if the patient weighs less than (but not including) 150 kg, administering an initial dose of 30 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO:41, to the patient. In some embodiments, if the patient weighs less than (but not including) 150 kg, administering an initial dose of 36 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO:41, to the patient. In some embodiments, if the patient weighs less than (but not including) 150 kg, an initial dose of 35 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than (but not including) 150 kg, an initial dose of 40 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than (but not including) 150 kg, an initial dose of 45 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than (but not including) 150 kg, an initial dose of 48 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs between 125 and 150 kg, an initial dose of 45 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient.

[0212] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering an initial dose of 30-50 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41, to the patient if the patient weighs more than 150 kg. In some embodiments, if the patient weighs more than 150 kg, administering an initial dose of 30 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41, to the patient. In some embodiments, if the patient weighs more than 150 kg, administering an initial dose of 36 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41, to the patient. In some embodiments, if the patient weighs more than 150 kg, an initial dose of 35 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs more than 150 kg, an initial dose of 40 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs more than 150 kg, an initial dose of 45 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs more than 150 kg, an initial dose of 48 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs more than 150 kg, an initial dose of 45 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 is administered to the patient.

[0213] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering to the patient an initial dose of about 10-50 mg of a human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41, if the patient weighs less than 150 kg. In some embodiments, if the patient weighs less than 150 kg, administering to the patient an initial dose of about 15-45 mg of a human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41. In some embodiments, if the patient weighs less than 150 kg, administering to the patient an initial dose of about 10 mg of a human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41. In some embodiments, if the patient weighs less than 150 kg, an initial dose of about 12 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO:32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO:41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, an initial dose of about 15 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO:32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO:41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, an initial dose of about 20 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO:32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO:41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, an initial dose of about 24 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, an initial dose of about 25 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, an initial dose of about 30 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient.In some embodiments, if the patient weighs less than 150 kg, an initial dose of about 35 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, an initial dose of about 36 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, an initial dose of about 40 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, an initial dose of about 45 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or a variant comprising SEQ ID NO: 32 lacking a C-terminal lysine, is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, an initial dose of about 48 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41, is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, an initial dose of about 50 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41, is administered to the patient.

[0214] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering to the patient an initial dose of about 10-20 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO:41, if the patient weighs less than (but not including) 75 kg. In some embodiments, if the patient weighs less than (but not including) 75 kg, administering to the patient an initial dose of about 10 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO:41. In some embodiments, if the patient weighs less than (but not including) 75 kg, administering to the patient an initial dose of about 12 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO:41. In some embodiments, if the patient weighs less than (but not including) 75 kg, an initial dose of about 15 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs between 50 and 75 kg, an initial dose of about 15 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient.

[0215] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering to the patient an initial dose of about 10-20 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO:41, if the patient weighs less than (but not including) 50 kg. In some embodiments, if the patient weighs less than (but not including) 50 kg, administering to the patient an initial dose of about 10 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO:41. In some embodiments, if the patient weighs less than (but not including) 50 kg, administering to the patient an initial dose of about 12 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO:41. In some embodiments, if the patient weighs less than (but not including) 50 kg, an initial dose of about 15 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs between 35 and 50 kg, an initial dose of about 15 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient.

[0216] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering to the patient an initial dose of about 20-40 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO:41, if the patient weighs less than (but not including) 125 kg. In some embodiments, if the patient weighs less than (but not including) 125 kg, administering to the patient an initial dose of about 20-30 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO:41. In some embodiments, if the patient weighs less than (but not including) 125 kg, administering to the patient an initial dose of about 20 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO:41. In some embodiments, if the patient weighs less than (but not including) 125 kg, an initial dose of about 24 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than (but not including) 125 kg, an initial dose of about 25 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than (but not including) 125 kg, an initial dose of about 30 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than (but not including) 125 kg, an initial dose of approximately 35 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than (but not including) 125 kg, an initial dose of approximately 36 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient.In some implementations, if the patient's weight is between [100-125) kg, the patient is given an initial dose of about 30 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41.

[0217] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering to the patient an initial dose of about 20-40 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO:41, if the patient weighs less than (but not including) 100 kg. In some embodiments, if the patient weighs less than (but not including) 100 kg, administering to the patient an initial dose of about 20 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO:41. In some embodiments, if the patient weighs less than (but not including) 100 kg, administering to the patient an initial dose of about 24 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO:41. In some embodiments, if the patient weighs less than (but not including) 100 kg, an initial dose of about 25 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than (but not including) 100 kg, an initial dose of about 30 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than (but not including) 100 kg, an initial dose of about 35 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than (but not including) 100 kg, an initial dose of about 36 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs between 75 and 100 kg, an initial dose of about 30 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering to the patient an initial dose of about 30-50 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO:41, if the patient weighs less than (but not including) 150 kg. In some embodiments, if the patient weighs less than (but not including) 150 kg, administering to the patient an initial dose of about 30 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO:41. In some embodiments, if the patient weighs less than (but not including) 150 kg, administering to the patient an initial dose of about 36 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO:41. In some embodiments, if the patient weighs less than (but not including) 150 kg, an initial dose of about 35 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than (but not including) 150 kg, an initial dose of about 40 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than (but not including) 150 kg, an initial dose of about 45 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient's weight is less than (but not including) 150 kg, an initial dose of about 48 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient's weight is between 125 and 150 kg, an initial dose of about 45 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient.

[0218] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering to the patient an initial dose of about 30-50 mg of a human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41, if the patient weighs more than 150 kg. In some embodiments, if the patient weighs more than 150 kg, administering to the patient an initial dose of about 30 mg of a human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41. In some embodiments, if the patient weighs more than 150 kg, administering to the patient an initial dose of about 36 mg of a human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41. In some embodiments, if the patient weighs more than 150 kg, an initial dose of about 35 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO:32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO:41 is administered to the patient. In some embodiments, if the patient weighs more than 150 kg, an initial dose of about 40 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO:32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO:41 is administered to the patient. In some embodiments, if the patient weighs more than 150 kg, an initial dose of about 45 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO:32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO:41 is administered to the patient. In some embodiments, if the patient weighs more than 150 kg, an initial dose of approximately 48 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO:32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO:41 is administered to the patient. In some embodiments, if the patient weighs more than 150 kg, an initial dose of approximately 45 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO:32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO:41 is administered to the patient.

[0219] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering an initial dose of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or an ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 to the patient on day 1, and administering a maintenance dose at least every three weeks thereafter, wherein if the patient weighs less than 150 kg, the maintenance dose is 20-100 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or an ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of 30-90 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or an ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of 30 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of 35 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of 36 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, an initial dose of 40 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of 45 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of 48 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient.In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of 50 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of 55 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of 60 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of 65 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of 70 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of 72 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of 75 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of 80 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of 84 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient.In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of 85 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of 90 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of 95 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of 96 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of 100 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 is administered to the patient.

[0220] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering to the patient a maintenance dose of 20-40 mg of a human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41, if the patient weighs less than (but not including) 50 kg. In some embodiments, if the patient weighs less than (but not including) 50 kg, administering to the patient a maintenance dose of 20 mg of a human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41. In some embodiments, if the patient weighs less than (but not including) 50 kg, administering to the patient a maintenance dose of 25 mg of a human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41. In some embodiments, if the patient weighs less than (but not including) 50 kg, a maintenance dose of 30 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs between 35 and 50 kg, an initial dose of 30 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient.

[0221] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering to the patient a maintenance dose of 40-50 mg of a human ActRIIA-Fc fusion protein containing SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41, if the patient weighs less than (but not including) 75 kg. In some embodiments, if the patient weighs less than (but not including) 75 kg, administering to the patient a maintenance dose of 40 mg of a human ActRIIA-Fc fusion protein containing SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41. In some embodiments, if the patient weighs less than (but not including) 75 kg, administering to the patient a maintenance dose of 45 mg of a human ActRIIA-Fc fusion protein containing SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41. In some embodiments, if the patient's weight is less than (but not including) 75 kg, a maintenance dose of 50 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient's weight is between 50 and 75 kg, a maintenance dose of 45 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering to the patient a maintenance dose of 50-70 mg of a human ActRIIA-Fc fusion protein comprising SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO:41, if the patient weighs less than (but not including) 100 kg. In some embodiments, if the patient weighs less than (but not including) 100 kg, administering to the patient a maintenance dose of 50 mg of a human ActRIIA-Fc fusion protein comprising SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO:41. In some embodiments, if the patient weighs less than (but not including) 100 kg, administering to the patient a maintenance dose of 55 mg of a human ActRIIA-Fc fusion protein comprising SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO:41. In some embodiments, if the patient's weight is less than (but not including) 100 kg, a maintenance dose of 60 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient's weight is less than (but not including) 100 kg, a maintenance dose of 65 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient's weight is less than (but not including) 100 kg, a maintenance dose of 70 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient's weight is less than (but not including) 100 kg, a maintenance dose of 72 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient's weight is between 75 and 100 kg, a maintenance dose of 60 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient.

[0222] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering to the patient a maintenance dose of 70-80 mg of a human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO:41, if the patient weighs less than (but not including) 125 kg. In some embodiments, if the patient weighs less than (but not including) 125 kg, administering to the patient a maintenance dose of 70 mg of a human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO:41. In some embodiments, if the patient weighs less than (but not including) 125 kg, administering to the patient a maintenance dose of 72 mg of a human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant containing SEQ ID NO:41. In some embodiments, if the patient's weight is less than (but not including) 125 kg, a maintenance dose of 75 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient's weight is less than (but not including) 125 kg, an 80 mg maintenance dose of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient's weight is less than (but not including) 125 kg, an 84 mg maintenance dose of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some implementations, if the patient's weight is between [100-125) kg, the patient is given a maintenance dose of 75 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41.

[0223] This document describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering to the patient, if the patient's weight is less than (but not including) 150 kg, a maintenance dose of 80-100 mg of human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41, to the patient. In some embodiments, if the patient's weight is less than (but not including) 150 kg, a maintenance dose of 80 mg of human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41, to the patient, is administered. In some embodiments, if the patient's weight is less than (but not including) 150 kg, a maintenance dose of 85 mg of human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41, is administered to the patient. In some embodiments, if the patient's weight is less than (but not including) 150 kg, a maintenance dose of 90 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient's weight is less than (but not including) 150 kg, a maintenance dose of 95 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient's weight is less than (but not including) 150 kg, a maintenance dose of 96 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient's weight is less than (but not including) 150 kg, a maintenance dose of 100 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient's weight is between 125 and 150 kg, a maintenance dose of 90 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient.

[0224] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering to the patient, if the patient weighs more than 150 kg, a maintenance dose of 80-100 mg of a human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41. In some embodiments, if the patient weighs more than 150 kg, administering to the patient, a maintenance dose of 80 mg of a human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41. In some embodiments, if the patient weighs more than 150 kg, administering to the patient, a maintenance dose of 84 mg of a human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41. In some embodiments, if the patient weighs more than 150 kg, a maintenance dose of 85 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs more than 150 kg, a maintenance dose of 90 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs more than 150 kg, a maintenance dose of 95 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs more than 150 kg, a maintenance dose of 100 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs more than 150 kg, a maintenance dose of 90 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 is administered to the patient.

[0225] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering an initial dose of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or an ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 to the patient on day 1, and administering a maintenance dose at least every three weeks thereafter, wherein if the patient weighs less than 150 kg, the maintenance dose is about 20-100 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or an ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41. In some embodiments, if the patient weighs less than 150 kg, the patient is administered a maintenance dose of about 30-90 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or an ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of approximately 30 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or a variant of the ActRIIA-Fc fusion protein comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of approximately 35 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or a variant of the ActRIIA-Fc fusion protein comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of approximately 36 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or a variant of the ActRIIA-Fc fusion protein comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, an initial dose of approximately 40 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or a variant of the ActRIIA-Fc fusion protein comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of approximately 45 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or a variant of the ActRIIA-Fc fusion protein comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of approximately 48 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or a variant of the ActRIIA-Fc fusion protein comprising SEQ ID NO: 41 is administered to the patient.In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of about 50 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of about 55 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of about 60 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of approximately 65 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or a variant of the ActRIIA-Fc fusion protein comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of approximately 70 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or a variant of the ActRIIA-Fc fusion protein comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of approximately 72 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or a variant of the ActRIIA-Fc fusion protein comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of approximately 75 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or a variant of the ActRIIA-Fc fusion protein comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of approximately 80 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or a variant of the ActRIIA-Fc fusion protein comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of approximately 84 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or a variant of the ActRIIA-Fc fusion protein comprising SEQ ID NO: 41 is administered to the patient.In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of approximately 85 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of approximately 90 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of approximately 95 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of approximately 96 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than 150 kg, a maintenance dose of approximately 100 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 is administered to the patient.

[0226] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering to the patient, if the patient's weight is less than (but not including) 50 kg, a maintenance dose of about 20-40 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or a variant of ActRIIA-Fc fusion protein containing SEQ ID NO:41. In some embodiments, if the patient's weight is less than (but not including) 50 kg, administering to the patient, if the patient's weight is less than (but not including) 50 kg, a maintenance dose of about 20 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or a variant of ActRIIA-Fc fusion protein containing SEQ ID NO:41, is administered to the patient. In some embodiments, if the patient's weight is less than (but not including) 50 kg, administering to the patient, if the patient's weight is less than (but not including) 50 kg, a maintenance dose of about 25 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO:32, or a variant of ActRIIA-Fc fusion protein containing SEQ ID NO:41, is administered to the patient. In some embodiments, if the patient weighs less than (but not including) 50 kg, a maintenance dose of about 30 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs between 35 and 50 kg, an initial dose of about 30 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient.

[0227] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering to the patient, if the patient's weight is less than (but not including) 75 kg, a maintenance dose of about 40-50 mg of a human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41. In some embodiments, if the patient's weight is less than (but not including) 75 kg, a maintenance dose of about 40 mg of a human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41, is administered to the patient. In some embodiments, if the patient's weight is less than (but not including) 75 kg, a maintenance dose of about 45 mg of a human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41, is administered to the patient. In some embodiments, if the patient weighs less than (but not including) 75 kg, a maintenance dose of about 50 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs between 50 and 75 kg, a maintenance dose of about 45 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient.

[0228] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering to the patient, if the patient's weight is less than (but not including) 100 kg, a maintenance dose of about 50-70 mg of human ActRIIA-Fc fusion protein comprising SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO:41, to the patient. In some embodiments, if the patient's weight is less than (but not including) 100 kg, a maintenance dose of about 50 mg of human ActRIIA-Fc fusion protein comprising SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO:41, to the patient. In some embodiments, if the patient's weight is less than (but not including) 100 kg, a maintenance dose of about 55 mg of human ActRIIA-Fc fusion protein comprising SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO:41, to the patient. In some embodiments, if the patient weighs less than (but not including) 100 kg, a maintenance dose of about 60 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than (but not including) 100 kg, a maintenance dose of about 65 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than (but not including) 100 kg, a maintenance dose of about 70 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than (but not including) 100 kg, a maintenance dose of about 72 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs between 75 and 100 kg, a maintenance dose of about 60 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient.

[0229] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering to the patient, if the patient's weight is less than (but not including) 125 kg, a maintenance dose of about 70-80 mg of a human ActRIIA-Fc fusion protein comprising SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO:41. In some embodiments, if the patient's weight is less than (but not including) 125 kg, a maintenance dose of about 70 mg of a human ActRIIA-Fc fusion protein comprising SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO:41, is administered to the patient. In some embodiments, if the patient's weight is less than (but not including) 125 kg, a maintenance dose of about 72 mg of a human ActRIIA-Fc fusion protein comprising SEQ ID NO:32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO:41, is administered to the patient. In some embodiments, if the patient weighs less than (but not including) 125 kg, a maintenance dose of approximately 75 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than (but not including) 125 kg, a maintenance dose of approximately 80 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than (but not including) 125 kg, a maintenance dose of approximately 84 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some implementations, if the patient's weight is between [100-125) kg, the patient is given a maintenance dose of about 75 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41.

[0230] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering to the patient, if the patient's weight is less than (but not including) 150 kg, a maintenance dose of about 80-100 mg of a human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41, to the patient. In some embodiments, if the patient's weight is less than (but not including) 150 kg, a maintenance dose of about 80 mg of a human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41, to the patient. In some embodiments, if the patient's weight is less than (but not including) 150 kg, a maintenance dose of about 85 mg of a human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41, to the patient. In some embodiments, if the patient's weight is less than (but not including) 150 kg, a maintenance dose of about 90 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient's weight is less than (but not including) 150 kg, a maintenance dose of about 95 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient's weight is less than (but not including) 150 kg, a maintenance dose of about 96 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs less than (but not including) 150 kg, a maintenance dose of about 100 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs between 125 and 150 kg, a maintenance dose of about 90 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41 is administered to the patient.

[0231] This article describes a method for treating pulmonary hypertension in patients with this need, the method comprising administering to the patient, if the patient weighs more than 150 kg, a maintenance dose of about 80-100 mg of a human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41. In some embodiments, if the patient weighs more than 150 kg, administering to the patient, about 80 mg of a maintenance dose of a human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41. In some embodiments, if the patient weighs more than 150 kg, administering to the patient, about 84 mg of a maintenance dose of a human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41. In some embodiments, if the patient weighs more than 150 kg, a maintenance dose of approximately 85 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO:32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO:41 is administered to the patient. In some embodiments, if the patient weighs more than 150 kg, a maintenance dose of approximately 90 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO:32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO:41 is administered to the patient. In some embodiments, if the patient weighs more than 150 kg, a maintenance dose of approximately 95 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO:32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO:41 is administered to the patient. In some embodiments, if the patient weighs more than 150 kg, a maintenance dose of approximately 100 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 is administered to the patient. In some embodiments, if the patient weighs more than 150 kg, a maintenance dose of approximately 90 mg of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41 is administered to the patient.

[0232] In some embodiments, the maintenance dose is administered to the patient at least three weeks after the initial dose. In some embodiments, the patient is given two or more maintenance doses, approximately three weeks apart. In other embodiments, the maintenance dose is administered to the patient three, four, five, six, seven, eight, nine, or ten weeks after the initial dose. In other embodiments, the maintenance dose is administered to the patient three weeks after the initial dose. In other embodiments, the maintenance dose is administered to the patient four weeks after the initial dose. In other embodiments, the maintenance dose is administered to the patient five weeks after the initial dose. In other embodiments, the maintenance dose is administered to the patient six weeks after the initial dose. In other embodiments, the maintenance dose is administered to the patient seven weeks after the initial dose. In other embodiments, the maintenance dose is administered to the patient eight weeks after the initial dose. In other embodiments, the maintenance dose is administered to the patient nine weeks after the initial dose. In other embodiments, the maintenance dose is administered to the patient ten weeks after the initial dose.

[0233] In some implementations, methods of treating pulmonary hypertension, including administering the ActRIIA-Fc fusion protein or a variant thereof, such as the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41, to patients in need, include the dosage regimens shown in Table 3 below. Table 3 In the table above and throughout this application, if a number is enclosed in square brackets, the number is included in the range; if a number is adjacent to parentheses, the number is not included in the range.

[0234] As shown in Table 3, weight ranges starting from 50 kg were established in 25 kg increments. Each weight range was associated with an initial dose and maintenance dose in multiples of 15. Patients weighing less than 50 kg were given an initial dose of 15 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of ActRIIA-Fc fusion protein containing SEQ ID NO: 41, followed by a maintenance dose of 30 mg. Patients weighing [50-75) kg were given an initial dose of 15 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of ActRIIA-Fc fusion protein containing SEQ ID NO: 41, followed by a maintenance dose of 45 mg. Patients weighing [75-100) kg were given an initial dose of 30 mg of human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of ActRIIA-Fc fusion protein containing SEQ ID NO: 41, followed by a maintenance dose of 60 mg. Patients weighing [100-125) kg were administered an initial dose of 30 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41, followed by a maintenance dose of 75 mg. Patients weighing 125 kg or more were administered an initial dose of 45 mg of the human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or the ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41, followed by a maintenance dose of 90 mg.

[0235] In any of the methods described herein, in some embodiments, a maintenance dose is administered to the patient every 3 weeks for 72 weeks or less. In other embodiments, a maintenance dose is administered to the patient every 3 weeks for 72 weeks or longer.

[0236] In some implementations, an initial dose and / or maintenance dose of human ActRIIA protein or a variant of human ActRIIA protein is administered to the patient via subcutaneous injection.

[0237] In some embodiments, an initial dose and / or maintenance dose of human ActRIIA protein or a variant of human ActRIIA protein is administered to the patient using an autoinjector. In some embodiments, a maintenance dose of human ActRIIA protein or a variant of human ActRIIA protein is administered to the patient using an autoinjector. In some embodiments, an initial dose of human ActRIIA protein or a variant of human ActRIIA protein is administered to the patient using an autoinjector. In some embodiments, the maintenance dose is administered as a single injection.

[0238] In some embodiments, the autoinjector contains 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, or 90 mg of sotexip. In some embodiments, the autoinjector contains 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, or 90 mg of a human ActRIIA-Fc fusion protein comprising the amino acid sequence shown in SEQ ID NO: 32, or a variant of the human ActRIIA-Fc fusion protein comprising the amino acid sequence shown in SEQ ID NO: 41. In some embodiments, the patient weighs 125 kg or more, wherein the maintenance dose is 90 mg, administered to the patient in a single injection. In some embodiments, the patient weighs 125 kg or more, wherein the maintenance dose is 90 mg, administered to the patient in two or more injections. An example of a suitable autoinjector is the currently commercially available Molly® autoinjector.

[0239] This article describes a method for administering the ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or a human ActRIIA-Fc fusion protein variant comprising the amino acid sequence shown in SEQ ID NO: 41 using an autoinjector, the method comprising administering an initial dose of the ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or a human ActRIIA-Fc fusion protein variant comprising the amino acid sequence shown in SEQ ID NO: 41 to a patient, wherein the initial dose is 15 mg or a multiple of 15 mg, and the initial dose is determined by comparing the patient’s weight to a list of predetermined weight intervals and selecting a pre-selected dose for a weight interval corresponding to the patient’s weight as the initial dose.

[0240] This article describes a method for administering the ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or a human ActRIIA-Fc fusion protein variant comprising the amino acid sequence shown in SEQ ID NO: 41 using an autoinjector, the method comprising administering an initial dose of the ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or a human ActRIIA-Fc fusion protein variant comprising the amino acid sequence shown in SEQ ID NO: 41 to a patient using a first autoinjector, wherein the initial dose is 15 mg or a multiple of 15 mg, and the initial dose is determined by comparing the patient’s weight to a list of predetermined weight ranges and selecting a pre-selected dose for a weight range corresponding to the patient’s weight as the initial dose.

[0241] This article describes a method for administering the ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or a human ActRIIA-Fc fusion protein variant comprising the amino acid sequence shown in SEQ ID NO: 41 using an autoinjector. The method comprises administering to a patient a maintenance dose of the ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or a human ActRIIA-Fc fusion protein variant comprising the amino acid sequence shown in SEQ ID NO: 41, wherein the maintenance dose is a multiple of 15 mg, and the maintenance dose is determined by comparing the patient's weight to a list of predetermined weight ranges and selecting a pre-selected dose for a weight range corresponding to the patient's weight as the maintenance dose, and the maintenance dose is administered to the patient approximately 3 weeks after the initial dose.

[0242] This article describes a method for administering the ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or a human ActRIIA-Fc fusion protein variant comprising the amino acid sequence shown in SEQ ID NO: 41 to a patient using an autoinjector. The method comprises administering a maintenance dose of the ActRIIA-Fc fusion protein comprising SEQ ID NO: 32 or a human ActRIIA-Fc fusion protein variant comprising the amino acid sequence shown in SEQ ID NO: 41 to a patient using a second autoinjector, wherein the maintenance dose is a multiple of 15 mg, and the maintenance dose is determined by comparing the patient's weight to a list of predetermined weight ranges and selecting a pre-selected dose for a weight range corresponding to the patient's weight as the maintenance dose, and the maintenance dose is administered to the patient approximately 3 weeks after the initial dose.

[0243] In some embodiments, the autoinjector contains an initial dose of sotexip of 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, or 90 mg. In some embodiments, the autoinjector contains a maintenance dose of 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, or 90 mg of a human ActRIIA-Fc fusion protein comprising the amino acid sequence shown in SEQ ID NO: 32, or a variant of the human ActRIIA-Fc fusion protein comprising the amino acid sequence shown in SEQ ID NO: 41. In some embodiments, the patient weighs 125 kg or more, wherein the maintenance dose is 90 mg and is administered to the patient in a single injection. In some embodiments, the patient weighs 125 kg or more, wherein the maintenance dose is 90 mg and is administered to the patient in two or more injections. An example of a suitable autoinjector is the currently commercially available Molly® autoinjector. In some embodiments, the autoinjector delivers a dose volume of 1.8 mL. In some embodiments, the autoinjector is used to deliver the dose to the thigh, arm, or abdomen. In some embodiments, the dose is delivered within 2-3 seconds. In some embodiments, the autoinjector includes a 27-gauge needle. In some embodiments, the needle length may be 6 mm. Methods, uses and drugs

[0244] This document describes a method for treating pulmonary arterial hypertension (PAH), the method comprising administering an ActRII peptide to a patient in need according to the dosing regimen described herein. In some embodiments, this disclosure contemplates methods for treating pulmonary arterial hypertension, preventing pulmonary arterial hypertension, or reducing the rate of progression and / or severity of pulmonary arterial hypertension, the method comprising administering an ActRII peptide to a patient in need according to the dosing regimen described herein.

[0245] In some implementations, administration of the ActRII peptide according to the dosing regimen described herein results in changes in one or more hemodynamic or functional parameters (e.g., a decrease in pulmonary vascular resistance (PVR); an increase in 6-minute walk distance (6MWD); a decrease in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels; prevention or delay of progression of the WHO-recognized functional classification of pulmonary hypertension; promotion or increase of regression of the WHO-recognized functional classification of pulmonary hypertension; improvement of right ventricular function; and improvement of pulmonary artery pressure).

[0246] In one aspect, this disclosure provides a method for treating PAH in a patient with this need, the method comprising administering a human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41, according to the dosing regimen described herein. In another aspect, this disclosure provides a method for treating PAH in a patient with this need, the method comprising administering to the patient a human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or an ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41, wherein the amount of the human ActRIIA-Fc fusion protein comprising SEQ ID NO: 32, or the ActRIIA-Fc fusion protein variant comprising SEQ ID NO: 41, is determined based on the patient's weight range.

[0247] Pulmonary hypertension treated by the methods described herein may include any one or more conditions recognized by the World Health Organization (WHO). See, for example, Simonneau (2019) Eur Respir J: 53:1801913. Table 4: Clinical classification of pulmonary hypertension

[0248] The clinical aim of PAH classification is to categorize PAH-related clinical conditions into specific subgroups based on their pathophysiological mechanisms, clinical manifestations, hemodynamic characteristics, and treatment strategies. This clinical classification may be updated when new data on these characteristics become available or when additional clinical entities are considered.

[0249] As used herein, the term “pulmonary hemodynamic parameter” refers to any parameter used to describe or assess blood flow through the cardiac and pulmonary vascular systems. Examples of pulmonary hemodynamic parameters include, but are not limited to, mean pulmonary artery pressure (mPAP), diastolic pulmonary artery pressure (dPAP) [also known as pulmonary artery diastolic pressure (PADP)], systolic pulmonary artery pressure (sPAP) [also known as pulmonary artery systolic pressure (PASP)], mean right atrial pressure (mRAP), pulmonary capillary wedge pressure (PCWP) [also known as pulmonary artery wedge pressure (PAWP)], pulmonary vascular resistance (PVR), and cardiac output (CO).

[0250] Many of the above-mentioned pulmonary hemodynamic parameters are interrelated. For example, PVR is related to mPAP, PCWP, and CO according to the following equation:

[0251] PVR = (mPAP - PCWP) / CO [Woods units]

[0252] PVR measures the flow resistance exerted by the pulmonary vascular system, unaffected by left-side filling pressure. PVR can also be measured using the following equation:

[0253] PVR = TPG × 80 / CO [Unit: dynes-sec-cm] -5 Or PVR = (mPAP – PCWP) × 80 / CO [Unit: dynes-sec-cm] -5 ]

[0254] In some implementations, total peripheral resistance (TPR) can be measured using the following equation:

[0255] TPR = mPAP / CO.

[0256] According to some implementation schemes, the contribution of the precapillary pulmonary artery to pH can be reflected by elevated PVR. In some implementation schemes, normal PVR is 20-130 dynes-sec-cm. -5 Or 0.5-1.1 Wood units. According to some implementation schemes, an increased PVR can refer to a PVR greater than 2 Wood units, greater than 2.5 Wood units, greater than 3 Wood units, or greater than 3.5 Wood units.

[0257] As yet another example, mPAP is related to dPAP and sPAP according to the following equation: mPAP = ( )dPAP+( )sPAP

[0258] In addition, dPAP and sPAP can be used to calculate pulse pressure (mmHg) using the following equation: Pulse pressure = sPAP - dPAP

[0259] Pulse pressure can be used to calculate pulmonary artery compliance using the following equation: Pulmonary artery compliance (mI.mmHg) -1 = Stroke volume / Pulse pressure

[0260] In some implementations, pulmonary hemodynamic parameters are measured directly, such as during right heart catheterization. In other implementations, pulmonary hemodynamic parameters are estimated and / or assessed using other techniques, such as magnetic resonance imaging (MRI) or echocardiography.

[0261] Exemplary pulmonary hemodynamic parameters include mPAP, PAWP, and PVR. One or more pulmonary hemodynamic parameters can be measured by any appropriate procedure, such as by right heart catheterization or echocardiography. Various hemodynamic characteristics of PH and PAH are shown in Table 5.

[0262] Table 5. Hemodynamic characteristics of pulmonary hypertension (PH) and PAH

[0263] The clinical classification or hemodynamic characteristics of PAH and the associated diagnostic parameters described in this article may be updated or changed based on the availability of new or existing data sources, or when additional clinical entities are considered.

[0264] This document also describes a method for treating pulmonary arterial hypertension (PAH), the method comprising administering an ActRII peptide to a patient in need of treatment according to the dosing regimen described herein, wherein the patient has already received PAH treatment (background therapy). In some embodiments, this disclosure contemplates methods for treating, preventing, or reducing the rate of progression and / or severity of pulmonary arterial hypertension, the methods comprising administering an ActRII peptide to a patient in need of treatment according to the dosing regimen described herein, wherein the patient has already received PAH treatment (background therapy).

[0265] In some implementations, the dosing regimens described herein are administered to patients who were already receiving standard care for the treatment of PAH as defined during the STELLAR trial and were considered to be receiving background therapy. Background therapy, defined as standard care for PAH during the STELLAR trial, includes single, dual, or triple therapy of certain combinations of endothelin receptor antagonists (ERAs), phosphodiesterase type 5 (PDE-5) inhibitors, soluble guanylate cyclase (sGC) stimulators, prostaglandin I2 (PGI2) analogs, and PGI2 agonists.

[0266] In some embodiments, the dosing regimen described herein is administered to a patient who is further treated with one or more PAH therapies. In some embodiments, one or more PAH therapies are selected from the group consisting of phosphodiesterase 5 inhibitors (PDE-5i), soluble guanylate cyclase stimulators (sGCS), endothelin receptor antagonists (ERA), and prostacyclin therapies (prostacyclin = PCY). pharmaceutical preparations

[0267] In some embodiments of the methods described herein, the ActRIIA protein described herein is administered as a pharmaceutical composition comprising the ActRIIA protein and one or more pharmaceutical additives and / or excipients. In some embodiments, the pharmaceutical formulation is lyophilized. In some embodiments, the formulation is reconstituted from a lyophilized formulation. In other embodiments, the pharmaceutical formulation is a liquid formulation. In other embodiments, the pharmaceutical formulation is a stable liquid formulation.

[0268] In one embodiment of the pharmaceutical formulation provided herein, 15, 30, 45, 60, 75, or 90 mg of ActRIIA protein; citrate monohydrate, trisodium citrate dihydrate, polysorbate 80, and sucrose are included.

[0269] In some embodiments, the dose is administered parenterally. In some embodiments, the dose is administered subcutaneously. In some embodiments, the dose is administered intradermally. In some embodiments, the dose is administered intramuscularly. In some embodiments, the dose is administered intravenously. In some embodiments, the dose is self-administered.

[0270] In some embodiments, the lyophilized pharmaceutical formulation comprises a protein comprising, substantially comprising, or comprising of the following amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 9 or SEQ ID NO: 32. In some such embodiments, the protein comprises at least 90%, 95%, or 99% identical to SEQ ID NO: 9 or SEQ ID NO: 32, wherein the protein binds activin and / or GDF11. In some embodiments, the protein comprises the amino acid sequence of SEQ ID NO: 10 or SEQ ID NO: 32. In other embodiments, the protein consists of the amino acid sequence of SEQ ID NO: 10 or SEQ ID NO: 32.

[0271] In some embodiments, the lyophilized pharmaceutical formulation comprises a protein containing at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical amino acid sequences to the amino acid sequence of SEQ ID NO: 32. In some embodiments, the protein consists substantially of the amino acid sequence of SEQ ID NO: 32. In other embodiments, the protein consists of the amino acid sequence of SEQ ID NO: 32. In other embodiments, the protein consists of a variant of SEQ ID NO: 32 lacking a C-terminal lysine residue (i.e., SEQ ID NO: 41).

[0272] In some implementations, the protein is part of a homodimeric protein complex.

[0273] In some implementations, the protein is glycosylated.

[0274] In some embodiments, the pH range of the liquid pharmaceutical formulation or the reconstituted lyophilized pharmaceutical formulation containing the ActRIIA-Fc fusion protein is from 5 to 7. In some embodiments, the pharmaceutical formulation containing the ActRIIA-Fc fusion protein also contains a buffer. In some embodiments, the buffer is added in an amount of at least 10 mM. In some embodiments, the buffer is added in an amount ranging from about 10 mM to about 200 mM. In some embodiments, the buffer contains citrate.

[0275] In some embodiments, the pharmaceutical formulation further comprises a surfactant. In some embodiments, the surfactant comprises polysorbate. In some embodiments, the surfactant comprises polysorbate 20 or polysorbate 80. In some embodiments, the surfactant comprises polysorbate 80.

[0276] In some embodiments, the pharmaceutical formulation further comprises a lyophilization protectant. In some embodiments, the lyophilization protectant comprises a sugar, such as a disaccharide (e.g., sucrose). In some embodiments, the lyophilization protectant comprises sucrose, trehalose, mannitol, polyvinylpyrrolidone (PVP), glucose, and / or glycine. In some embodiments, the lyophilization protectant comprises sucrose. In some embodiments, the lyophilized pharmaceutical formulation comprises a lyophilization protectant and a protein, wherein the weight ratio of the protein to the lyophilization protectant is at least 1:1. In some embodiments, the lyophilized pharmaceutical formulation comprises a lyophilization protectant and a protein, wherein the weight ratio of the protein to the lyophilization protectant is from 1:1 to 1:10. In some embodiments, the lyophilized pharmaceutical formulation comprises a lyophilization protectant and a protein, wherein the weight ratio of the protein to the lyophilization protectant is 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10. In some embodiments, the pharmaceutical formulation comprises a lyophilization protectant and a protein, wherein the weight ratio of the protein to the lyophilization protectant is 1:6. In some of the aforementioned embodiments, the lyophilized pharmaceutical formulation contains a lyophilization protectant in an amount sufficient to stabilize the protein.

[0277] In some embodiments of the methods described herein, the ActRIIA-Fc fusion protein described herein is administered as a liquid pharmaceutical formulation comprising human ActRIIA-Fc fusion protein or a variant thereof, a buffer, a surfactant, a stabilizer, and optionally one or more antioxidants. In some embodiments, the pharmaceutical formulation described herein comprises human ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or an ActRIIA-Fc fusion protein variant containing SEQ ID NO: 41, a buffer, a surfactant, a stabilizer, and optionally one or more antioxidants.

[0278] In some embodiments of the method described herein, the ActRIIA-Fc fusion protein described herein is administered as a liquid pharmaceutical formulation comprising the ActRIIA-Fc fusion protein containing SEQ ID NO: 32 or a variant of the ActRIIA-Fc fusion protein containing SEQ ID NO: 41, a buffer, a surfactant, a stabilizer, and optionally one or more antioxidants, wherein the buffer is not histidine. Reagent test kit

[0279] This disclosure provides a kit comprising the pharmaceutical formulation and injection device provided herein. In some embodiments of the kit disclosed herein, the injection device comprises a syringe. In some such embodiments, the syringe is pre-filled with a stable liquid formulation.

[0280] In some embodiments of the kit disclosed herein, the kit further includes an injection device for parenteral administration of the sterile injectable solution. In some embodiments, the sterile injectable solution is administered via subcutaneous injection. In some embodiments, the sterile injectable solution is administered via intradermal injection. In some embodiments, the sterile injectable solution is administered via intramuscular injection. In some embodiments, the sterile injectable solution is administered via intravenous injection.

[0281] In some embodiments of the kit disclosed herein, the kit further includes an autoinjector for administering the sterile injection solution. In some embodiments, the sterile injection solution is self-administered. In some embodiments, the sterile injection solution contains a therapeutically effective dose. Example 1: Analyzing clinical trial data of sotexip to establish weight zones

[0282] An integrated population pharmacokinetic model was developed using data from two phase 1 studies in healthy participants, two phase 2 studies (SPECTRA and PULSAR) in participants with pulmonary arterial hypertension (PAH), and one phase 3 study (STELLAR), as described in Ait-Oudhia S, Jaworowicz D, Hu Z, Bihorel S, Hu S, Balasubrahmanyam B, Mistry B, de Oliveira Pena J, Wenning L, Gheyas F. Population pharmacokinetic modeling of sotatercept in healthy participants and patients with pulmonary arterial hypertension. CPT Pharmacometrics SystPharmacol. 2024 Aug;13(8):1380-1393. doi: 10.1002 / psp4.13166. Epub 2024 May29. PMID: 38812074; PMCID: PMC11330185. The relationship between sotexip exposure and efficacy (e.g., 6MWD, PVR) and safety (e.g., hemoglobin) endpoints was assessed, and the mean steady-state concentration (Cavg) of sotexip within the dosing interval was determined to be associated with the assessed endpoints. Therefore, similar sotexip Cavg values ​​are expected to result in similar safety and efficacy characteristics.

[0283] Population pharmacokinetic models were used to predict the mean steady-state caveg of sotexip based on both body weight and weight-zone dosing. A total of 250 simulations were performed using population pharmacokinetic models, incorporating parameter uncertainties (fixed-effects only) and inter-individual variability. For each simulation, a virtual population of 2000 PAH patients was generated by sampling with replacement from PAH participants (n=286) treated with sotexip in STELLAR (n=162), PULSAR (n=103), and SPECTRA (n=21) studies (body weight range 39.6–136.4 kg across all three studies). For each virtual patient, the caveg value was calculated as the area under the concentration-time curve (AUC) divided by the three-week dosing interval. For each simulation, the 5th, 25th, 50th, 75th, and 95th percentiles of the caveg values ​​for the 2000 virtual patients were calculated. For each weight zone and dose combination, the median of these percentiles from the 250 simulations was reported. For the maintenance dose (e.g., 0.7 mg / kg for a weight-based dosing regimen), steady-state Cavg values ​​were calculated; for the initial dose (e.g., 0.3 mg / kg for a weight-based dosing regimen), Cavg values ​​were calculated for weeks 1 through 3.

[0284] After exploring numerous weight ranges and dose combinations, five weight ranges from <50 kg to ≥125 kg and their corresponding doses (a total of six dose intensities, including initial and maintenance doses) were selected. The selection of weight ranges and corresponding doses was based on a balance between: a) the overall and comparable Cavg distribution for each weight range; b) convenience for patients and healthcare providers; and c) the practically reasonable number of weight ranges and dose intensities. Fewer proposed weight ranges / dose intensities would be more convenient but would result in greater variability in exposure.

[0285] The distribution of predicted Cavg for maintenance dose, weight-bound dosing, and weight-based dosing is shown in... Figure 2 And in Table 6; for the initial dose, its distribution is shown in Figure 3 And in Table 7. In the proposed weight-range dosing regimens, the central tendency (median) and distribution range of Cavg for maintenance and initial doses are similar to those of weight-based dosing regimens.

[0286] For maintenance doses, the proposed median Cavg values ​​for dosing across weight ranges are generally comparable (within 1% of the median Cavg for weight-based dosing) and within individual weight ranges (within 10% of the median Cavg for weight-based dosing), such as... Figure 2See Table 6. The efficacy and safety of sotexip are primarily driven by maintenance dose, and given similar predicted exposures, efficacy and safety are expected to be comparable between weight-range dosing and weight-based dosing.

[0287] For the initial dose, the proposed median Cavg for dosing across weight intervals is similar overall (within 9% of the median Cavg for weight-based dosing) and within a single weight interval (within 20% of the median Cavg for weight-based dosing), as... Figure 3 See Table 7. For the initial dose, slightly lower exposure in some weight ranges is not expected to affect efficacy. Similarly, slightly higher exposure in some weight ranges is not expected to affect safety, as the exposure at the initial dose (0.3 mg / kg) is several times lower than the steady-state exposure at the maintenance dose (0.7 mg / kg Q3W).

[0288] Overall, simulation results indicate that the proposed weight-range doses of sotexip (initial and maintenance doses) are expected to provide exposure comparable to weight-based dosing.

[0289] Table 6: Predicted steady-state Cavg after administration of body weight interval doses and body weight-based doses (0.7 mg / kg)

[0290] Table 7: Predicted Cavg after administration of body weight interval doses and body weight-based doses (0.3 mg / kg) (Week 1 to Week 3)

[0291] The subject matter of this disclosure should not be limited to the specific embodiments and examples described herein. In fact, various modifications to this disclosure will become apparent to those skilled in the art from the foregoing description and drawings, in addition to those described. Such modifications are intended to fall within the scope of the appended claims.

[0292] All references cited herein (e.g., publications, patents, or patent applications) are incorporated herein in their entirety by reference and for all purposes, to the extent that each individual reference (e.g., publications, patents, or patent applications) is specifically and individually indicated as incorporated herein in its entirety by reference for all purposes. Other embodiments are within the scope of the following claims.

Claims

1. A method for treating pulmonary hypertension in a patient with this need, the method comprising administering to the patient an initial dose of a human ActRIIA-Fc fusion protein comprising an amino acid sequence as shown in SEQ ID NO: 32 or a variant of the human ActRIIA-Fc fusion protein comprising an amino acid sequence as shown in SEQ ID NO: 41, wherein the initial dose is 15 mg or a multiple of 15 mg, and the initial dose is determined by comparing the patient's weight with a list of predetermined weight intervals and selecting a pre-selected dose for a weight interval corresponding to the patient's weight as the initial dose.

2. The method of claim 1, wherein the initial dose is selected from one of the following predetermined weight ranges: (a) For patients weighing less than 50 kg, 15 mg, (b) For patients weighing between 50 kg and 75 kg but excluding 75 kg, 15 mg, (c) For patients weighing between 75 kg and 100 kg but not exceeding 100 kg, 30 mg, (d) For patients weighing between 100 kg and 125 kg but excluding 125 kg, 30 mg, or (e) For patients weighing 125 kg or more, 45 mg.

3. The method of claim 2, further comprising: The patient is given a maintenance dose of a human ActRIIA-Fc fusion protein containing the amino acid sequence shown in SEQ ID NO: 32 or a variant of the human ActRIIA-Fc fusion protein containing the amino acid sequence shown in SEQ ID NO: 41, wherein the maintenance dose is a multiple of 15 mg, and the maintenance dose is determined by comparing the patient’s weight with a list of predetermined weight ranges and selecting a pre-selected dose for the weight range corresponding to the patient’s weight as the maintenance dose, wherein the maintenance dose is administered to the patient approximately 3 weeks after the initial dose.

4. The method of claim 3, wherein the maintenance dose is selected from one of the following predetermined weight ranges: (a) For patients weighing less than 50 kg, 30 mg, (b) For patients weighing between 50 kg and 75 kg but excluding 75 kg, 45 mg, (c) For patients weighing between 75 kg and 100 kg but not exceeding 100 kg, 60 mg, (d) For patients weighing between 100 kg and 125 kg but excluding 125 kg, 75 mg, or (e) For patients weighing 125 kg or more, 90 mg.

5. The method of claim 4, wherein the maintenance dose is administered to the patient every 3 weeks.

6. The method of any one of claims 3-5, wherein the initial dose and / or maintenance dose of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient via subcutaneous injection.

7. The method of any one of claims 3-6, wherein the initial dose and / or maintenance dose of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient using an autoinjector.

8. The method of claim 7, wherein the maintenance dose of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient using an autoinjector.

9. The method of claim 7 or 8, wherein the initial dose of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient using an autoinjector.

10. The method of any one of claims 3-9, wherein each maintenance dose is administered by a single injection.

11. The method of any one of claims 3-9, wherein the patient weighs 125 kg or more, and wherein the maintenance dose of 90 mg is administered to the patient in a single injection.

12. The method of any one of claims 3-9, wherein the patient weighs 125 kg or more, and wherein the maintenance dose of 90 mg is administered to the patient in two or more injections.

13. The method of any one of claims 3-12, wherein the maintenance dose is administered to the patient every 3 weeks for a period of 72 weeks or less.

14. The method of any one of claims 3-13, wherein the maintenance dose is administered to the patient every 3 weeks for 72 weeks or longer.

15. The method of any one of claims 1-14, wherein the patient is treated with one or more additional PAH therapies.

16. The method of claim 15, wherein the one or more additional PAH therapies are selected from the group consisting of phosphodiesterase-5 inhibitors (PDE-5i), soluble guanylate cyclase stimulators (sGCS), endothelin receptor antagonists (ERA), and prostacyclin therapies.

17. A method for treating pulmonary hypertension in a patient with this need, the method comprising administering to the patient an initial dose of sotexip or a sotexip variant lacking a C-terminal lysine, wherein the initial dose is selected from the group consisting of: (a) For patients weighing less than 50 kg, 15 mg, (b) For patients weighing between 50 kg and 75 kg but excluding 75 kg, 15 mg, (c) For patients weighing between 75 kg and 100 kg but not exceeding 100 kg, 30 mg, (d) For patients weighing between 100 kg and 125 kg but excluding 125 kg, 30 mg, and (e) For patients weighing 125 kg or more, 45 mg.

18. The method of claim 17, further comprising administering a maintenance dose of sotexip or a sotexip variant lacking a C-terminal lysine to the patient approximately 3 weeks after the initial dose, wherein the maintenance dose is selected from the group consisting of: (a) For patients weighing less than 50 kg, 30 mg, (b) For patients weighing between 50 kg and 75 kg but excluding 75 kg, 45 mg, (c) For patients weighing between 75 kg and 100 kg but not exceeding 100 kg, 60 mg, (d) For patients weighing between 100 kg and 125 kg but excluding 125 kg, 75 mg, and (e) For patients weighing 125 kg or more, 90 mg.

19. The method of claim 18, wherein two or more maintenance doses are administered to the patient, with approximately three weeks between each dose.

20. The method of any one of claims 17-19, wherein the initial dose and / or the maintenance dose are administered to the patient via subcutaneous injection.

21. The method of any one of claims 17-20, wherein the initial dose and / or the maintenance dose are administered to the patient using an autoinjector.

22. A method for treating pulmonary hypertension in a patient with this need, the method comprising administering to the patient an initial dose of 10-50 mg of a human ActRIIA-Fc fusion protein comprising an amino acid sequence as shown in SEQ ID NO: 32 or a variant of the human ActRIIA-Fc fusion protein comprising an amino acid sequence as shown in SEQ ID NO: 41, wherein the patient weighs less than 150 kg.

23. The method of claim 22, wherein 15-45 mg of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient.

24. The method of claim 22, wherein 10-20 mg of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs less than 75 kg.

25. The method of claim 22, wherein 20-30 mg of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs less than 125 kg.

26. The method of claim 22, wherein 30-50 mg of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs less than 150 kg.

27. The method of claim 22, wherein 15 mg of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs less than 75 kg.

28. The method of claim 22, wherein 15 mg of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs less than 50 kg.

29. The method of claim 22, wherein 30 mg of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs between 75 kg and 100 kg, but not including 100 kg.

30. The method of claim 22, wherein 30 mg of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs between 100 kg and 125 kg, but not including 125 kg.

31. The method of claim 22, wherein 45 mg of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs between 125 kg and 150 kg, but not including 150 kg.

32. The method of any one of claims 22 to 32, further comprising: The patient is given a maintenance dose of 20-100 mg of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein, wherein the patient weighs less than 150 kg.

33. The method of claim 32, wherein 20-40 mg of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs less than 50 kg.

34. The method of claim 32, wherein 40-50 mg of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs less than 75 kg.

35. The method of claim 32, wherein 50-70 mg of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs less than 100 kg.

36. The method of claim 32, wherein 70-80 mg of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs less than 125 kg.

37. The method of claim 32, wherein 80-90 mg of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs less than 150 kg.

38. The method of claim 32, wherein 30 mg of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs less than 50 kg.

39. The method of claim 32, wherein 45 mg of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs between 50 kg and 75 kg, but not including 75 kg.

40. The method of claim 32, wherein 60 mg of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs between 75 kg and 100 kg, but not including 100 kg.

41. The method of claim 32, wherein 75 mg of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs between 100 kg and 125 kg, but not including 125 kg.

42. The method of claim 32, wherein 75 mg of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs between 125 kg and 150 kg, but not including 150 kg.

43. A method for treating pulmonary hypertension in a patient with this need, the method comprising administering to the patient an initial dose of 40-50 mg of a human ActRIIA-Fc fusion protein comprising an amino acid sequence as shown in SEQ ID NO: 32 or a variant of the human ActRIIA-Fc fusion protein comprising an amino acid sequence as shown in SEQ ID NO: 41, wherein the patient weighs 125 kg or more.

44. The method of claim 43, wherein 40-50 mg of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs 150 kg or more.

45. The method of claim 43, wherein 45 mg of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs 125 kg or more.

46. ​​The method of claim 43, wherein 45 mg of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs 150 kg or more.

47. The method of claim 43, further comprising administering to the patient a maintenance dose of 50-100 mg of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein, wherein the patient weighs 125 kg or more.

48. The method of claim 47, wherein 75-100 mg of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs 125 kg or more.

49. The method of claim 47, wherein 90 mg of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient, wherein the patient weighs 150 kg or more.

50. The method of any one of claims 47-49, wherein the patient is given the initial dose of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein and the maintenance dose of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein, wherein the maintenance dose is given to the patient approximately 3 weeks after the initial dose.

51. A method for treating pulmonary hypertension in a patient with this need, the method comprising administering an initial dose of 15 mg of a human ActRIIA-Fc fusion protein comprising the amino acid sequence shown in SEQ ID NO: 32 or a variant of the human ActRIIA-Fc fusion protein comprising the amino acid sequence shown in SEQ ID NO: 41 to the patient on day 1, and administering a maintenance dose of 30 mg of the human ActRIIA-Fc fusion protein comprising the amino acid sequence shown in SEQ ID NO: 32 or a variant of the human ActRIIA-Fc fusion protein comprising the amino acid sequence shown in SEQ ID NO: 41 to the patient every three weeks starting from day 1, wherein the patient weighs less than 50 kg.

52. A method for treating pulmonary hypertension in a patient with this need, the method comprising administering an initial dose of 15 mg of a human ActRIIA-Fc fusion protein comprising the amino acid sequence shown in SEQ ID NO: 32 or a variant of the human ActRIIA-Fc fusion protein comprising the amino acid sequence shown in SEQ ID NO: 41 to the patient on day 1, and administering a maintenance dose of 45 mg of the human ActRIIA-Fc fusion protein comprising the amino acid sequence shown in SEQ ID NO: 32 or a variant of the human ActRIIA-Fc fusion protein comprising the amino acid sequence shown in SEQ ID NO: 41 to the patient every three weeks starting from day 1, wherein the patient weighs [50-75) kg.

53. A method for treating pulmonary hypertension in a patient with this need, the method comprising administering an initial dose of 30 mg of a human ActRIIA-Fc fusion protein comprising the amino acid sequence shown in SEQ ID NO: 32 or a variant of the human ActRIIA-Fc fusion protein comprising the amino acid sequence shown in SEQ ID NO: 41 to the patient on day 1, and administering a maintenance dose of 50-100 mg of the human ActRIIA-Fc fusion protein comprising the amino acid sequence shown in SEQ ID NO: 32 or a variant of the human ActRIIA-Fc fusion protein comprising the amino acid sequence shown in SEQ ID NO: 41 to the patient every three weeks starting from day 1, wherein the patient weighs ≥75 kg.

54. A method for treating pulmonary hypertension in a patient with this need, the method comprising administering an initial dose of 30 mg of a human ActRIIA-Fc fusion protein comprising the amino acid sequence shown in SEQ ID NO: 32 or a variant of the human ActRIIA-Fc fusion protein comprising the amino acid sequence shown in SEQ ID NO: 41 to the patient on day 1, and administering a maintenance dose of 60 mg of the human ActRIIA-Fc fusion protein comprising the amino acid sequence shown in SEQ ID NO: 32 or a variant of the human ActRIIA-Fc fusion protein comprising the amino acid sequence shown in SEQ ID NO: 41 to the patient every three weeks starting from day 1, wherein the patient weighs between [75-100) kg.

55. A method for treating pulmonary hypertension in a patient with this need, the method comprising administering an initial dose of 30 mg of a human ActRIIA-Fc fusion protein comprising the amino acid sequence shown in SEQ ID NO: 32 or a variant of the human ActRIIA-Fc fusion protein comprising the amino acid sequence shown in SEQ ID NO: 41 to the patient on day 1, and administering a maintenance dose of 75 mg of the human ActRIIA-Fc fusion protein comprising the amino acid sequence shown in SEQ ID NO: 32 or a variant of the human ActRIIA-Fc fusion protein comprising the amino acid sequence shown in SEQ ID NO: 41 to the patient every three weeks starting from day 1, wherein the patient's weight is between [100-125) kg.

56. A method for treating pulmonary hypertension in a patient with this need, the method comprising administering an initial dose of 45 mg of a human ActRIIA-Fc fusion protein comprising the amino acid sequence shown in SEQ ID NO: 32 or a variant of the human ActRIIA-Fc fusion protein comprising the amino acid sequence shown in SEQ ID NO: 41 to the patient on day 1, and administering a maintenance dose of 90 mg of the human ActRIIA-Fc fusion protein comprising the amino acid sequence shown in SEQ ID NO: 32 or a variant of the human ActRIIA-Fc fusion protein comprising the amino acid sequence shown in SEQ ID NO: 41 to the patient every three weeks starting from day 1, wherein the patient weighs ≥125 kg.

57. The method of any one of claims 50-56, wherein the initial dose and / or maintenance dose of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient via subcutaneous injection.

58. The method of any one of claims 50-56, wherein the initial dose and / or maintenance dose of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient using an autoinjector.

59. The method of claims 50-56, wherein the maintenance dose of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient using an autoinjector.

60. The method of claims 50-56, wherein the initial dose of the human ActRIIA-Fc fusion protein or a variant of the human ActRIIA-Fc fusion protein is administered to the patient using an autoinjector.

61. The method of any one of claims 50-56, wherein the maintenance dose is administered by a single injection.

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