Combination therapy for treating interstitial lung disease

Abstract

Disclosed herein are methods for treating interstitial lung disease (ILD), including interstitial lung disease-associated pulmonary hypertension (ILD-PH), comprising administering to a subject in need thereof: a therapeutically effective amount of a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a dimeric fusion protein comprising: the extracellular domain of the activin type 2A (ACTR IIA) or the activin type 2B receptor (ACTR IIB); and the Fc domain of human immunoglobulin G1 (IgG1). In some embodiments, the tyrosine kinase inhibitor is Seralutinib or a pharmaceutically acceptable salt thereof and the fusion protein is Sotatercept. Methods related to other diseases and / or conditions are also disclosed, as are related kits.

Description

COMBINATION THERAPY FOR TREATING INTERSTITIAL LUNG DISEASEFIELD OF THE INVENTION

[0001] The present invention relates to the combination of a tyrosine kinase inhibitor and a dimeric fusion protein for treatment of interstitial lung disease (ILD), including interstitial lung disease-associated pulmonary hypertension (ILD-PH), and to methods and products related thereto.BACKGROUND

[0002] Interstitial lung disease (ILD) is an umbrella term used for a large group of diseases characterized by inflammation or fibrosis within the lung interstitium, the primary consequence of which is impaired gas exchange, resulting in breathlessness, diminished exercise tolerance, and decreased quality of life. Outcomes vary considerably for each of the different interstitial lung diseases. In some conditions, spontaneous reversibility or stabilization can occur, but in many people with interstitial lung disease prognosis it poor. The field of interstitial lung disease has had important advances, with the approval of drugs to treat systemic sclerosis-associated interstitial lung disease (SSc-ILD), interstitial lung disease-associated pulmonary hypertension (ILD-PH), and different forms of progressive pulmonary fibrosis (PPF). While advances have been made in this field, there remains a significant and urgent need for methods and products for treating ILD.BRIEF SUMMARY

[0003] In one embodiment, described herein are methods for treating interstitial lung disease (ILD), comprising administering to a subject in need thereof:a therapeutically effective amount of a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof; anda therapeutically effective amount of a dimeric fusion protein comprising:the extracellular domain of the activin type 2A (ACTR IIA) or the activin type 2B receptor (ACTR IIB); andthe Fc domain of human immunoglobulin G1 (IgGl).

[0004] In some embodiments, the tyrosine kinase inhibitor is a PDGF receptor inhibitor, a CSF1R receptor inhibitor, a c-KIT kinase inhibitor or a combination thereof. In some1#11321063.1embodiments, the tyrosine kinase inhibitor is Seralutinib or a pharmaceutically acceptable salt thereof

[0005] In some embodiments, the dimeric fusion protein comprises the extracellular domain of the activin type 2A receptor. In other embodiments, the dimeric fusion protein comprises the extracellular domain of the activin type 2B receptor. In yet other embodiments, the dimeric fusion protein is Sotatercept.

[0006] In other embodiments, methods are provided for treating ILD, comprising administering to a subject in need thereof:a therapeutically effective amount of Seralutinib or a pharmaceutically acceptable salt thereof; anda therapeutically effective amount of Sotatercept.

[0007] In further embodiments, methods are provided for treating ILD-PH, comprising administering to a subject in need thereof:a therapeutically effective amount of Seralutinib or a pharmaceutically acceptable salt thereof; anda therapeutically effective amount of Sotatercept.

[0008] In still other embodiments, kits are provided comprising:one or more doses of a therapeutically effective amount of a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof; andone or more doses of a therapeutically effective amount of a dimeric fusion protein comprising:the extracellular domain of the activin type 2A (ACTR IIA) or the activin type 2B receptor (ACTR IIB); andthe Fc domain of human immunoglobulin G1 (IgGl).

[0009] In more specific embodiments, such kits comprise:one or more doses of a therapeutically effective amount of Seralutinib or a pharmaceutically acceptable salt thereof; andone or more doses of a therapeutically effective amount of Sotatercept.BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 is a bar graph showing the anti-fibrotic effect of the combination of Seralutinib and Sotatercept in a human cardiac fibrogenesis assay.2#11321063.1

[0011] Figure 2 is a bar graph showing the anti-fibrotic effect of the combination of Seralutinib and Sotatercept in a human lung fibrogenesis assay.DETAILED DESCRIPTION

[0012] As mentioned above, described herein are methods for treating interstitial lung disease (ILD), comprising administering to a subject in need thereof:a therapeutically effective amount of a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof; anda therapeutically effective amount of a dimeric fusion protein comprising:the extracellular domain of the activin type 2A (ACTR IIA) or the activin type 2B receptor (ACTR IIB); andthe Fc domain of human immunoglobulin G1 (IgGl).

[0013] In a more specific embodiment, the therapeutically effective amount of the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is a therapeutically effective amount of Seralutinib or a pharmaceutically acceptable salt thereof, and the therapeutically effective amount of a dimeric fusion protein is a therapeutically effective amount of Sotatercept.

[0014] In more specific embodiments, the ILD is sarcoidosis, idiopathic pulmonary fibrosis (IPF), autoimmune disease-related ILD, pneumoconiosis, extrinsic allergic alveolitis (hypersensitivity pneumonitis), and nonspecific interstitial pneumonia.

[0015] In another embodiment, the condition is interstitial lung disease-associated pulmonary hypertension (ILD-PH).

[0016] lin still further embodiments, methods are provided for treating the diseases and / or conditions disclosed herein below.

[0017] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described. For the purposes of the present invention, the following terms are defined below.

[0018] The articles “a” and “an” are used herein to refer to one or to more than one ( / .<?., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.3#11321063.1

[0019] As used herein, the term “about” refers to a quantity, level, value, dimension, size, or amount that varies by as much as 30%, 25%, 20%, 15%, 10%, or 5% to a reference quantity, level, value, dimension, size, or amount.

[0020] Throughout this specification, unless the context requires otherwise, the words “comprise”, “comprises” and “comprising” will be understood to imply the inclusion of a stated step or element or group of steps or elements but not the exclusion of any other step or element or group of steps or elements.

[0021] As used herein, a “subject” is a mammal, a bird, an aquatic animal such as a fish, or a reptile. In some embodiments, the subject is a human, a laboratory animal such as a mouse, rat or rabbit, a companion animal such as a dog or cat, a working animal such as a horse, donkey and the like, a livestock animal such as a cow, bull, pig, sheep, goat, deer, llama, alpaca and the like, or a captive wild animal such as those in zoos or wildlife parks including lions, leopards, cheetah, elephant, zebra, antelope, giraffe, koala, kangaroo and reptiles such as crocodiles, lizards, snakes and the like, a bird, especially a captive bird, such as a budgerigar or canary, cockatoo, parakeet, macaw, parrot and the like, or a fish, especially a captive fish such as tropical fish (zebra fish, guppy, Siamese fighting fish, clown fish, cardinal tetra and the like), dolphins, whales, and the like. In particular embodiments, the subject is a human.

[0022] The subject to be treated according to the methods described herein may be one who has been diagnosed with interstitial lung disease (ILD). Diagnosis may be performed by any method or technique known in the art. One skilled in the art will understand that a subject to be treated according to the present disclosure may have been subjected to standard tests or may have been identified, without examination, as one at risk due to the presence of one or more risk factors associated with the disease or condition. Further, it is understood that a subject to be treated according to the present disclosure may have been subjected to prior standard of care treatments, including monotherapy, dual therapy, triple therapy, or quadruple therapy.

[0023] As mentioned in the background, interstitial lung disease (ILD) is an umbrella term used for a large group of diseases. Most interstitial lung diseases are characterized by inflammation or fibrosis within the interstitial space, the primary consequence of which is impaired gas exchange, resulting in breathlessness, diminished exercise tolerance, and decreased quality of life. While ILD encompasses a large number of diseases, they all affect the interstitium of the lung. During breathing, air enters through the trachea and flows down the bronchi to the left and right lungs. As the air flows deeper into the lungs, the airways become smaller with more and more branches (bronchioles). At the end of the smallest branches are4#11321063.1clusters of air sacs called alveoli. The interstitium is a very thin layer of lung tissue located in and around the walls of the alveoli and allows oxygen to move from the alveoli and into capillaries and carbon dioxide to pass out. In healthy lungs, the interstitium is very thin and cannot be seen on x-ray or CT scan. The air sacs are flexable and gas exchange happens easily and quickly. For subjects with ILD, inflammation or fibrosis (scarring) thickens the interstitium, making the air sacs much less flexible and gas exchange becomes slow and difficult. As a result, a common feature of ILD is that subjects with this condition typically report feeling breathless, especially when they exercise or move around, often feel very fatigued even after sleeping or resting, and may have a dry cough.

[0024] Approximately 35% of ILD has a known cause, including:• Pneumoconioses which is caused by breathing dust from asbestos, silica, coal, or heavy metals, usually over a long time, specific names include asbestosis, silicosis, and coal workers’ pneumoconiosis;• Extrinsic allergic alveolitis (hypersensitivity pneumonitis) which is caused by breathing in animal or vegetable dust, sometimes called “farmer’s lung” or “pigeon breeder’s lung”, and common sources of such dust include husks, bark, wood, animal dander, bacteria, fungi, insects and insect fragments, bird droppings, dried urine of rodents, moldy hay / straw / grain, and bird feathers;• Latrogenic ILD which is caused by medical treatment, either from medication side effects or radiation treatment side effects, including some types of chemotherapy medications, anti-inflammatory medications, biologic therapies, and heart disease medications;• Post-infectious ILD which is caused by complications from a lung infection, such from fungus, bacteria, parasites, or viruses;• Autoimmune disease-related ILD which is caused by an underlying autoimmune disease, including systemic sclerosis, scleroderma, rheumatoid arthritis, dermatomyositis, polymyositis, mixed connective tissue disease, Sjogren’s syndrome, sarcoidosis, and inflammatory myositis; and• Inherited ILD which is caused by an underlying genetic disease, such as Dyskeratosis congenita, neurofibromatosis type 1, lymphangioleiomyomatosis, tuberous sclerosis complex, autosomal dominant hyper IgE syndrome, Hermansky-Pudlak syndrome, Gaucher syndrome, Niemann-Pick disease, lysinuric protein intolerance, surfactant metabolism dysfunction (type 1, type 2, type 3, or type 4), familial adult-onset pulmonary fibrosis, familial5#11321063.1pulmonary fibrosis associated with telomerase mutations, familial pulmonary fibrosis associated with mutations in surfactant protein A, and familial pulmonary alveolar microlithiasis.

[0025] The other 65% of ILD has an unknown cause (idiopathic) and includes the following:• Sarcoidosis;• Idiopathic interstitial pneumonias (IIPs), including idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia, respiratory bronchiolitis ILD, desquamative interstitial pneumonia, cryptogenic organizing pneumonia, lymphoid interstitial pneumonia, and bronchiolitis obliterans organizing pneumonia (BOOP); and• Acute interstitial pneumonia (AIP), including lymphangioleiomyomatosis, pulmonary Langerhans’ cell histiocytosis / histiocytosis X, and eosinophilic pneumonia.

[0026] Fibrosis features of ILD may vary depending upon the specific disease, exemplary embodiments of which are listed in Table 1.Table 16#11321063.1&7#11321063.1

[0027] More common forms of ILD include sarcoidosis, idiopathic pulmonary fibrosis (IPF), autoimmune disease-related ILD, pneumoconiosis, extrinsic allergic alveolitis (hypersensitivity pneumonitis), and nonspecific interstitial pneumonia.

[0028] In addition, there may be other conditions associated with ILD. For example, pulmonary hypertension (PH) is a chronic disorder affecting the small arteries in the lungs associated with high morbidity and mortality. The World Health Organization (WHO) classifies PH into five groups based on the underlying associated disease. Group 3 within this classification is PH due to lung diseases and / or hypoxia. When such lung diseases and / or hypoxia are associated with an ILD, the condition is referred to as interstitial lung disease-associated pulmonary hypertension (ILD-PH). PH is a frequent complication in patients with ILD and associated with poor functional status, need for supplemental oxygen, and / or poor outcomes.

[0029] In still other embodiments, the PH may be associated with other lung diseases as defined by WHO as Group 3 PH, including PH due to chronic lung disease and / or hypoxia. These lung diseases include obstructive lung disease where the lung airways narrow and make it harder to exhale (e.g. COPD or emphysema); restrictive lung disease in which the lungs have a tough time expanding when one inhales (e.g. ILD as noted above or pulmonary fibrosis); sleep apnea; and living in an area of high altitude for a long period of time. Arteries in the lungs tighten so that blood can only go to areas of the lungs that are receiving the most air and oxygen. This tightening leads to high blood pressure throughout the lungs.

[0030] Accordingly, in one embodiment a method is provided for treating ILD-PH, comprising administering to a subject in need thereof:a therapeutically effective amount of a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof; anda therapeutically effective amount of a dimeric fusion protein comprising:the extracellular domain of the activin type 2A (ACTR IIA) or the activin type 2B receptor (ACTR IIB); andthe Fc domain of human immunoglobulin G1 (IgGl).

[0031] In a more specific embodiment, a method is provided for treating ILD-PH, comprising administering to a subject in need thereof:a therapeutically effective amount of Seralutinib or a pharmaceutically acceptable salt thereof; anda therapeutically effective amount of Sotatercept.8#11321063.1

[0032] In still other embodiments, methods are provided for treating WHO Group 3 PH, including COPD-PH, by administering to a subject in need thereof:a therapeutically effective amount of a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof; anda therapeutically effective amount of a dimeric fusion protein comprising:the extracellular domain of the activin type 2A (ACTR IIA) or the activin type 2B receptor (ACTR IIB); andthe Fc domain of human immunoglobulin G1 (IgGl).

[0033] In still more specific embodiments, methods are provided for treating WHO Group 3 PH, including COPD-PH, by administering to a subject in need thereof:a therapeutically effective amount of Seralutinib or a pharmaceutically acceptable salt thereof; anda therapeutically effective amount of Sotatercept.

[0034] As used herein, the term “effective amount” or “therapeutically effective amount” refers to a quantity of a tyrosine kinase inhibitor and a dimeric fusion protein sufficient to achieve a desired effect in a subject being treated with those agents. Ideally, an effective amount is an amount sufficient to prevent or treat the disease without causing substantial toxicity in the subject. It is possible that the effective amount required for a tyrosine kinase inhibitor, either alone or in combination with other therapies that are not a dimeric fusion protein, is different to the effective amount required for a tyrosine kinase inhibitor in combination with a dimeric fusion protein. Likewise, it is possible that the effective amount required for a dimeric fusion protein either alone or in combination with other therapies that are not a tyrosine kinase inhibitor, is different to the effective amount required for a dimeric fusion protein in combination with a tyrosine kinase inhibitor. The effective amount will be dependent on the subject being treated, the severity of the disease, whether the subject has received prior treatment for the disease and the manner of administration of the agent. Methods of determining an effective amount of the disclosed therapies sufficient to achieve a desired effect in a subject will be understood by those of skill in the art.

[0035] The term “in combination with” as used herein refers to the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof and the dimeric fusion protein being administered in a single composition, or separately, either simultaneously or sequentially. The tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof and the dimeric fusion9#11321063.1protein may be administered at different times and different frequencies but in combination they exert biological effects at the same time or at overlapping times.

[0036] As used herein, “Seralutinib” refers to A-{3-[(15)-l-{[6-(3,4-dimethoxyphenyl)-pyrazin-2-yl]amino}ethyl]phenyl}-5-methylpyridine-3-carboxamide, also known as GB002 or PK10571, and is shown below:Seralutinib

[0037] Seralutinib is a highly potent and selective inhibitor of PDGFRa and PDGFRP, CSF1R, and c-KIT. An amorphous form of Seralutinib is described in US Patent Nos. 9,815,815 and 10,231,966. Formulations comprising Seralutinib are described in US Patent No. 9,925,184 and published US patent application US 2021 / 0038510. Combinations comprising Seralutinib are described in US Patent Nos. 10,231,966 and 11,364,238, and published PCT WO2024 / 035884.

[0038] As used herein, “Sotatercept” refers to a soluble fusion protein composed of the extracellular domain of the activin receptor type IIA (ActR IIA) linked to the Fc portion of human IgGl with anabolic bone activity. Sotatercept traps multiple members of the TGF-P superfamily, including activins and growth differentiation factors. Mutations in bone morphogenetic protein receptor type 2 (BMPR2), a member of the transforming growth factor P (TGF-P) superfamily, are a major factor underlying heritable pulmonary arterial hypertension (PAH). BMPR2 is important in maintaining endothelial integrity in pulmonary arteries.Mutations that reduce signaling in the BMPR-II pathway promote endothelial dysfunction, increased cellular proliferation and pulmonary vascular remodeling. Sotatercept restores balance between the growth-promoting activin growth differentiation factor pathway and the growthinhibiting BMP pathway and has recently approved by the US FDA for treatment of pulmonary arterial hypertension.

[0039] Receptor tyrosine kinases (RTK) or tyrosine kinase receptors (TKR) are polypeptides that regulate the regeneration, remodeling, development, and differentiation of cells. They are high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Mutations in receptor tyrosine kinases lead to activation of a series of signaling cascades which in turn effects protein expression. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins 10#11321063.1which contain a transmembrane domain, and the non-receptor tyrosine kinases which lack transmembrane domains. Approximately 20 different RTK classes have been identified including the EGF (or ErbB), Insulin, PDGF, VEGF, FGF, CCK, NGF, HGF, Eph, AXL, TIE, RYK, DDR, RET, ROS, LTK, ROR, and MuSK receptor families.

[0040] Platelet-derived growth factor receptors (PDGF-R) are tyrosine kinase receptors for members of the platelet-derived growth factor (PDGF) family. PDGF subunits -A and -B are important factors regulating cell proliferation, cellular differentiation, cell growth, and development. There are two forms of the PDGF-R, alpha and beta each encoded by a different gene. The platelet derived growth factor receptor (PDGFR) is associated with pulmonary diseases, tissue fibrosis and solid tumors.

[0041] In one embodiment, the tyrosine kinase inhibitor of the method of treating ILD is a PDGF receptor inhibitor or a pharmaceutically acceptable salt thereof, a CSF1R receptor inhibitor or a pharmaceutically acceptable salt thereof, a c-KIT kinase inhibitor or a pharmaceutically acceptable salt thereof, or a combination thereof. In some embodiments, the tyrosine kinase inhibitor is Acalabrutinib or a pharmaceutically acceptable salt thereof, Afatinib or a pharmaceutically acceptable salt thereof, Alectinib or a pharmaceutically acceptable salt thereof, Avapritinib or a pharmaceutically acceptable salt thereof, Axitinib (Inlyta®) or a pharmaceutically acceptable salt thereof, Baricitinib or a pharmaceutically acceptable salt thereof, Binimetinib or a pharmaceutically acceptable salt thereof, Bosutinib (Bosulif®) or a pharmaceutically acceptable salt thereof, Brigatinib or a pharmaceutically acceptable salt thereof, Cabozantinib or a pharmaceutically acceptable salt thereof, Capmatinib or a pharmaceutically acceptable salt thereof, Ceritinib or a pharmaceutically acceptable salt thereof, Cobimetinib or a pharmaceutically acceptable salt thereof, Crizotinib or a pharmaceutically acceptable salt thereof, Dacomitinib or a pharmaceutically acceptable salt thereof, Entrectinib or a pharmaceutically acceptable salt thereof, Erdafitinib or a pharmaceutically acceptable salt thereof, Erlotinib (Tarceva®) or a pharmaceutically acceptable salt thereof, Fedratinib or a pharmaceutically acceptable salt thereof, Fostamatinib or a pharmaceutically acceptable salt thereof, Gefitinib or a pharmaceutically acceptable salt thereof, Gilteritinib or a pharmaceutically acceptable salt thereof, Ibrutinib or a pharmaceutically acceptable salt thereof, Imatinib (Gleevec®) or a pharmaceutically acceptable salt thereof, Lapatinib or a pharmaceutically acceptable salt thereof, Larotrectinib or a pharmaceutically acceptable salt thereof, Lenvatinib or a pharmaceutically acceptable salt thereof, Lorlatinib or a pharmaceutically acceptable salt thereof, Midostaurin or a pharmaceutically acceptable salt thereof, Neratinib (Tasigna®) or a pharmaceutically acceptable11#11321063.1salt thereof, Osimertinib or a pharmaceutically acceptable salt thereof, Pazopanib (Votrient®) or a pharmaceutically acceptable salt thereof, Pemigatinib or a pharmaceutically acceptable salt thereof, Pexidartinib or a pharmaceutically acceptable salt thereof, Ponatinib or a pharmaceutically acceptable salt thereof, Regorafenib or a pharmaceutically acceptable salt thereof, Ripretinib or a pharmaceutically acceptable salt thereof, Ruxolitinib or a pharmaceutically acceptable salt thereof, Selpercatinib or a pharmaceutically acceptable salt thereof, Selumetinib or a pharmaceutically acceptable salt thereof, Seralutinib or a pharmaceutically acceptable salt thereof, Sorafenib or a pharmaceutically acceptable salt thereof, Sunitinib (Sutent®) or a pharmaceutically acceptable salt thereof, Tofacitinib or a pharmaceutically acceptable salt thereof, Trametinib or a pharmaceutically acceptable salt thereof, Tucatinib or a pharmaceutically acceptable salt thereof, Upadacitinib or a pharmaceutically acceptable salt thereof, Vandetanib or a pharmaceutically acceptable salt thereof, Zanubrutinib or a pharmaceutically acceptable salt thereof, or a combination thereof.

[0042] In some embodiments, the tyrosine kinase inhibitor is Seralutinib or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is Seralutinib. In some embodiments, the tyrosine kinase inhibitor is a pharmaceutically acceptable salt of Seralutinib.

[0043] In some embodiments, the dimeric fusion protein comprises the extracellular domain of the activin type 2A receptor. In other embodiments, the dimeric fusion protein comprises the extracellular domain of the activin type 2B receptor. In other embodiments, the dimeric fusion protein is Sotatercept.

[0044] The combination therapy described herein is intended to embrace the administration of the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof and a dimeric fusion protein as both a stand-alone dual combination therapy, as well as in further combination with other biologically active ingredients as well as non-drug therapies (e.g., holistic therapies). Where the combination therapy further comprises a non-drug treatment, the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.

[0045] In some embodiments, the subject is receiving stable background therapy for ILD. In other embodiments the subject is receiving stable background therapy for PH or ILD-PH.12#11321063.1

[0046] In some embodiments of the present invention, the tyrosine kinase inhibitor is administered by inhalation. In some embodiments, Seralutinib or a pharmaceutically acceptable salt thereof, is administered by inhalation. In some embodiments, Seralutinib or a pharmaceutically acceptable salt thereof, is administered by inhalation with a dry powder inhaler. In some embodiments, Seralutinib or a pharmaceutically acceptable salt thereof, is administered once daily or twice daily. In some embodiments, Seralutinib or a pharmaceutically acceptable salt thereof, is administered once. In some embodiments, Seralutinib or a pharmaceutically acceptable salt thereof, is administered twice daily. In some embodiments, Seralutinib or a pharmaceutically acceptable salt thereof, is administered three times a day.

[0047] In some embodiments, the dimeric fusion protein is administered by injection. In some embodiments, Sotatercept is administered by injection. In some embodiments, Sotatercept is administered by subcutaneous injection. In some embodiments, Sotatercept is administered once a week, once every two weeks, once every three weeks, or once a month. In other embodiments, Sotatercept is administered once a week. In some embodiments, Sotatercept is administered once every two weeks. In some embodiments, Sotatercept is administered every three weeks. In some embodiments, Sotatercept is administered once a month.

[0048] Therapeutic agents described herein can be administered before, during, or after the occurrence or diagnosis of a disease, and the timing of administering the agents can vary. For example, the agents can be used as a prophylactic and can be administered to subjects with a propensity to particular diseases in order to lessen a likelihood of the occurrence of the disease. The agents can be administered to a subject during or as soon as possible after the onset of the symptoms. The initial administration can be via any route practical. A therapeutic agent can be administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. The length of treatment can vary for each subject.

[0049] In some embodiments, the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject in need thereof separately from the dimeric fusion protein.

[0050] In some embodiments, the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is administered by inhalation. In some embodiments, Seralutinib or a pharmaceutically acceptable salt thereof is administered by inhalation.

[0051] In some embodiments, the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is administered once daily or twice daily. In some embodiments,13#11321063.1Seralutinib or a pharmaceutically acceptable salt thereof is administered once daily. In other embodiments, Seralutinib or a pharmaceutically acceptable salt thereof is administered twice daily.

[0052] In some embodiments, the dimeric fusion protein is administered by injection. In some embodiments, the dimeric fusion protein is administered by subcutaneous injection. In some embodiments, Sotatercept is administered by injection. In some embodiments, Sotatercept is administered by subcutaneous injection.

[0053] In some embodiments, the dimeric fusion protein is administered twice a week, once a week, once every two weeks, once every three weeks, or once a month. In some embodiments, Sotatercept is administered twice a week, once a week, once every two weeks, once every three weeks, or once a month. In some embodiments, Sotatercept is administered twice a week. In other embodiments, Sotatercept is administered once a week. In other embodiments, Sotatercept is administered once every two weeks. In other embodiments, Sotatercept is administered once every three weeks. In other embodiments, Sotatercept is administered once a month.

[0054] In some embodiments, the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is administered at least once, prior to, simultaneously, or sequentially with the dimeric fusion protein. In particular embodiments, multiple doses of the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof are administered over a period of time beginning before or together with administration of the dimeric fusion protein and then continuing after administration of the dimeric fusion protein.

[0055] In some embodiments, the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is administered more than once and on a regular basis before, simultaneously, and after administration of the dimeric fusion protein. In some embodiments, the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is administered before administration of the dimeric fusion protein. In other embodiments, the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is administered simultaneously or sequentially with the administration of the dimeric fusion protein, and at least once subsequently to administration of the dimeric fusion protein. The tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof may be administered 1 week to 1 day prior to administration of the dimeric fusion protein, especially 1 to 3 days before the administration of the dimeric fusion protein. The tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof may be administered simultaneously or sequentially with the dimeric fusion protein, either immediately before or14#11321063.1immediately after the administration of the dimeric fusion protein. The tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof may also be administered one or more times over the month after administration of the dimeric fusion protein, for example, once a week, once every 5 days, once every 4 days, once every 3 days, once every 2 days, once every day, or twice every day, especially once or twice every day. Subsequent administration of the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof may continue such that 1 to 10 doses of the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof are administered after administration of the dimeric fusion protein, especially 1 to 70 doses, 1 to 60 doses, 1 to 50 doses, 1 to 40 doses, 1 to 30 doses, 1 to 20 doses, 1 to 10 doses, 1 to 8 doses, 1 to 6 doses, 1 to 4 doses, or 1 to 2 doses.

[0056] The dimeric fusion protein is administered in an effective amount. An “effective amount” means an amount necessary to at least partly attain the desired therapeutic response. The amount varies depending upon the health and physical condition of the individual to be treated, the taxonomic pulmonary hypertension group of the individual to be treated, the formulation of the composition, the severity of the pulmonary hypertension, the assessment of the medical situation, and other relevant factors. It is expected that the amount will fall in a relatively broad range. An effective amount, for example, may lie in the range of about 0.1 ng per kg of body weight to 1 g per kg of body weight per dosage. The dosage is preferably in the range of 1 |ig to 0.5 g per kg of body weight per dosage, such as is in the range of 0.1 mg to 100 mg per kg of body weight per dosage, 1 mg to 25 mg per kg of body weight per dosage, or 5 mg per kg of body weight per dosage. In some embodiments, where the dimeric fusion protein dosage is administered by injection subcutaneously, the dosage is in the range of 0.1 mg to 25 mg per kg of body weight, for example 1 mg to 10 mg per kg of body weight, such as 1 mg / kg of body weight, 2 mg / kg of body weight, 3 mg / kg of body weight, 4 mg / kg of body weight, or 5 mg / kg of body weight. Dosage regimes may be adjusted to provide the optimum therapeutic response. For example, in some embodiments, where administration of the dimeric fusion protein is by subcutaneous injection, the dimeric fusion protein is administered once a month and the progress of treatment monitored. In other embodiments, the dimeric fusion protein is administered once every three weeks and the progress of treatment monitored. In other embodiments, the dimeric fusion protein is administered once every two weeks and the progress of treatment monitored. In other embodiments, the dimeric fusion protein is administered once every week and the progress of treatment monitored. In other embodiments, the dimeric fusion protein is administered twice a week and the progress of treatment monitored.15#11321063.1

[0057] The tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof may also be administered in an effective amount. Again, the amount of the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof considered to be effective will depend on the health and physical condition of the individual to be treated, the taxonomic pulmonary hypertension group of the individual to be treated, the formulation of the composition, the severity of the pulmonary hypertension, the assessment of the medical situation, and other relevant factors. It is expected that the amount of the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof will fall within a fairly broad range of amounts. An effective amount may lie in the range of about 0.1 ng per kg to about 500 mg per kg body weight per dosage. The dosage is preferably in the range of 100 pg to 100 mg per kg of body weight per dosage, 1 mg to 50 mg per kg of body weight per dosage, 1 mg to 20 mg per kg of body weight per dosage, or 5 mg to 15 mg per kg of body weight per dosage. In some embodiments, where the dosage of the tyrosine kinase inhibitor or pharmaceutically acceptable salt thereof is administered by inhalation, the dosage is in the range of 1 mg to 100 mg per kg of body weight, for example 5 mg to 25 mg per kg of body weight, such as 5 mg / kg of body weight, 10 mg / kg of body weight, 15 mg / kg of body weight, 20 mg / kg of body weight, or 25 mg / kg of body weight. Dosage regimes may be adjusted to provide the optimum therapeutic response. For example, in some embodiments, where administration of the tyrosine kinase inhibitor of a pharmaceutically acceptable salt thereof is by inhalation, the tyrosine kinase inhibitor of a pharmaceutically acceptable salt thereof is administered twice a day and the progress of treatment monitored. In other embodiments, the tyrosine kinase inhibitor of a pharmaceutically acceptable salt thereof is administered once a day and the progress of treatment monitored. In other embodiments, the tyrosine kinase inhibitor of a pharmaceutically acceptable salt thereof is administered once every two days and the progress of treatment monitored. In other embodiments, the tyrosine kinase inhibitor of a pharmaceutically acceptable salt thereof is administered once every three days and the progress of treatment monitored. In other embodiments, the tyrosine kinase inhibitor of a pharmaceutically acceptable salt thereof is administered once every five days and the progress of treatment monitored. In other embodiments, the tyrosine kinase inhibitor of a pharmaceutically acceptable salt thereof is administered once every six days and the progress of treatment monitored. In other embodiments, the tyrosine kinase inhibitor of a pharmaceutically acceptable salt thereof is administered once every week and the progress of treatment monitored.

[0058] The compositions of a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof and a dimeric fusion protein may be formulated separately and sold together in a kit16#11321063.1or package. In one embodiment, each kit may comprise one or more doses of each compound useful in the treatment of ILD. In another embodiment, each kit may comprise one or more containers. In a further embodiment, each container of the kit may contain one or more doses of one or more compounds useful in the treatment ILD. In one embodiment, each container of the kit contains one or more doses of a different compound useful in the treatment of ILD.

[0059] In one embodiment a kit is provided comprising one or more containers containing:a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof; and a dimeric fusion protein comprising:the extracellular domain of the activin type 2A (ACTR IIA) or the activin type 2B receptor (ACTR IIB); andthe Fc domain of human immunoglobulin G1 (IgGl).

[0060] In one embodiment, at least one container of the kit contains a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is Seralutinib or a pharmaceutically acceptable salt thereof. In another embodiment, at least one container of the kit contains the dimeric fusion protein. In a preferred embodiment, the dimeric fusion protein is Sotatercept. In one embodiment, the kit comprises at least one container containing Seralutinib or a pharmaceutically acceptable salt thereof and at least one separate container containing Sotatercept.

[0061] In another embodiment, a kit is provided comprising:one or more doses of a therapeutically effective amount of a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof; andone or more doses of a therapeutically effective amount of a dimeric fusion protein comprising:the extracellular domain of the activin type 2A (ACTR IIA) or the activin type 2B receptor (ACTR IIB); andthe Fc domain of human immunoglobulin G1 (IgGl).

[0062] In more specific embodiments of the above kits, the therapeutically effective amount of the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is a therapeutically effective amount of Seralutinib or a pharmaceutically acceptable salt thereof, and the therapeutically effective amount of a dimeric fusion protein is a therapeutically effective amount of Sotatercept.17#11321063.1

[0063] In some embodiments, the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is formulated for administration by inhalation. In one embodiment, the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is formulated as a dry powder for administration by inhalation with a dry powder inhaler. In some embodiments, the kit comprises one or more doses of the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof and a dry powder inhaler.

[0064] In some embodiments, the dimeric fusion protein is formulated for subcutaneous injection in a single bolus dose or in a multiple dose form. For example, the kit may contain the dimeric fusion protein in a pre-filled syringe, as a liquid in a vial ready for uptake into a syringe, or as a solid ready for dissolution before uptake into a syringe. The liquid or solid formulations may be single dose formulations or multiple dose formulations. In other embodiments, the kit may contain multiple doses of the dimeric fusion protein each formulated separately in a prefilled syringe, as a liquid in a vial ready for uptake into a syringe, or as a solid ready for dissolution and uptake into a syringe.

[0065] The kit may further comprise one or more of various pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers. The kit may further comprise an insert or a label with instructions for use of each formulation. The insert or label may further comprise how to prepare each dosage form if required, including quantities of the components to be administered and / or guidelines for mixing the components, how to administer each dosage, and / or when to administer each dosage.EXAMPLES

[0066] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein. While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.18#11321063.1EXAMPLE 1SERALUTINIB PLUS SOTATERCEPT SHOWS SYNERGISTIC BENEFIT IN DECREASING RELEASE OF PRO-COLLAGEN IAI AND FIBRONECTIN FROM HUMAN FIBROBLASTS

[0067] Lung fibrosis is histopathologically characterized by an excessive production and deposition of collagen that converts normal tissue into scar tissue with associated loss of function. The anti-fibrotic effect of Seralutinib, Sotatercept and their combination were measured in an in vitro Scar-in-a-Jar (SIAJ) fibrogenesis assay that recapitulates the cellular microenvironment with the pathological extracellular matrix. The SIAJ assays were run as described by Chen, et al., British Journal of Pharmacology, 158(5), 1196-1209 (2009) and Ronnow et al., Respiratory Research, 21, 1-14 (2020).

[0068] Primary human lung fibroblasts and primary cardiac fibroblasts were purchased from Lonza (Basel, Switzerland). Cells were seeded in 48-well TC-treated plates in DMEM supplemented with 10% FBX, GlutaMax and IX Antibiotic-Antimycotic solution. The cells were starved overnight with low serum media (0.4% FBS) in the same DMEM formulation. On Day 0, cells were stimulated with 3 nM PDGF-AB plus 50 ng / mL Activin A in low serum media containing ficoll (37.5 mg / mL ficoll 70, 25 mg / mL ficoll 400) and 1% L-ascorbic acid phosphate magnesium salt n-hydrate. Cells were treated with Seralutinib (luM) or Sotatercept (ActR II A-Fc) (lug / mL) alone or in combination for 6 days for human cardiac fibroblasts SIAJ assays and pro-collagen lai release was measured in the supernatant using ELISA. For human lung fibroblasts, Seralutinib (O.luM) or Sotatercept alone or in combination for 8 days and fibronectin release were measured using ELISA .

[0069] The results of these assays are presented in Figure 1 for human cardiac fibroblasts and in Figure 2 for human lung fibroblasts. Data is represented as percent change in procollagen lai or fibronectin, where unstimulated control = 0% and vehicle stimulation control =100%. Bar graphs represent mean ± SD. One-way ANOVA followed by Fisher’s LSD test were performed in GraphPad Prism 10.0 on all experimental conditions, comparing mean of each treatment group with mean of every other group. Differences were considered significant when * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001.HUMAN CARDIAC FIBROBLAST SIAJ FIBROGENESIS ASSAY

[0070] As shown in Figure 1, a dual stim of PDGF-AB and Activin A showed a significant increase of pro-collagen lai (p-value <0.0001) compared to the untreated control.19#11321063.1Seralutinib alone treatment significantly decreased pro-collagen lai (64%, p-value <0.001), whereas Sotatercept alone (lug / mL) showed a 13% decrease, but did not reach statistical significance compared to vehicle control stimulated with PDGF-AB and Activin A. The combination treatment of Seralutinib plus Sotatercept completely inhibited release of procollagen lai (97% decrease; p= <0.0001 vs vehicle control; not significant vs unstimulated control), showing a synergistic effect in inhibiting collagen production due to the dual treatment. In addition, the combination treatment group pro-collagen lai levels were significantly lower that Seralutinib (p<0.001) and Sotatercept alone treatment (p<0.0001).HUMAN LUNG FIBROBLAST SIAJ FIBROGENESIS ASSAY

[0071] As shown in Figure 2, a dual stim of PDGF-AB and Activin A shows a significant increase of Fibronectin (p-value <0.0001) compared to the untreated control. Seralutinib (O.OluM) and Sotatercept (lug / mL) alone treatment significantly decrease fibronectin by 64% (p<0.0001) and 32% (p<0.001), respectively, compared to vehicle control stimulated with PDGF-AB and Activin A. The combination treatment of Seralutinib plus Sotatercept completely inhibited release of fibronectin (98% decrease; p= <0.0001 vs vehicle control; not significant, vs unstimulated group), showing a synergistic effect of the two treatments. In addition, the combination treatment group the fibronectin levels were significantly lower that Seralutinib (p<0.001) and Sotatercept alone treatment (p<0.0001).

[0072] The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and / or listed in the Application Data Sheet are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications, and publications to provide yet further embodiments.

[0073] This application claims the benefit of priority to U.S. Application No. 63 / 743,524, filed January 9, 2025, which application is hereby incorporated by reference in its entirety.20#11321063.1

Claims

CLAIMS1. A method for treating interstitial lung disease-associated pulmonary hypertension (ILD-PH), comprising administering to a subject in need thereof:a therapeutically effective amount of a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof; anda therapeutically effective amount of a dimeric fusion protein comprising:the extracellular domain of the activin type 2A (ACTR IIA) or the activin type 2B receptor (ACTR IIB); andthe Fc domain of human immunoglobulin G1 (IgGl).

2. The method of claim 1, wherein the tyrosine kinase inhibitor is a PDGF receptor inhibitor or a pharmaceutically acceptable salt thereof, a CSF1R receptor inhibitor or a pharmaceutically acceptable salt thereof, a c-KIT kinase inhibitor or a pharmaceutically acceptable salt thereof, or a combination thereof.

3. The method of claim 1, wherein the tyrosine kinase inhibitor is Acalabrutinib or a pharmaceutically acceptable salt thereof, Afatinib or a pharmaceutically acceptable salt thereof, Alectinib or a pharmaceutically acceptable salt thereof, Avapritinib or a pharmaceutically acceptable salt thereof, Axitinib (Inlyta®) or a pharmaceutically acceptable salt thereof, Baricitinib or a pharmaceutically acceptable salt thereof, Binimetinib or a pharmaceutically acceptable salt thereof, Bosutinib (Bosulif®) or a pharmaceutically acceptable salt thereof, Brigatinib or a pharmaceutically acceptable salt thereof, Cabozantinib or a pharmaceutically acceptable salt thereof, Capmatinib or a pharmaceutically acceptable salt thereof, Ceritinib or a pharmaceutically acceptable salt thereof, Cobimetinib or a pharmaceutically acceptable salt thereof, Crizotinib or a pharmaceutically acceptable salt thereof, Dacomitinib or a pharmaceutically acceptable salt thereof, Entrectinib or a pharmaceutically acceptable salt thereof, Erdafitinib or a pharmaceutically acceptable salt thereof, Erlotinib (Tarceva®) or a pharmaceutically acceptable salt thereof, Fedratinib or a pharmaceutically acceptable salt thereof, Fostamatinib or a pharmaceutically acceptable salt thereof, Gefitinib or a pharmaceutically acceptable salt thereof, Gilteritinib or a pharmaceutically acceptable salt thereof, Ibrutinib or a pharmaceutically acceptable salt thereof, Imatinib (Gleevec®) or a pharmaceutically acceptable salt thereof, Lapatinib or a pharmaceutically acceptable salt thereof,21#11321063.1Larotrectinib or a pharmaceutically acceptable salt thereof, Lenvatinib or a pharmaceutically acceptable salt thereof, Lorlatinib or a pharmaceutically acceptable salt thereof, Midostaurin or a pharmaceutically acceptable salt thereof, Neratinib (Tasigna®) or a pharmaceutically acceptable salt thereof, Osimertinib or a pharmaceutically acceptable salt thereof, Pazopanib (Votrient®) or a pharmaceutically acceptable salt thereof, Pemigatinib or a pharmaceutically acceptable salt thereof, Pexidartinib or a pharmaceutically acceptable salt thereof, Ponatinib or a pharmaceutically acceptable salt thereof, Regorafenib or a pharmaceutically acceptable salt thereof, Ripretinib or a pharmaceutically acceptable salt thereof, Ruxolitinib or a pharmaceutically acceptable salt thereof, Selpercatinib or a pharmaceutically acceptable salt thereof, Selumetinib or a pharmaceutically acceptable salt thereof, Seralutinib or a pharmaceutically acceptable salt thereof, Sorafenib or a pharmaceutically acceptable salt thereof, Sunitinib (Sutent®) or a pharmaceutically acceptable salt thereof, Tofacitinib or a pharmaceutically acceptable salt thereof, Trametinib or a pharmaceutically acceptable salt thereof, Tucatinib or a pharmaceutically acceptable salt thereof, Upadacitinib or a pharmaceutically acceptable salt thereof, Vandetanib or a pharmaceutically acceptable salt thereof, Zanubrutinib or a pharmaceutically acceptable salt thereof, or a combination thereof.

4. The method of claim 1, wherein the tyrosine kinase inhibitor is Seralutinib or a pharmaceutically acceptable salt thereof.

5. The method of claim 1, wherein the dimeric fusion protein comprises the extracellular domain of the activin type 2A receptor.

6. The method of claim 1, wherein the dimeric fusion protein comprises the extracellular domain of the activin type 2AFc receptor.

7. The method of claim 1, wherein the dimeric fusion protein comprises the extracellular domain of the activin type 2B receptor.

8. The method of claim 1, wherein the dimeric fusion protein is Sotatercept.

9. The method of claim 1, wherein the tyrosine kinase inhibitor is Seralutinib or a pharmaceutically acceptable salt thereof and the dimeric fusion protein is Sotatercept.22#11321063.

110. The method of claim 1, wherein the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is administered by inhalation.

11. The method of claim 4, wherein Seralutinib or a pharmaceutically acceptable salt thereof is administered by inhalation.

12. The method of claim 4, wherein Seralutinib or a pharmaceutically acceptable salt thereof is administered once daily or twice daily.

13. The method of claim 1, wherein the dimeric fusion protein is administered by injection.

14. The method of claim 8, wherein Sotatercept is administered by injection.

15. The method of claim 8, wherein Sotatercept is administered by subcutaneous injection.

16. The method of claim 8, wherein Sotatercept is administered once a week, once every two weeks, once every three weeks, or once a month.

17. The method of claim 1, wherein the therapeutically effective amount of the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is administered prior to, simultaneously with, and / or subsequent to the administration of the therapeutically effective amount of the dimeric fusion protein.

18. The method of claim 17, wherein the therapeutically effective amount of the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is administered prior to the administration of the therapeutically effective amount of the dimeric fusion protein.

19. The method of claim 17, wherein the therapeutically effective amount of the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is administered simultaneously with the administration of the therapeutically effective amount of the dimeric fusion protein.23#11321063.

120. The method of claim 17, wherein the therapeutically effective amount of the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is administered subsequent to the administration of the therapeutically effective amount of a dimeric fusion protein.

21. The method of claim 1, wherein the therapeutically effective amount of the tyrosine kinase inhibitor is Seralutinib or a pharmaceutically acceptable salt thereof, and the therapeutically effective amount of a dimeric fusion protein is Sotaterept.

22. A method for treating interstitial lung disease (ILD), comprising administering to a subject in need thereof:a therapeutically effective amount of a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof; anda therapeutically effective amount of a dimeric fusion protein comprising:the extracellular domain of the activin type 2A (ACTR IIA) or the activin type 2B receptor (ACTR IIB); andthe Fc domain of human immunoglobulin G1 (IgGl).

23. The method of claim 22, wherein the therapeutically effective amount of the tyrosine kinase inhibitor is Seralutinib or a pharmaceutically acceptable salt thereof, and the therapeutically effective amount of a dimeric fusion protein is Sotaterept.

24. A kit comprising:one or more doses of a therapeutically effective amount of a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof; andone or more doses of a therapeutically effective amount of a dimeric fusion protein comprising:the extracellular domain of the activin type 2A (ACTR IIA) or the activin type 2B receptor (ACTR IIB); andthe Fc domain of human immunoglobulin G1 (IgGl).

25. The kit of claim 24, wherein the tyrosine kinase inhibitor is Seralutinib or a pharmaceutically acceptable salt thereof.24#11321063.

126. The kit of claim 24, wherein the dimeric fusion protein is Sotatercept.

27. The kit of claim 24, wherein the tyrosine kinase inhibitor is Seralutinib or a pharmaceutically acceptable salt thereof and the dimeric fusion protein is Sotatercept.

28. The kit of claim 24, wherein the one or more doses of a therapeutically effective amount of the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is formulated for administration by inhalation.

29. The kit of claim 25, wherein the one or more doses of a therapeutically effective amount of Seralutinib or a pharmaceutically acceptable salt thereof is formulated as a dry powder for administration by inhalation with a dry powder inhaler.

30. The kit of claim 29, further comprising a dry powder inhaler.

31. The kit of claim 24, wherein the one or more doses of a therapeutically effective amount of the dimeric fusion protein is formulated for administration by injection.

32. The kit of claim 31, wherein the one or more doses of a therapeutically effective amount of Sotatercept is formulated for administration by injection.

33. The kit of claim 32, wherein the one or more doses of a therapeutically effective amount of Sotatercept is formulated for administration by subcutaneous injection.

34. The kit of claim 33, wherein the one or more doses of a therapeutically effective amount of Sotatercept is formulated for subcutaneous injection in a single bolus dose or in a multiple dose form.

35. The kit of claim 33, wherein the one or more doses of a therapeutically effective amount of Sotatercept is formulated for subcutaneous injection in one or more pre-filled syringes.25#11321063.

136. The kit of claim 33, wherein the one or more doses of a therapeutically effective amount of Sotatercept is formulated for subcutaneous injection as a liquid in a vial ready for uptake into a syringe.

37. The kit of claim 36, wherein the liquid in the vial is a single dose formulation of a therapeutically effective amount of Sotatercept.

38. The kit of claim 36, wherein the liquid in the vial is a multiple dose formulation of a therapeutically effective amount of Sotatercept.

39. The kit of claim 34, wherein the one or more doses of a therapeutically effective amount of Sotatercept is formulated for subcutaneous injection as a solid ready for dissolution before uptake into a syringe.

40. The kit of claim 39, wherein the solid ready for dissolution before uptake into a syringe is a single dose formulation of a therapeutically effective amount of Sotatercept.

41. The kit of claim 39, wherein solid ready for dissolution before uptake into a syringe is a multiple dose formulation of a therapeutically effective amount of Sotatercept.

42. The kit of claim 24, comprising at least one container containing Seralutinib or a pharmaceutically acceptable salt thereof.

43. The kit of claim 24, comprising at least one container containing Soteracept.

44. The kit of claim 24, comprising at least one container containing Soteracept and at least one other container containing Soteracept.

45. The kit of claim 24, further comprising an insert or a label with instructions for use.26#11321063.1

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