Functional respiratory imaging studies for cerartinib in the treatment of pulmonary arterial hypertension (PAH)

Abstract

A method for evaluating the efficacy of cerartinib treatment for PAH in subjects suffering from PAH, and a method for increasing the ratio of distal pulmonary artery volume to proximal pulmonary artery volume (BV510ARatio) by administering an effective dose of cerartinib to the subject are also provided. A method for increasing the pulmonary vascular volume of small arteries and reducing hypertrophy of larger pulmonary artery vessels by administering an effective dose of cerartinib to subjects who require it is also provided.

Description

[Technical Field]

[0001] Field of the present invention The present invention relates to functional respiratory imaging and analysis, particularly to functional respiratory imaging and analysis in patients with pulmonary arterial hypertension (PAH). The present invention further relates to the treatment and treatment monitoring of such patients, particularly those treated with PDGFR inhibitors, CSF1R inhibitors, c-KIT kinase inhibitors, or combinations thereof. In some embodiments, PAH patients are treated with cerartinib. [Background technology]

[0002] Brief Overview Respiratory conditions such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) result in reduced gas exchange and are therefore sometimes evaluated using pulmonary function tests. Vital capacity measurement (measurement of respiration) is the most common pulmonary function test, measuring the amount (volume) and / or velocity (flow) of air that can be inhaled and exhaled. However, in restrictive diseases (such as pulmonary fibrosis), vital capacity is reduced, and therefore the measured values ​​are distorted as a result of decreased lung compliance. Due to the limited availability and sensitivity of pulmonary function tests, it has been known that evaluating treatment and their effectiveness is difficult. Therefore, the object of the present invention is to provide an improved method for evaluating the effectiveness of treatment for respiratory conditions. [Overview of the project] [Means for solving the problem]

[0003] Therefore, in one embodiment, the present invention is a method for evaluating the effectiveness of treatment for a respiratory condition, comprising the following steps: a) Obtain image data of two or more three-dimensional images of the patient's respiratory system (images previously acquired during the evaluation period); b) Calculate a detailed three-dimensional structural model of the patient's respiratory system from each of the data obtained in step a); and c) Compare the three-dimensional structural models of the patient's respiratory system for each image data obtained in step a) to evaluate the effectiveness of the treatment on the respiratory condition. This provides a method that includes [something].

[0004] The patent or application file includes at least one color drawing. A copy of the published version of this patent or patent application, including one or more color drawings, will be provided by the Patent Office upon request and payment of the required fees. [Brief explanation of the drawing]

[0005] [Figure 1] This is a schematic representation of the pulmonary arteries in healthy lung tissue and lung tissue in a patient with PAH, showing the cross-sectional area of ​​the blood vessels throughout the lung.

[0006] [Figure 2] The following graphs show linear regression models of (a) pulmonary artery compliance (PAC) versus BV510ARATIO and (b) stroke volume (SV) versus BV510ARATIO (black dots = cerartinib; gray dots = placebo).

[0007] [Figure 3] Plots of BV510ARatio (ratio of pulmonary artery cross-sectional area >5 mm² to pulmonary artery cross-sectional area >10 mm² (BV10A)) values ​​for individual patients at baseline and 24 weeks after administration of cerartinib or placebo.

[0008] [Figure 4] Case study 1: (a) baseline and (b) 24-week lung images of patients who received placebo.

[0009] [Figure 5] Case study 2: (a) baseline and (b) 24-week lung images of patients who received cerartinib. [Modes for carrying out the invention]

[0010] Detailed explanation Receptor tyrosine kinases are transmembrane polypeptides that regulate cell regeneration, remodeling, development, and differentiation. Among receptor tyrosine kinases is platelet-induced growth factor receptor (PDGFR), which is associated with respiratory diseases, histofibrosis, and solid tumors. Among respiratory diseases, pulmonary hypertension (PH) is a rare pulmonary vascular disorder associated with high morbidity and mortality. The pathology of this disease involves reticular lesions consisting of disorderly angiogenesis and abnormal neointimal cell proliferation, which obstruct blood flow through the pulmonary arterioles.

[0011] Seraltinib (chemical name N-{3‐[(1S)-1-{[6-(3,4-dimethoxyphenyl)pyrazine-2-yl]aminoethyl]phenyl}-5-methylpyridine-3-carboxamide, also known as GB002) is a highly potent and selective inhibitor of PDGFRα and PDGFRβ signaling, based on clinical development as an inhalation therapy for pulmonary arterial hypertension (PAH). Seraltinib has the following structure: [ka] It has the following properties. The amorphous form of cerartinib is described in U.S. Patent Nos. 9,815,815 and 10,231,966, and the spray-dried powder formulation is described in U.S. Patent No. 9,925,184.

[0012] Therapies available for the treatment of PAH include, but are not limited to, prostanoids, endothelin antagonists, cytoplasmic kinase inhibitors, receptor kinase inhibitors, endothelin receptor antagonists, e.g., ambrisentan, bosentan, and cytaxentan; PDE5 (PDE-V) inhibitors, e.g., sildenafil, tadalafil, and vardenafil; calcium channel blockers, e.g., amlodipine, felodipine, valepamil, diltiazem, and menthol; Rostacyclin, treprostinil, iloprost, beraprost, nitric oxide, oxygen, heparin, warfarin, diuretics, digoxin, cyclosporine, antibodies such as cyclosporine A, CTLA4-Ig, ICAM-3, anti-IL-2 receptor (anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, drugs that block the interaction between CD40 and gp39, such as antibodies specific to CD40 and / or gp39, i.e., fusion proteins constructed from CD154, CD40 and gp39 (CD40 1g and CD8 gp39), inhibitors such as NF-κB function transposition inhibitors like deoxysperguarin (DSG), HMGCholesterol biosynthesis inhibitors such as CoA reductase inhibitors (lovastatin and simvastatin), non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, aspirin, and acetaminophen, cyclooxygenase inhibitors such as leflunomide, deoxyspergualin, and celecoxib, steroids such as prednisolone or dexamethasone, gold compounds, beta agonists such as salbutamol, long-acting beta agonists (LABAs) such as salmeterol, leukotriene antagonists such as montelukast, antiproliferatives such as methotrexate, cytotoxic drugs such as FK506 (tacrolimus, Prograf), mycophenolate mofetil, and azathioprine, VP-16, etoposide, fludarabine, doxorubicin, adriamycin, amsacrine, camptothecin, cytarabine, gemcitabine, fluorodeoxyuridine, melphalan, and cyclophosphamide, metabolic antagonists such as methotrexate, topoisomerase inhibitors such as camptothecin, DNA alkylating agents such as cisplatin, kinase inhibitors such as sorafenib, microtubule poisons such as paclitaxel, TNF-α inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptors, hydroxyurea, rapamycin (sirolimus or Rapamune), or derivatives thereof.

[0013] Similarly, the terms "effective amount" or "medically effective amount" refer to an amount sufficient to achieve the desired therapeutic and / or prophylactic effect, for example, an amount that results in the prevention or reduction of symptoms associated with the disease being treated. The amount of ceritinib administered to a subject will depend on the type and severity of the disease, as well as individual characteristics such as general health, age, gender, weight, and drug tolerance. Those skilled in the art will be able to determine the appropriate dosage according to these and other factors.

[0014] Representative diseases or conditions that can be treated with cerartinib include, but are not limited to, PAH, primary PAH, idiopathic PAH, hereditary PAH, refractory PAH, BMPR2, ALK1, endoglin associated with hereditary hemorrhagic telangiectasia, endoglin not associated with hereditary hemorrhagic telangiectasia, drug-induced PAH, and toxin-induced PAH, PAH associated with or secondary to one or more systemic sclerosis conditions, mixed connective tissue disease, cancer, refractory cancer, metastatic cancer, neoplasia, hypoplasia, hyperplasia, dysplasia, pleoplasia, pleoplasia, fibroplasia, and angiogenesis. Pulmonary dysfunction, cardiovascular dysfunction, HIV infection, hepatitis, portal hypertension, pulmonary hypertension, congenital heart disease, hypoxia, chronic hemolytic anemia, persistent pulmonary hypertension of the newborn, pulmonary veno-occlusive disease (PVOD), pulmonary capillary hemangioma (PCH), pulmonary hypertension due to left heart disease, systolic dysfunction, diastolic dysfunction, valvular heart disease, lung disease, interstitial lung disease, pulmonary fibrosis, schistosomiasis, chronic obstructive pulmonary disease (COPD), sleep-disordered breathing, alveolar hypoventilation, chronic exposure to high altitude, developmental abnormalities, chronic thromboembolic pulmonary hypertension (CTEPH), multifactorial pulmonary hypertension, hematological disorders, myeloproliferative disorders, splenectomy, Systemic diseases, sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangiocarcinomatosis, neurofibromatosis, vasculitis, metabolic diseases, glycogen storage disorders, Gaucher disease, thyroid diseases, neoplastic obstruction, fibrous mediastinitis, and chronic renal failure in dialysis; as well as diseases such as pulmonary hypertension, congenital heart disease, hypoxia, chronic hemolytic anemia, persistent pulmonary hypertension of the newborn, pulmonary veno-occlusive disease (PVOD), pulmonary capillary hemangiomatosis (PCH), left heart disease pulmonary hypertension, systolic dysfunction, diastolic dysfunction, valvular heart disease, lung diseases, interstitial lung diseases, pulmonary fibrosis, schistosomiasis, and chronic obstructive pulmonary disease (COPD). ), sleep-disordered breathing, impaired alveolar hypoventilation, chronic exposure to high altitude, developmental abnormalities, chronic thromboembolic pulmonary hypertension (CTEPH), multifactorial pulmonary hypertension, hematological disorders, myeloproliferative disorders, splenectomy, systemic diseases, sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioligotomy, neurofibromatosis, vasculitis, metabolic diseases, glycogen storage disorders, Gaucher disease, thyroid diseases, neoplastic obstructive diseases, fibrous mediastinitis, immune and inflammatory diseases, hyperproliferative disorders, kidney and renal diseases, bone remodeling disorders, metabolic diseases, vascular diseases, and chronic renal failure in dialysis.

[0015] In one aspect, the disease or condition is pulmonary arterial hypertension (PAH), and a therapeutically effective amount of the crystalline form of ceritinib is administered to a subject that needs it. In a specific embodiment, the disease or condition is PAH, primary PAH, idiopathic PAH, hereditary PAH, refractory PAH, drug-induced PAH, toxin-induced PAH, or PAH associated with secondary diseases.

[0016] Functional respiratory imaging For example, conventional pulmonary function measurements such as FEV1 or FVC provide information about the general state of the entire lung, but do not reveal the details of specific regions of the lung. Local information is important for understanding the pathophysiology of individual patients and for providing guidance for optimal disease treatment. Functional respiratory imaging (FRI) is a non-invasive measurement method of the patient's individual respiratory system.

[0017] FRI first obtains a low-dose, high-resolution computed tomography (HRCT) scan of the patient. The measurements are typically performed on the segmented 3D shapes obtained from these scans, and then computational fluid dynamics (CFD) quantifies the airflow and the exposure to inhaled particles.

[0018] This results in a series of biomarkers (e.g., lung, blood vessels, nodules, and airway volume, airway resistance, and internal airflow distribution, ventilation mapping, and blood flow reserve capacity), and they comprehensively evaluate the exposure, structure, and function of the lung and airways. This provides important information regarding the stage of the lung disease and the response (or non-response) to treatment, and as a result, it serves as a guideline for comprehensive improvement of clinical judgment and patient care. The use of FRI biomarkers is expandable and easy to implement, so it becomes an important reinforcement to the toolkits for respiratory disease research and clinical practice.

[0019] The measurement, treatment, and monitoring of respiratory-type conditions (such as chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis (CF), amyotrophic lateral sclerosis (ALS), myotonic dystrophy (Steinate's disease), Duchenne muscular dystrophy, acid D-maltase deficiency, and Emery-Dreyfus myopathy) in patients with respiratory-type conditions using three-dimensional imaging data of the patient's respiratory system have been described previously. For example, see US 11,109,830, Jan De Backer, "Method for determining a respiratory condition based on functional respiratory imaging"; US 8,886,500, Jan De Backer, "Method for determining treatments using patient-specific lung models and computer methods"; or US-2012-0072193, Jan De Backer, "Method for determining treatments using patient-specific lung models and computer methods".

[0020] For example, in asthma and COPD patients, FRI was used to determine responsive / non-responsive phenotypes and for phenotyping to evaluate various therapeutic interventions.

[0021] Methods for evaluating the effectiveness of treatment for patients with PAH are described herein. In some embodiments, the methods are for evaluating the effectiveness of cerartinib treatment for patients with PAH.

[0022] Figure 1 shows a schematic representation of the pulmonary arteries in healthy lung tissue and lung tissue in a patient with PAH, illustrating the cross-sectional area of ​​the blood vessels throughout the lung. Pulmonary artery volume using cross-sectional area (CSA): BV5A = CSA < 5mm 2 ; BV5-10A = CSA 5~10mm 2 and BV10A = CSA > 10mm 2 . In healthy lung tissue, the BV5A to BV10A ratio (BV510ARatio) is higher than in diseased tissue.

[0023] Images may be acquired in advance using any of the methods in the art. Such methods include magnetic resonance imaging, positron emission tomography, and computed tomography (CT) imaging.

[0024] The "respiratory system" refers to the intrathoracic and extrathoracic airways, as well as the lungs. Sometimes, images are acquired at total lung volume (TLC), which is the lung level reached after a deep inhale.

[0025] The present invention will be further illustrated by the following embodiments, which should not be construed as limiting in any way.

[0026] Further embodiments can be provided by combining the various embodiments described above. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned herein and / or listed in the application data sheet are incorporated herein by reference in their entirety. The aspects of the embodiments can be further provided by modifying them as necessary using concepts from various patents, applications, and publications.

[0027] In consideration of the detailed description above, these and other modifications may be made to the embodiments. In general, the terms used in the following Claims should not be interpreted as limiting the Claims to the specific embodiments disclosed in the Specification and Claims, but rather as including all possible embodiments along the entire scope of the equivalents for which such Claims are granted. Accordingly, the Claims are not limited by the disclosure herein.

[0028] All publications, patents, and patent applications referenced herein are incorporated by reference to the same extent that each individual publication, patent, or patent application is specifically and individually indicated as being incorporated by reference. [Examples]

[0029] Example 1 A clinical study to investigate pulmonary vascular remodeling in patients with pulmonary arterial hypertension (PAH) treated with cerartinib. As demonstrated by the diagram shown in Figure 1, typically, the pulmonary vascular volume of small arteries decreases in PAH, leading to hypertrophy of larger vessels (also known as remodeling).

[0030] The clinical study was conducted to investigate the effect of cerartinib on pulmonary artery volume distribution in PAH patients. Cerartinib was administered twice daily (BID) for 24 weeks by dry powder inhalation to PAH patients (World Health Organization Group I, functional class II or III). Thin-slice, non-contrast chest CT for volume measurement was obtained (at baseline and week 24, minimum 64 slices), and the reverse remodeling ability of cerartinib was subsequently evaluated by automated pulmonary vascular segmentation.

[0031] From the scan, high-resolution non-contrast computed tomography (CTM) studies of inspiratory-expiratory phases were performed to reconstruct the lung lobe tissue, airways, and vascular system. Vascular volume is provided as total blood volume (BV) and BVX values, where the BVX value divides the pulmonary blood volume depending on the size of the blood vessels containing the blood, and in this specification, BV5 has a CSA <5mm 2 Refers to blood vessels that have; BV5-10 is CSA 5~10mm 2 Refers to blood vessels that have; BV10 has a CSA > 10mm 2 Refers to blood vessels having; and BV510 ratio = BV5 / BV10, That is the case.

[0032] CSA < 5mm 2 (BV5A) and >10mm 2 The pulmonary artery volume (BVV) of pulmonary arteries with (BV10A) was calculated, and the BV5A to BV10A ratio (BV510ARATIO) was used to represent the relative redistribution of pulmonary artery volume. Linear regression was used to model the treatment effect.

[0033] CT scans were taken at baseline and at 24 weeks in 19 subjects (7 received cerartinib and 12 received placebo), as shown in Tables 1 and 2. The mean age was 49 ± 12 years, and 18 subjects were female. All subjects were receiving two or three approved PAH-specific therapies. Table 1: Patient background information [Table 1] Table 2: Patient characteristics [Table 2] PAC = Pulmonary Artery Compliance

[0034] The correlation analysis provided the following data, as shown in Table 3, regarding changes in arterial blood volume (from baseline to week 24) versus changes in clinical parameters: Table 3

Table 3

[0035] The estimated effect values of the regression model were as shown in Table 4 below: Table 4

Table 4

[0036] The BV510A ratio was significantly higher in the ceritinib group compared to placebo (p = 0.028), and was correlated with stroke volume (R = 0.65, p = 0.0041) and pulmonary compliance (R = 0.56, p = 0.017). Figure 2 supported that the BV510A Ratio was correlated with hemodynamics.

[0037] Figure 2(a) shows a linear regression model adjusted for baseline values and treatment ability, regarding pulmonary compliance (PAC) vs. BV510A RATIO (ratio of cross-sectional area < 5mm 2 of pulmonary artery (BV5A) to cross-sectional area > 10mm 2 of pulmonary artery (BV10A)). (Black dots = ceritinib; grey dots = placebo).

[0038] Figure 2(b) shows a linear regression model adjusted for baseline values and treatment ability, regarding stroke volume (SV) vs. BV510A RATIO (ratio of cross-sectional area < 5mm 2 of pulmonary artery (BV5A) to cross-sectional area > 10mm 2 of pulmonary artery (BV10A)). (Black dots = ceritinib; grey dots = placebo).

[0039] BV510A RATIO (ratio of cross-sectional area < 5mm 2 of pulmonary artery (BV5A) to cross-sectional area > 10mm 2The least-squares mean difference in the ratio of pulmonary artery (BV5A) to cerartinib increased by 0.845 (with a 95% CI of 0.105, 1.585, and a p-value of 0.028), meaning that cerartinib increases the BV510ARatio (see Figure 3, which shows plots of individual patients' BV510ARatio values ​​at baseline and 24 weeks after administration of cerartinib or placebo).

[0040] The BV510A ratio correlates with RV-PA coupling, an important measurement that is determined by pulmonary artery compliance and cardiopulmonary hemodynamics (i.e., stroke volume).

[0041] In patients with pulmonary artery disease (PAH) undergoing dual or triple therapy, the addition of cerartinib led to a significant redistribution of pulmonary artery volume to more distal vessels, suggesting a reverse remodeling effect of cerartinib in PAH.

[0042] Example 2 Case study Two case studies were conducted, as described below.

[0043] Case study 1 (placebo)

[0044] Case Study 1 is the case of a 24-year-old woman with WHO functional class II idiopathic PAH who is receiving approved PAH-specific drug therapy (phosphodiesterase type 5i and prostacyclin / PRA).

[0045] Figure 4 shows baseline and 24-week lung images after administering placebo twice daily (BID) for 24 weeks via dry powder inhalation, as follows: A 6% decrease in BV5APRA (red area); A 5% increase in BV10APRA (blue area); A decrease in the BV5A / BV10A ratio; and A 283-dyne increase in PVR coincidence accompanied by arterial volume shift. This was demonstrated. BVA5PRA = Cross-sectional area of ​​all arteries < 5 mm²2 The percentage of pulmonary arteries. BVA10PRA = Cross-sectional area relative to all arteries > 10 mm² 2 The percentage of pulmonary arteries. [Table 5]

[0046] Case study 2 (Cerartinib) Case Study 2 involved a 58-year-old woman with WHO functional class II idiopathic PAH and severe rheumatoid arthritis who was receiving approved triple therapy for PAH (ERA + PDE-5i + PRA).

[0047] Figure 4 shows baseline lung images and lung images at week 24 after administering cerartinib twice daily (BID) for 24 weeks via dry powder inhalation, as follows: A 6% increase in BV5APRA (red area); 8% decrease in BV10APRA (blue area); Increase in the BV5A / BV10A ratio; and Improvement of PVR coincidence accompanied by arterial volume shift, This was demonstrated. [Table 6]

[0048] This application claims priority to U.S. Patent Application No. 63 / 493,192, filed on March 30, 2023, which is incorporated herein by reference in its entirety.

Claims

1. A method for evaluating the efficacy of cerartinib treatment for PAH in subjects suffering from PAH, comprising the following steps: a) Obtain data on pre-treatment three-dimensional images of the patient's respiratory system and post-treatment three-dimensional images of the respiratory system of the subject; b) Calculate a unique three-dimensional structural model of the patient's lung structure from the pre-treatment and post-treatment image data obtained in step a); c) Calculate a unique three-dimensional structural model of the patient's airway structure from the pre-treatment and post-treatment image data obtained in step a); d) From the pre-treatment and post-treatment lung structural models obtained in step b), calculate a patient-specific three-dimensional structural model of the lung lobe structure in question; e) Using the pre- and post-treatment models of the airway structure and lobe structure of the subject obtained in steps c) and d), the airflow through the airway structure in the pre- and post-treatment conditions is modeled by computer; f) Using the pre- and post-treatment models of the airway structure and lobe structure of the subject obtained in steps c) and d), the structural behavior of the airway structure and its interaction with airflow in the pre- and post-treatment conditions are modeled by computer; and g) To measure the effectiveness of cerartinib treatment by comparing modeled airflow before and after treatment, and by comparing structural behavior before and after treatment, where effective treatment means reducing airway resistance, and thereby measuring the effectiveness of cerartinib treatment. The method, including the method described above.

2. A method for reverse remodeling of the pulmonary vascular system of a subject requiring such remodeling, comprising administering an effective amount of cerartinib to the subject.

3. A method for increasing the ratio of the volume of the distal pulmonary artery to the volume of the proximal pulmonary artery (BV510ARatio) in a subject requiring a high BV510ARatio, comprising administering an effective amount of cerartinib to the subject.

4. The method according to claim 3, wherein the increase in BV510ARatio is at least 0.

5.

5. The method according to claim 3, wherein the increase in BV510ARatio is 0.5 to 1.

0.

6. The method according to claim 3, wherein the increase in BV510ARatio is at least 0.

8.

7. A method for increasing the pulmonary vascular volume of small arterial vessels in a subject in need thereof, comprising administering an effective amount of cerartinib to the subject.

8. A method for reducing greater pulmonary artery hypertrophy in a subject in need thereof, comprising administering an effective amount of cerartinib to the subject.

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