Oral formulations of N-pyridinylacetamide derivatives for treating interstitial lung diseases - Patent Application 20070122999

Abstract

The present disclosure relates to oral formulations of n-pyridinylacetamide derivatives and the use of such formulations in the treatment of interstitial lung diseases.

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 382,311, filed November 04, 2022, the contents of which are incorporated herein by reference in their entirety for all purposes.

[0002] The present disclosure relates to oral formulations of n-pyridinylacetamide derivatives and the use of such formulations in the treatment of interstitial lung diseases. [Background technology]

[0003] Interstitial lung diseases (ILDs) are a group of rare diffuse parenchymal lung disorders associated with substantial morbidity and mortality, sharing common clinical and pathophysiological features but also diverse etiologies and prognoses (Olsen et al., 2018). ILDs affect the interstitium, or connective tissue stroma, which separates the epithelial and endothelial barriers of the lung. ILDs are classified into five broad clinical categories: ILDs associated with different primary diseases (e.g., sarcoidosis), ILDs associated with environmental exposures (e.g., hypersensitivity pneumonitis), ILDs induced by drugs or irradiation, ILDs associated with connective tissue diseases (e.g., scleroderma and rheumatoid arthritis), and idiopathic interstitial pneumonias (e.g., idiopathic pulmonary fibrosis, IPF). Although ILDs are heterogeneous, they share common genetic risk factors and downstream pathways leading to fibrosis.

[0004] Among ILD-PF, IPF is the most common and fatal. The incidence of IPF has increased over time, with conservative estimates of incidence in Europe and North America ranging from 3 to 9 cases per 100,000 people per year (Hutchinson 2015). IPF generally occurs in individuals over the age of 50 and is more common in men than women (Richeldi 2017). Smoking is a known risk factor (Baumgartner 1997). IPF is characterized by the deposition of excessive amounts of extracellular matrix proteins in the lungs, which replace the normal architecture of the distal lung, impair gas exchange, and lead to progressive exertional dyspnea and decline in lung function, ultimately resulting in respiratory failure and death (Richeldi 2017).

[0005] Idiopathic pulmonary fibrosis is pathologically characterized by the usual interstitial pneumonia pattern and the presence of characteristic clusters of activated (myofibroblasts) (fibroblast nests). The etiology of IPF remains unknown, but it is thought to result from repeated epithelial injury in genetically susceptible individuals, which induces an abnormal wound healing response. This is characterized by excessive and abnormal epithelial repair, (myofibroblast activation) driven by increased production of profibrotic growth factors such as TGF-β, epithelial-mesenchymal transition, interstitial collagen deposition by (myofibroblasts), and immune cell dysfunction, including the accumulation of profibrotic macrophages in the lungs (Richeldi 2017). While the disease course can vary, the fibrotic response in the lungs of IPF patients is often relentlessly progressive, leading to progressive impairment of gas exchange, respiratory failure, and death. In the absence of antifibrotic therapy, the median survival from the time of diagnosis is approximately 2–4 years (Ley 2011).

[0006] A proportion of patients with ILDs other than IPF also develop a progressive fibrotic phenotype associated with decreased lung function, worsening symptoms and quality of life, and premature death. These include idiopathic nonspecific interstitial pneumonia, autoimmune-associated ILDs such as rheumatoid arthritis-associated interstitial lung disease (RA-ILD) and systemic sclerosis-associated interstitial lung disease (SSc-ILD), chronic hypersensitivity pneumonitis, chronic sarcoidosis, exposure-related ILDs such as silicosis, and unclassifiable idiopathic interstitial pneumonia (Wollin 2019). The etiology and clinical features of other ILDs are similar to those of IPF.

[0007] Currently, only two therapies are approved for treating patients with IPF: pirfenidone and nintedanib. Both of these therapies have antifibrotic activity and slow the rate of decline in lung function (King 2014 and Richeldi 2014). However, both therapies are associated with troublesome GI side effects, and many IPF patients cannot tolerate these medications. Nintedanib is also approved to treat patients with ILD-PF other than IPF and has been shown to slow the rate of decline in lung function in these patients (Wells 2020). Tocilizumab, a monoclonal antibody against the IL-6 receptor, has been shown to slow the progression of lung disease in a subset of ILD patients with SSc-ILD (Khanna 2020) and was recently approved to treat this disease. However, none of the approved antifibrotic therapies relieves symptoms, halts the decline in lung function, or restores normal lifespan in patients with IPF or other ILD-PF. Thus, there is an urgent unmet need for more effective and better tolerated therapies for patients with IPF and other ILD-PF.

[0008] WNT ligands are glycoproteins secreted by various cells and bind to extracellular receptors, including the 10 members of the Frizzled receptor family (FZD) and their co-receptors (LRP5 / 6). Binding of WNT ligands to FZD and LRP5 / 6 can induce either canonical or non-canonical WNT signaling (Baarsma and Konigshoff 2017).

[0009] The LEF / TCF family induces downstream expression of profibrotic genes in multiple cell cultures involved in the pathogenesis of IPF, including alveolar epithelial cells, (myo)fibroblasts, and alveolar macrophages. TGF-β can activate canonical WNT signaling in lung and skin fibroblasts, resulting in increased nuclear translocation of β-catenin and transcription of WNT target genes. Further activation of WNT signaling by TGF-β occurs via downregulation of endogenous WNT antagonists (Distler 2019). Non-canonical WNT signaling follows the binding of specific WNTs (e.g., WNT4 and 5a) to FZD receptors but is independent of the LRP5 / 6 coreceptor. Non-canonical WNT signaling leads to the activation of intracellular signaling molecules involved in planar cell polarity, calcium / calmodulin-dependent protein kinase II, and other less well-defined pathways (Baarsma and Konigshoff 2017). However, WNT signaling is complex, and individual WNTs can activate both canonical and non-canonical pathways.

[0010] Enhanced WNT signaling contributes to the pathogenesis of IPF, and antibody-mediated inhibition of WISP-1 reduces pulmonary fibrosis in bleomycin-treated mice by altering alveolar epithelial cell function, reprogramming, and reducing fibroblast activation (Konighoff 2009). Unbiased gene expression profiling in IPF lung tissue identified a WNT signature (Konighoff 2008). In addition, canonical WNT signaling is elevated in various cells in the lungs of IPF patients and experimental animals with pulmonary fibrosis. Expression of WNT1, 7B, 10B, FZD2, FDZ3, and β-catenin, LEF1, and WISP-1 genes is elevated in the lungs of IPF patients compared with healthy controls (Konighoff 2008). Increased staining for WNT1 and 3A has been detected in bronchial and alveolar epithelial cells, and increased nuclear staining for β-catenin has been detected in bronchiolar epithelial cells and fibroblasts in fibroblastic lesions (Konigshoff 2008, Chilosi 2003). Furthermore, increased WNT10A expression in the lungs is associated with decreased survival in IPF patients (Oda 2016).

[0011] Further support for canonical WNT signaling in the pathogenesis of IPF comes from studies showing that expression of LRP-5 and -6 is elevated in IPF lungs, and that LRP5 transcript levels correlate with IPF progression and negatively correlate with the lung's diffusing capacity for carbon monoxide. Additionally, mice genetically deficient in LRP5 were protected from bleomycin-induced pulmonary fibrosis (Lam 2014).

[0012] Non-canonical WNT signaling also contributes to the pathogenesis of IPF. Mutant growth factor-β has been shown to drive the secretion of non-canonical WNTs. Expression of the non-canonical WNT ligand, WNT5A, is increased in fibroblasts from IPF patients and is strongly regulated by TGF-β (Distler 2019). WNT5B signals through FZD8 in a β-catenin-independent manner. High levels of FZD8 expression are present in IPF lungs, and expression levels correlate with disease progression (Lam 2014). Gene silencing of FZD8 reduces profibrotic signaling in fibroblasts in vitro and reduces bleomycin-mediated pulmonary fibrosis in mice (Spanjer 2016).

[0013] Increased WNT signaling has also been implicated in the pathogenesis of other ILD-PFs (Adegunsoye 2019, Distler 2019). Preliminary gene expression studies indicate that WNT gene expression is elevated in lung samples from patients with other ILD-PFs. Microarray analysis of human tissue samples from patients with systemic sclerosis demonstrates alterations in the expression of many β-catenin target genes (matrix metalloproteinase-7, osteopontin, cyclin D1, secreted FZD-related protein 2, peroxisome proliferator-activated receptor δ, and WISP-1) and pathway components (WNT2b, WNT5b, and WNT inhibitor 1). Patients with SSc-related progressive pulmonary fibrosis have increased nuclear β-catenin accumulation in pulmonary fibroblastic lesions (Lam 2011).

[0014] Forced activation of β-catenin signaling in three independently derived sources of normal human lung fibroblasts promoted proliferation and migration, suggesting that activation of β-catenin signaling in lung fibroblasts may be a common feature of pulmonary fibrosis and contributes to the fibroproliferative and migratory activity of (myo)fibroblasts associated with this disease. WNT5a protein levels were elevated in plasma samples from RA-ILD patients compared with non-RA-ILD patients, and levels positively correlated with plasma levels of rheumatoid factor (RHF) (Yu 2019). Higher plasma levels of WNT5a were also found in UIP patients compared with patients with nonspecific interstitial pneumonia and other ILD patterns. RA-ILD disease severity, as assessed by high-resolution computed tomography-UIP score, correlated with circulating WNT5a levels (Yu 2019).

[0015] Three porcupine inhibitors (CGX1321: NCT03507998; ETC-159: NCT02521844; WNT974: NCT01351103) are currently being evaluated in phase I clinical trials in patients with advanced or metastatic cancer (Shah 2021). To date, there have been no clinical trials evaluating PORCN inhibitors in patients with IPF or other ILD-PF. However, in experimental fibrosis models, treatment with different PORCN inhibitors significantly reduced fibrosis in the kidney in a renal fibrosis model (Madan 2016) and in the skin and lung in two mouse models of scleroderma (Chen 2017). Summary of the Invention

[0016] In some embodiments, a method of treating interstitial lung disease in a subject in need thereof is disclosed, the method comprising orally administering to the subject AZD5055 at a dose of 5 to 35 mg per day.

[0017] The dose can be delivered in a single dosage unit or in multiple dosage units.

[0018] In some embodiments, oral dosage units containing AZD5055 in an amount of 2.5 to 35 mg are disclosed. DETAILED DESCRIPTION OF THE INVENTION

[0019] The term AZD5055 refers to the compound having the chemical name 2-[4-(2-methyl-4-pyridyl)pyrrolo[3,2-c]pyridin-1-yl]-N-(5-pyrazin-2-yl-2-pyridyl)acetamide and the structure shown below.

[0020] [ka]

[0021] AZD5055, also known as RXC006, is a potent and selective inhibitor of the intracellular enzyme porcupine (PORCN), a membrane-bound O-acyltransferase required for and dedicated to the palmitoylation of all Wnt ligands, an essential step in their processing for secretion (Herr 2012).

[0022] WNT signaling contributes significantly to the pathogenesis of ILD-PF through its activity on multiple key cell types involved in the pathogenesis of these diseases. AZD5055 inhibits WNT signaling in epithelial cells, fibroblasts, and alveolar macrophages in the lungs of patients with IPF and other ILD-PF, thereby limiting the progression of pulmonary fibrosis and improving quality of life and survival in patients with these diseases.

[0023] Preliminary studies of AZD5055 show that it reduces bleomycin-mediated fibrosis in the lungs of rats, carbon tetrachloride-induced liver fibrosis in mice, and kidney fibrosis in a UUO model in mice (Bunyard 2019).

[0024] The synthesis of AZD5055 is described in WO 2016 / 055790 (Compound ID No. 23), the contents of which are incorporated herein by reference in their entirety. In some embodiments, free base AZD5055 is administered to a subject. In some embodiments, crystalline AZD5055 is administered to a subject.

[0025] The term "proton pump inhibitors" refers to a class of drugs that cause a significant and long-lasting reduction in gastric acid production. + / K + They do so by irreversibly inhibiting the ATPase proton pump. Examples of proton pump inhibitors include omeprazole, lansoprazole, dexlansoprazole, esomeprazole, pantoprazole, rabeprazole, and ilaprazole.

[0026] The term "rabeprazole" refers to the compound having the chemical name (RS)-2-([4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl)-1H-benzo[d]imidazole and the structure shown below.

[0027] [ka]

[0028] The term "nintedanib" refers to the compound having the chemical name methyl (3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}phenyl)amino](phenyl)methylidene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylate and having the structure shown below.

[0029] [ka]

[0030] The terms "treat," "treating," and "treatment" include reducing or inhibiting PORCN- or WNT-related enzyme or protein activity in a subject, ameliorating one or more symptoms of an interstitial lung disease, such as idiopathic pulmonary fibrosis, in a subject, or slowing or delaying the progression of an interstitial lung disease, such as idiopathic pulmonary fibrosis, in a subject. The terms "treat," "treating," and "treatment" also include reducing or inhibiting the growth of clusters of activated (myo)fibroblasts in a subject.

[0031] The terms "inhibit," "inhibition," or "inhibiting" include a decrease in the baseline activity of a biological activity or process.

[0032] The term "subject" includes warm-blooded mammals, such as primates, dogs, cats, rabbits, rats, and mice. In some embodiments, the subject is a primate, such as a human. In some embodiments, the subject is suffering from an interstitial lung disease, such as idiopathic pulmonary fibrosis.

[0033] In some embodiments, a method of treating interstitial lung disease in a subject in need thereof is disclosed, the method comprising orally administering to the subject AZD5055 at a dose of 5 to 35 mg per day.

[0034] Further disclosed is AZD5055 for use in the treatment of interstitial lung disease, a method comprising oral administration of AZD5055 at a dose of 5 to 35 mg per day. Further disclosed is the use of AZD5055 in the manufacture of a medicament for the treatment of interstitial lung disease by oral administration at a dose of 5 to 35 mg per day.

[0035] In further embodiments, the daily dose is 10-30 mg per day, or 15-25 mg per day.

[0036] In some embodiments, AZD5055 is administered at a dose of 5 mg per day, about 10 mg per day, about 15 mg per day, about 20 mg per day, about 25 mg per day, about 30 mg per day, or about 35 mg per day. In some embodiments, AZD5055 is administered at a dose of about 5 mg per day, about 10 mg per day, about 15 mg per day, about 20 mg per day, about 25 mg per day, about 30 mg per day, or about 35 mg per day. In some embodiments, AZD5055 is administered at a dose of about 5 mg per day. In some embodiments, AZD5055 is administered at a dose of about 15 mg per day.

[0037] The daily dose may be 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, or 35 mg.

[0038] In some embodiments, AZD5055 is administered once daily (QD). In some embodiments, AZD5055 is administered at a dose of 5 mg QD, about 10 mg QD, about 15 mg QD, about 20 mg QD, about 25 mg QD, about 30 mg QD, or 35 mg QD. In some embodiments, AZD5055 is administered at a dose of about 5 mg QD, about 10 mg QD, about 15 mg QD, about 20 mg QD, about 25 mg QD, about 30 mg QD, or 35 mg QD. In some embodiments, AZD5055 is administered at a dose of about 5 mg QD. In some embodiments, AZD5055 is administered at a dose of about 15 mg QD.

[0039] In some embodiments, AZD5055 is administered twice daily (BID). In some embodiments, AZD5055 is administered at a dose of 2.5 mg BID, about 5 mg BID, about 7.5 mg BID, about 10 mg BID, about 12.5 mg BID, about 15 mg BID, or 17.5 mg BID. In some embodiments, AZD5055 is administered at a dose of about 2.5 mg BID, about 5 mg BID, about 7.5 mg BID, about 10 mg BID, about 12.5 mg BID, about 15 mg BID, or about 17.5 mg BID.

[0040] In some embodiments, AZD5055 is administered continuously in a treatment cycle.

[0041] The terms "continuous" or "sequentially" refer to the administration of a therapeutic agent, e.g., AZD5055, at regular intervals without stopping or interruption, i.e., without drug holidays. A "drug holiday" means a day when the therapeutic agent is not administered.

[0042] As used herein, a "cycle," "treatment cycle," or "administration schedule" refers to a period of combination treatment that is repeated on a regular schedule. For example, when administering AZD5055, treatment can be administered for 1 week, 2 weeks, or 3 weeks. In some embodiments, a treatment cycle is from about 1 week to about 3 months. In some embodiments, a treatment cycle is from about 5 days to about 1 month. In some embodiments, a treatment cycle is from about 1 week to about 3 weeks. In some embodiments, a treatment cycle is from about 1 week, about 10 days, about 2 weeks, about 3 weeks, about 4 weeks, about 2 months, or about 3 months. In some embodiments, a treatment cycle is one year or longer.

[0043] The daily dose of 5-35 mg per day is significantly lower than the human therapeutic dose of 164 mg (administered as 83 mg BID) originally predicted based on preclinical data for AZD5055. This initially predicted therapeutic dose was associated with an in vitro IC of 0.64 nmol / L (269.7 ng / L or 0.0003 mg / L) generated in a β-catenin reporter assay using rodent cells. 50 Based on the values ​​(Bunyard 2019), the magnitude of continuous inhibition of PORCN over the dosing interval was expected to be >75%, so 3× in vitro IC over 24 hours in vivo was used to achieve target engagement and efficacy. 50 A coverage of 3x in vitro IC over 24 hours in vivo was selected based on exposure reducing pulmonary fibrosis in bleomycin in vivo studies in rats and mice. 50 A coverage of 3× in vitro IC was predicted to be effective (Bunyard 2019). 50 The approach was also supported by published clinical data for Wnt974, a PORCN inhibitor currently in clinical development for the treatment of subjects with advanced cancer (Rodon 2021). The predicted therapeutic exposure of AZD5055 is similar to the once-daily clinical dose of 10 mg Wnt974, with similar target coverage and free C. trough A once-daily clinical dose of 10 mg Wnt974 resulted in an approximately 90% reduction in Axin2 (a Wnt pathway biomarker) expression levels in skin samples from subjects with advanced cancer. In subjects receiving this dose, the mean C at steady state trough is 3.7 × IC 50 Human PK parameters were predicted from in vitro and non-clinical in vivo studies. Total plasma clearance was 9.1 mL / min / kg, volume of distribution under steady-state conditions was 2.4 L / kg, and t 1 / 2 The C was predicted to be 3 hours. The bioavailability and absorption rate constant (ka) were predicted to be 22% and 1.0 h-1, respectively. Using these PK parameters, the plasma steady-state exposure (total concentration) was predicted to have a C of 0.023 μmol / L (0.010 mg / L) at the originally predicted twice-daily therapeutic dose of 83 mg.min (minimum plasma concentration), C of 0.18 μmol / L (0.076 mg / L) max (maximum plasma concentration), and AUC of 2.24 μmol·h / L (0.944 mg·h / L). (0-24) The plasma concentration was estimated as the area under the plasma concentration-time curve from 0 to 24 hours.

[0044] In some embodiments, AZD5055 is taken on an empty stomach, without food, 2 hours before and 1 hour after, hi other embodiments, AZD5055 is taken with food.

[0045] Taking AZD5055 with or without food may increase the risk of C max , AUC inf (area under the plasma concentration-time curve from zero to infinity), and AUC last (area under the plasma concentration-time curve from zero to the time of the last quantifiable concentration). When AZD5055 is taken with food, the AUC inf and AUC last may increase.

[0046] In some embodiments, the method of treating interstitial lung disease in a subject in need thereof further comprises separate, sequential, or simultaneous administration of a proton pump inhibitor or a pharmaceutically acceptable salt thereof.

[0047] Further disclosed is AZD5055 for use in the treatment of interstitial lung disease, the method further comprising separate, sequential or simultaneous administration of a proton pump inhibitor or a pharmaceutically acceptable salt thereof. Also disclosed is the use of AZD5055 in the manufacture of a medicament for the treatment of interstitial lung disease, the treatment further comprising separate, sequential or simultaneous administration of a proton pump inhibitor or a pharmaceutically acceptable salt thereof.

[0048] Administration of AZD5055 with a proton pump inhibitor is expected to be important in patients suffering from conditions in which excess stomach acid is produced, including dyspepsia, peptic ulcer disease, and gastroesophageal reflux disease. Proton pump inhibitors reduce the acidity of gastric contents, but the solubility of AZD5055 is known to be pH-dependent. Therefore, such a combination might be expected to require a higher daily dose of AZD5055 and / or a shift from once-daily to twice-daily dosing.

[0049] In some of these embodiments, the proton pump inhibitor is rabeprazole. In some embodiments, rabeprazole is orally administered. In some embodiments, rabeprazole is in tablet form, more particularly, in a delayed-release tablet form. In some embodiments, rabeprazole is orally administered once daily (QD) at a dose of about 10 or 20 mg, or orally administered twice daily (BID) at a dose of 10 or 20 mg. In some embodiments, the dose comprises one 10 mg tablet, two 10 mg tablets, or one 20 mg tablet.

[0050] In some embodiments, AZD5055 and rabeprazole are taken together on an empty stomach without food 2 hours before and 1 hour after administration, hi other embodiments, rabeprazole is taken on an empty stomach without food 2 hours before and 1 hour after administration, and AZD5055 is taken with food.

[0051] In some embodiments, oral dosage units containing AZD5055 in an amount of 2.5 to 35 mg are disclosed.

[0052] In some embodiments, the oral dosage unit comprises a daily dose of AZD5055. In other embodiments, the oral dosage unit comprises half of a daily dose of AZD5055.

[0053] In some embodiments, the oral dosage unit is an aqueous suspension.

[0054] The suspension may contain additional excipients, including viscosity agents (e.g., sodium carboxymethylcellulose), sweeteners, and colorants. In some embodiments, the viscosity agent is sodium carboxymethylcellulose, present in an amount of 5 mg per mL of suspension.

[0055] In some embodiments, the oral dosage unit is a tablet.

[0056] In some of these embodiments, the tablet comprises one or more pharmaceutical excipients selected from the group consisting of diluents, compression aids, disintegrants, and glidants / lubricants.

[0057] In some embodiments, the diluent is a sugar or sugar-containing substance, excluding mannitol. For example, the diluent may be lactose, dextrin, glucose, sucrose, or sorbitol. In some embodiments, the diluent comprises microcrystalline cellulose. Compatibility testing has shown that the commonly used diluent mannitol is incompatible with AZD5055. When used as a diluent, additional amounts of degradation products have been identified.

[0058] In some embodiments, the diluent is an inorganic compound such as silicates, calcium and magnesium salts, sodium chloride, or potassium chloride.

[0059] In some embodiments, the compression aid (which may also be called a binder or granulating agent) is selected from microcrystalline cellulose (MCC), xylitol, dicalcium phosphate, lactose monohydrate, and starch, hi some embodiments, the compression aid is dicalcium phosphate (also known as dibasic calcium phosphate).

[0060] In some embodiments, the compression aid is 10-30% by weight of the tablet core. In some of these embodiments, the compression aid is 15-25% by weight of the tablet core. In some embodiments, the compression aid is 22% by weight of the tablet core.

[0061] In some embodiments, the lubricant / glidant is glyceryl behenate. Compatibility studies have shown that the commonly used glidant, silicon dioxide, and lubricant, magnesium stearate, are incompatible with AZD5055. When used as a glidant and lubricant, respectively, additional amounts of degradation products were identified.

[0062] In some embodiments, the lubricant / glidant is 2-15% by weight of the tablet core. In some of these embodiments, the lubricant / glidant is 5-12% by weight of the tablet core. In some embodiments, the lubricant / glidant is 10% by weight of the tablet core.

[0063] In some embodiments, the disintegrant is a compound that swells or dissolves in water, such as starch, cellulose derivatives, alginates, and crospovidone, hi some embodiments, the disintegrant is croscarmellose sodium.

[0064] In some embodiments, the disintegrant is 2-15% by weight of the tablet core. In some of these embodiments, the disintegrant is 5-12% by weight of the tablet core. In some embodiments, the disintegrant is 10% by weight of the tablet core.

[0065] In some embodiments, the tablet does not contain mannitol, silicon dioxide, or magnesium stearate.

[0066] In some embodiments, the tablet is coated. The coating may include one or more excipients such as film-forming agents, plasticizers, opacifiers, and colorants.

[0067] In other embodiments, the tablets are uncoated.

[0068] In some embodiments, a kit is disclosed that includes a first pharmaceutical composition comprising AZD5055, a second pharmaceutical composition comprising a proton pump inhibitor or a pharmaceutically acceptable salt thereof, and instructions for using the first and second pharmaceutical compositions in combination.

[0069] Interstitial lung diseases (ILDs) include ILD associated with different primary diseases (e.g., sarcoidosis), ILD associated with environmental exposure (e.g., hypersensitivity pneumonitis), ILD induced by drugs or irradiation, ILD associated with connective tissue diseases (e.g., scleroderma and rheumatoid arthritis), and idiopathic interstitial pneumonias (e.g., IPF).

[0070] Sarcoidosis is a systemic disease characterized by the formation of immune granulomas in organs, particularly the lungs and lymphatic system. It is estimated that up to 20% of patients diagnosed with sarcoidosis develop fibrotic lung disease, which manifests as dyspnea, cough, and hypoxemia.

[0071] ILDs associated with environmental exposures include hypersensitivity pneumonitis, asbestosis, and silicosis. Hypersensitivity pneumonitis (HP) is an immunologically initiated lung disease triggered by repeated inhalation of a wide variety of environmental organic antigens and / or chemicals to which genetically susceptible subjects have previously been sensitized. Asbestosis is caused by exposure to asbestos. Silicosis is caused by exposure to free crystalline silicon dioxide or silica.

[0072] There is a spectrum of connective tissue diseases (CTDs) characterized by mechanisms underlying systemic autoimmunity and immune-mediated organ damage, which can develop pulmonary complications throughout the disease course. These CTDs include rheumatoid arthritis (RA), scleroderma (systemic sclerosis (SSc)), idiopathic inflammatory myopathies (polymyositis and dermatomyositis), Sjögren's syndrome, systemic lupus erythematosus, and mixed CTDs. RA and SSc are most commonly associated with progressive fibrosing ILD.

[0073] Idiopathic pulmonary fibrosis (IPF) is characterized by the deposition of excessive amounts of extracellular matrix proteins in the lungs, which replace the normal architecture of the distal lung, impair gas exchange, and lead to progressive exertional dyspnea and decline in lung function, ultimately resulting in respiratory failure and death.

[0074] In some embodiments, treatment with nintedanib may be administered simultaneously. Such additional treatment may be given with the current standard of care or at a reduced dose.

[0075] In some embodiments, the subject may have been previously treated with nintedanib. [Example]

[0076] The compounds of the present application will now be further described by reference to the following non-limiting examples.

[0077] [Table 1]

[0078] [Table 2]

[0079] [Table 3]

[0080] Tablets are formed as 7 mm round biconvex tablets by roller compaction and then coated with about 4.3 wt % of the coating premix to give a coverage of about 5 mg / cm 2 .

[0081] The coating premix was Aquarius™ Prime BAP312542 Brown, containing HPMC (film former), PEG (plasticizer), TiO2 (opacifier), and FeO x (coloring agent).

[0082] Example 1. First Clinical Trial to Investigate Safety, Tolerability, and Pharmacokinetics The study is divided into two parts: Part 1 involves testing a single ascending dose, while Part 2 involves testing multiple ascending doses.

[0083] Part 1 will include a screening period of up to 6 weeks. This will be followed by a treatment period during which subjects will reside in the clinical unit from 1 day before administration of the investigational medicinal product (IMP) (Day -1) until at least 72 hours after IMP administration (Day 4). Subjects will receive a single oral dose of AZD5055 or placebo on Day 1. This will be followed by a follow-up visit within 6±1 days of IMP administration.

[0084] Part 2 involves a screening period of up to 6 weeks, followed by a treatment period during which subjects reside in the clinical unit from 1 day before IMP administration (Day -1) until at least 72 hours after the last dose given on Day 16 (Day 19). Subjects are medicated for a total of 15 days, receiving a single, once-daily morning dose of AZD5055 or placebo on Days 1 and 3-16, with no dose on Day 2. This is followed up with a follow-up visit within 6±1 days of IMP administration and an additional follow-up visit within 29±2 days of the last IMP administration.

[0085] For the cohort with the QD dosing regimen, the screening period is followed by a treatment period in which subjects stay in the clinical unit from 1 day before IMP administration (Day -1) until at least 72 hours after the last dose given on Day 16 (Day 19). Subjects are dosed for a total of 15 days and receive a single QD morning dose of AZD5055 or placebo on Days 1 and 3 through 16.

[0086] For cohorts with a BID dosing regimen, the screening period is followed by a treatment period in which subjects reside in the clinical unit from one day before IMP administration (Day -1) until at least 72 hours after the last dose given on Day 16 (Day 19). Subjects are medicated for a total of 15 days, receiving a single morning dose of AZD5055 or placebo on Days 1 and 16, with repeat BID dosing at 12-hour (±30-minute) intervals from Days 3 through 15.

[0087] For both cohorts, the treatment period will be followed by a follow-up visit within 6±1 days after the last IMP dose, and an additional follow-up visit within 29±2 days after the last IMP dose.

[0088] Test Purpose Primary purpose(s) Part 1: SAD (Single Ascending Dose) - To evaluate the safety and tolerability of AZD5055 following oral administration of single ascending doses to healthy subjects.

[0089] Part 2: MAD (Multiple Ascending Dose) - To evaluate the safety and tolerability of AZD5055 following oral administration of multiple ascending doses to healthy subjects.

[0090] Secondary purpose(s) Part 1: SAD - To characterize the PK of AZD5055 after oral administration of single ascending doses to healthy subjects.

[0091] Part 2: MAD - To characterize the PK of AZD5055 after oral administration of multiple ascending doses to healthy subjects.

[0092] Exploratory objective(s) Part 1: SAD • To assess target engagement in hair follicles (Cohorts 1 and 2). • To assess target engagement in whole blood. To assess the effect of AZD5055 on biomarkers of bone turnover. • Assess cardiac safety as assessed by 12-lead safety electrocardiograms (ECGs) and dECGs, including intent to obtain TQT surrogates. • To assess changes in a panel of urinary renal biomarkers if indicated by a 3-month preclinical toxicity study. To investigate the presence and measure levels of metabolites of AZD5055 in plasma and urine. The results will be used to guide future investigations of exposure to metabolites of AZD5055.

[0093] Part 2: MAD • To assess target involvement in skin biopsies. • To assess target engagement in hair follicles. • To assess target engagement in whole blood. • Searching for further exploratory biomarkers in blood samples. • To evaluate the effect of AZD5055 on biomarkers of bone turnover in serum samples after oral administration of multiple ascending doses to healthy subjects. • Assess cardiac safety as assessed by 12-lead safety ECGs and dECGs, including intent to obtain TQT surrogates. • To assess changes in a panel of urinary renal biomarkers if indicated by a 3-month preclinical toxicity study. To investigate the presence and measure the levels of metabolites of AZD5055 in plasma and urine. • To assess the effect of AZD5055 on CYP3A (4-β-hydroxy-cholesterol).

[0094] The clinical trial was conducted according to the above protocol and can be summarized as follows:

[0095] Main inclusion criteria The study was conducted in healthy male and female subjects of non-childbearing potential with veins suitable for intubation or repeated venipuncture. 2Participants had a body mass index of 0.05 (inclusive) and weighed at least 50 kg. Participants were aged between 18 and 55 years for both men and women in Part 1 and for men only in Part 2. For female participants in Part 2, the age range was 18 to 49 years (inclusive).

[0096] Part 1 of the study investigated three dose levels of AZD5055 in three cohorts. Each cohort included eight subjects. Within each cohort, six subjects were randomized to receive AZD5055 and two subjects were randomized to receive placebo. Part 2 of the study investigated three dose levels of AZD5055 in three cohorts. Within each cohort, nine subjects were randomized to receive AZD5055 and three subjects were randomized to receive placebo. Untreated subjects, i.e., subjects who did not participate in Part 1 of the study, were included in Part 2 of the study. One subject in Cohort 1 randomized to receive AZD5055 did not receive AZD5055 treatment and withdrew from the study due to headache.

[0097] Evaluation criteria Safety Variables Safety endpoints included adverse events; vital signs (supine blood pressure, pulse, respiratory rate, and temperature); 12-lead ECG, 12-lead dECG, telemetry, physical examination, laboratory assessments (hematology, clinical chemistry [including serum creatinine and creatine phosphokinase], urinalysis [including protein and albumin:creatinine ratio], and cardiac biomarkers [including cardiac troponin T (cTNT), cardiac troponin I (cTNI), and B-type natriuretic peptide]), and peripheral oxygen saturation (SpO2).

[0098] Pharmacokinetic parameters Key PK parameters: C max , AUC inf , and AUC lastSecondary PK parameters: including, but not limited to, tmax, AUC(0-12) or AUC(0-24) (one is not the primary parameter), t1 / 2λz, MRTinf, CL / F, Vz / F, Rac, TCP, Ae(t1-t2), fe(t1-t2), and CLR.

[0099] Pharmacodynamic parameters Change from baseline in blood 4-beta-hydroxy-cholesterol levels.

[0100] statistical methods Sample size determination The sample sizes for Parts 1 and 2 of the study were selected to obtain an adequate assessment of safety and tolerability without exposing an excessive number of subjects to the compound in this phase of clinical development. Previous experience with Phase 1 studies indicated that the proposed sample sizes for Parts 1 and 2 of the study were adequate to achieve the objectives of the study. To allow for adequate analysis of the PK and safety of AZD5055, eight evaluable subjects in the AZD5055 treatment group were selected in Part 2 (MAD) cohorts 1, 2, and 3. Eight evaluable subjects in the placebo group were selected in the Part 2 (MAD) cohort.

[0101] Safety data presentation and analysis All safety data (scheduled and unscheduled) were presented in data listings. Continuous variables were summarized by treatment using descriptive statistics (n, mean, standard deviation, minimum, median, maximum). Categorical variables were summarized in frequency tables (frequency and percentage) by treatment (both Part 1 and 2). Analysis of safety variables was based on the safety analysis set. Adverse events were summarized by system organ class (SOC) and preferred term (PT) using the International Medical Dictionary vocabulary. In addition, lists of serious adverse events (SAEs) and adverse events leading to discontinuation of IMP (DAEs) were generated, and the number of subjects with any adverse events (AEs), SAEs, DAEs, and severe AEs were summarized. Adverse events occurring before dosing were reported separately. Tables and lists of data for ECG, vital signs, AEs, and laboratory measurements were presented.

[0102] Pharmacokinetic data presentation and analysis No formal statistical hypothesis testing was performed. Analyses of safety, tolerability, PK, and PD data were summarized narratively by treatment / dose / study day separately using appropriate descriptive statistics, including tables, lists, and graphs, as appropriate. Preliminary dose proportionality of AZD5055 after single dosing in Parts 1 and 2 (Day 1) and multiple dosing in Part 2 (Day 16) was assessed graphically, and logarithms of PK parameters (AUC and C on Day 1) were assessed. max ) and (AUC(0-τ) and C on day 16 max The data collected in Part 2 were analyzed using a power model approach with AUC(0-τ) (day 16) as the dependent variable and the logarithm of dose as the independent variable. For data collected in Part 2, the time dependence of PK was assessed by comparing AUC(0-τ) (day 16) with AUC(day 1), and accumulation was assessed by comparing AUC(0-τ) (day 16) with AUC(0-τ) (day 1), and C max (16th day) C max (Day 1). A linear mixed-effects analysis of variance model was performed using the logarithms of the above PK parameters as response variables and treatment, day, and the interaction of treatment by day as fixed effects. Day was treated as a within-subject repeated effect.

[0103] Exploratory data presentation and analysis Plasma 4-β-hydroxy-cholesterol levels at baseline and on the last day of dosing were statistically analyzed using a linear mixed model analysis of covariance with treatment as a fixed effect and baseline concentration of 4-β-hydroxy-cholesterol as a covariate.

[0104] Protocol Deviation A total of 11 significant protocol deviations were reported in eight subjects. In part one of the study, two subjects missed PK urine measurements, one subject vomited within two hours of AZD5055 administration, and one subject had another protocol deviation related to urine sample collection. Of these subjects, one subject was excluded from the PK analysis set (descriptive and inferential statistics) due to vomiting within two hours of AZD5055 administration (at / before twice the median tmax). In part two of the study, four subjects had time window deviations for PK plasma processing, two subjects missed dECG measurements, and one subject had time window deviations for PK urine processing, which were reported. One subject was excluded from the PK analysis set because a PK sample was unavailable, and one subject was excluded from the PD set because a PD sample was unavailable. The reported protocol deviations did not affect the interpretation of the study results.

[0105] result Pharmacokinetics AZD5055 was rapidly absorbed after administration of single ascending doses of 7 to 40 mg of AZD5055 oral suspension. AZD5055 exposure increased approximately proportionally across the dose range tested, from 5 to 40 mg, after single and multiple dose administration. Similar ranges of median and tmax values ​​of 1.00 to 1.30 hours were observed after multiple daily doses of 5 to 20 mg of AZD5055. AZD5055 concentrations declined in a biphasic manner, with geometric mean terminal half-life values ​​ranging from 9.7 to 11.4 hours after single doses of AZD5055 and from 12.2 to 17.2 hours after multiple daily doses. The extent of peak and maximal exposure (C) varied between subjects. max Variability in AUC and AUC was low (<25%) to moderate (>25%, <40%), respectively. Variability in systemic exposure over time was expected to be minimal. Little to moderate accumulation of AZD5055 was observed after repeated daily dosing. Renal clearance of AZD5055 accounted for a small proportion of the total clearance of AZD5055. Less than 2.3% of the administered dose was recovered unchanged (as AZD5055) in the urine.

[0106] Pharmacodynamics There was no effect on 4-β-hydroxy-cholesterol after 14 days of once-daily AZD5055 administration, suggesting that AZD5055 has no significant effect on CYP3A4 activity in healthy subjects.

[0107] safety In Part 1, AZD5055 oral doses of 7, 20, and 40 mg (n=6 per dose level) administered as a single-dose oral suspension were well tolerated. In Part 2, AZD5055 was administered at 5 mg QD, 15 mg QD, and 20 mg QD as a single-dose oral suspension, and all doses were well tolerated. These assessments were based on the following:

[0108] Part 1 There were no SAEs, deaths, or AEs that led to discontinuation of AZD5055 or withdrawal from the study. Overall, four subjects (22.2%) across all AZD5055 doses and one subject (16.7%) in the pooled placebo group experienced at least one AE. There were no notable trends for AEs by system organ class (SOC) or preferred term (PT). All AEs across all AZD5055 doses were reported only once. Overall, three subjects (16.7%) across all AZD5055 doses had at least one AE considered possibly related to AZD5055 as assessed by the investigator, compared with none in the pooled placebo group. These AEs included dizziness, ventricular tachycardia, wheezing, upper abdominal pain, vomiting, and nausea. All AEs were grade 1 (mild) in intensity and resolved / resolved by the end of the study. No clinically relevant trends were observed for laboratory test results, vital signs, physical examination, and ECG.

[0109] Part 2 There were no SAEs or deaths. There were three AEs leading to discontinuation of AZD5055. Two subjects receiving the 5 mg AZD5055 dose experienced grade 2 (moderate) intensity ventricular tachycardia / non-sustained ventricular tachycardia AEs, both of which were considered possibly related to AZD5055 as assessed by the investigator. One subject receiving the 15 mg AZD5055 dose experienced a Grade 1 (mild) intensity coronavirus infection AE that was not considered possibly related to AZD5055 as assessed by the investigator. Overall, 21 subjects across all AZD5055 doses and 5 subjects in the pooled placebo group experienced at least one AE. There were no significant trends in A4 by system organ class (SOC) or preferred term (PT). The majority of AEs16 were Grade 1 (mild) in intensity, with five subjects experiencing AEs (across all AZD5055 doses) of Grade 2 (moderate) intensity. All AEs recovered / resolved by the end of the study. There were a total of seven AEs across all AZD5055 doses, none in the pooled placebo group, that were considered possibly related to AZD5055 treatment as assessed by the investigator. These AEs included dysgeusia (1), headache (3), photophobia (1), ventricular tachycardia (2), and halitosis (1). No clinically relevant trends were observed for laboratory test results, vital signs, physical examination, and ECG.

[0110] Example 2. Second Clinical Trial to Investigate Safety, Tolerability, and Pharmacokinetics The study includes a screening period of up to 28 days and five periods in which subjects will participate from day -1 of period 1 through 72 hours after administration of AZD5055 in period 5.

[0111] Period 1: On Day 1, subjects receive either 5 mg AZD5055 as a 20 minute IV infusion in the overnight fasted state (Treatment A) or 20 mg AZD5055 as an oral suspension in the overnight fasted state (Treatment B).

[0112] Period 2: On Day 1 (Study Day 4), subjects will receive 20 mg AZD5055 film-coated tablets (Treatment C) in the overnight fasted state.

[0113] Period 3: On Day 1 (Study Day 8), subjects receive a standardized high-fat breakfast 30 minutes prior to 20 mg of AZD5055 (Treatment D) administered as a film-coated tablet.

[0114] Period 4: On Study Day 10, 20 mg of rabeprazole will be administered twice daily for 3 days prior to Day 1. On Day 1 (Study Day 13), 20 mg of AZD5055 film-coated tablets will be administered with rabeprazole, and rabeprazole will be continued twice daily (Treatment E).

[0115] Period 5: On Day 1 (Study Day 17), participants will receive a low-fat breakfast 30 minutes before receiving a 20 mg AZD5055 film-coated tablet along with 20 mg rabeprazole, which will be administered twice daily, with the final dose being administered on the evening of Study Day 18 (Treatment F).

[0116] Follow-up visit or phone call approximately 6 days after the last AZD5055 dose in Period 5.

[0117] There will be a minimum washout of 3 days between AZD5055 doses in Period 1 and Period 2, and a minimum washout of 4 days between AZD5055 doses in subsequent study periods. Repeated PK (pharmacokinetic) sampling will be conducted from pre-dose through 48 hours post-dose of AZD5055 in each period. Subjects will be discharged on Study Day 20 (Day 4 of Period 5) after all samples have been collected and all assessments have been performed.

[0118] For single oral dose administration, approximately 20 mg once daily provides a C of 23 nmol / L. trough 20 mg of AZD5055 was selected because it is predicted to achieve the in vitro IC 50This provides 3x the 24-hour coverage of the efficacy assay. This exposure is predicted to result in a magnitude of continuous inhibition of PORCN of >75% between doses. In Example 1, AZD5055 oral doses of 7, 20, and 40 mg (n=6 per dose level) administered as a single-dose oral suspension were well tolerated.

[0119] The predicted human intestinal permeability is high, with the fraction absorbed estimated to be close to 100%, and clearance is low, with limited first-pass effects predicted. Based on in vitro data, the predicted human oral bioavailability is 70%. The observed oral bioavailability in several animal species ranges from 40% to 60%. Based on these data, a reasonable lower limit for the oral bioavailability (F) of AZD5055 F was selected as 25% or 0.25. The observed t 1 hour after oral administration was 0.25. max (C max Based on the time to absorption (C), it is estimated that approximately 75% of the dose is absorbed within 20 minutes. Therefore, a conservative estimate is that the C after IV infusion over 20 minutes is max However, after correcting for F, it is less than two-fold higher compared to the oral dose.

[0120] Rabeprazole is administered as an oral dose of 20 mg BID in the morning and evening. Three days of rabeprazole pretreatment are required to achieve a pharmacodynamic (PD) steady state of pH elevation before administration of AZD5055. The most commonly recommended dose of 20 mg BID has not raised any significant safety concerns in preclinical and clinical trials.

[0121] breakfast The high-fat, high-calorie breakfast consisted of two eggs fried in batter, two slices of bacon, two slices of buttered toast, 112g / 4oz hash brown potatoes, and 240mL / 8oz whole milk. This test meal could be substituted as long as the meal provided a similar amount of calories from protein, carbohydrates, and fat and had a comparable meal volume and consistency.

[0122] A low-fat, low-calorie breakfast consisted of one boiled egg, one packet of flavored instant oatmeal with water, and 240 mL / 8 oz of milk (1% fat). This test meal could be substituted as long as the meal provided a similar amount of calories from fat and had a comparable meal volume and consistency.

[0123] [Table 4]

[0124] Primary endpoint Area under the concentration-time curve (AUC) from time 0 to infinity inf ) [Timeframes: Days 1-6, 8-10, 13-15, 17-19] Area under the drug blood concentration-time curve (AUC) from time 0 to the last quantifiable concentration last ) [Timeframes: Days 1-6, 8-10, 13-15, 17-19] ●Maximum observed concentration (C max ) [Timeframes: Days 1-6, 8-10, 13-15, 17-19] To assess the relative bioavailability of AZD5055 film-coated tablet formulations versus AZD5055 oral suspension. To assess the absolute bioavailability of AZD5055 oral suspension and AZD5055 film-coated tablet formulations. To evaluate the effect of the proton pump inhibitor rabeprazole on the PK of AZD5055 alone and in combination with an acid reducing agent. To evaluate the effect of the proton pump inhibitor, rabeprazole, on the PK of AZD5055 when administered with food.

[0125] Secondary endpoints In the time frames of days 1-6, 8-10, 13-15, and 17-19: Time to reach maximum observed concentration (t max ) ●Terminal disappearance rate constant (λz) ●Terminal elimination half-life (t 1 / 2 λz) Apparent total body clearance (extravascular administration only) (CL / F) ● Systemic clearance (intravascular administration only) (CL) Apparent volume of distribution based on terminal phase (extravascular administration only) (Vz / F) Volume of distribution based on terminal phase (intravascular administration only) (Vz) ●Mean residence time (MRT) Absolute bioavailability (calculated based on the geometric mean AUCinf of Treatment B or C versus the geometric mean AUCinf of Treatment A) (F) Absolute bioavailability (calculated based on the geometric mean AUCinf of treatment B or C versus the geometric mean AUCinf of treatment A) (F rel ) Ratio of test treatment to reference treatment based on AUC (calculated for Treatment D vs. Treatment C, Treatment E vs. Treatment C, Treatment F vs. Treatment C, Treatment F vs. Treatment E) (RAUC) AUC inf Ratio of test treatment to reference treatment based on (Treatment D vs. Treatment C, Treatment E vs. Treatment C, Treatment F vs. Treatment C, Treatment F vs. Treatment E) (RC max ) was calculated) To assess the relative bioavailability of AZD5055 film-coated tablet formulations versus AZD5055 oral suspension. To assess the absolute bioavailability of AZD5055 oral suspension and AZD5055 film-coated tablet formulations. To assess the effect of food on the pharmacokinetic (PK) parameters of AZD5055 in the fed and fasted states. To evaluate the effect of the acid-reducing agent, rabeprazole, on the PK of AZD5055 alone and in combination with an acid-reducing agent. To assess the effect of the acid-reducing agent, rabeprazole, on the PK of AZD5055 when administered in the fasted and fed state. To assess the safety of AZD5055 after single oral and IV administration in healthy participants. Number of subjects with adverse events and serious adverse events [time frame: screening (days -28 to -2) to follow-up (day 23)] To evaluate the safety of AZD5055 after single oral and IV administration in healthy subjects

[0126] The clinical trial was conducted according to the above protocol and can be summarized as follows:

[0127] Main inclusion criteria Healthy male and female (non-childbearing potential) participants aged 18-55 years with a body mass index (BMI) of 18-30 kg / m2.

[0128] Evaluation criteria Pharmacokinetic Parameters—Pharmacokinetic parameters of AZD5055 included, but were not limited to, Cmax, AUCinf, and AUClast.

[0129] Safety Variables—Safety endpoints included adverse events (AEs), clinical laboratory assessments (hematology, clinical chemistry, urinalysis, and urinary albumin:creatinine ratio), vital signs and peripheral oxygen saturation (SpO2), standard 12-lead electrocardiogram (ECG), telemetry, and physical examination.

[0130] statistical methods Sample size determination Approximately 18 healthy participants were enrolled to ensure at least 15 participants completed the five-period study. The proposed sample size was expected to provide sufficient information on the effects of formulation and concomitant treatment on AZD5055 exposure while minimizing participant exposure to study procedures. Interpretation of results was based on estimated geometric mean ratios (GMRs) and associated 90% confidence intervals (CIs) between the test and reference combinations for AUC and Cmax.

[0131] Pharmacokinetic data presentation and analysis Plasma concentrations were listed for each participant at each actual sampling time and summarized by treatment and nominal sampling time using the same descriptive statistics as for PK parameters. Graphical displays included individual and geometric mean time-concentration curves (actual sampling times for individual curves and nominal sampling times for mean curves) on linear and semi-logarithmic scales. Pharmacokinetic and PK analysis diagnostics were listed, and PK variables were summarized by treatment using descriptive statistics (n, geometric mean, geometric coefficient of variation [gCV; %], arithmetic mean, arithmetic standard deviation [SD], minimum [min], median, and maximum [max]) for all variables except tmax, which were summarized using n, min, median, and max. The following statistical comparisons were performed on the PK analysis sets to assess the absolute and relative bioavailability of AZD5055. AZD5055 film-coated tablets, fasted, C (test) / AZD5055 oral suspension, fasted, B (reference). ○AZD5055 film-coated tablets, fasted, C (test) / AZD5055 solution for injection, A (reference).

[0132] The analysis is max , AUC inf , and AUC last The analysis was performed using a linear mixed-effects analysis of variance (ANOVA) model with the natural logarithm of as the response variable; sequence, period, and treatment as fixed effects, and participant nested within sequence as a random effect. The data were back-transformed from the logarithmic scale and used as a C max , AUC inf , and AUC last Geometric means were estimated and presented along with CIs (two-sided 95%) for .

[0133] True * Results were transformed back to the original scale to obtain estimates of the geometric standard deviation (gSD) ratios and the 90% CI for these ratios. In addition, the 90% CI for the differences was calculated and presented.

[0134] For evaluation of food effects and acid-reducing agent effects, the following statistical comparisons were performed on the PK analysis sets. ○AZD5055 film-coated tablets 20 mg, fed state, D (test) / AZD5055 film-coated tablets 20 mg, overnight fasted state, C (reference). AZD5055 film-coated tablets with rabeprazole, fed, F (test) / AZD5055 film-coated tablets with rabeprazole, overnight fast, E (reference). ○AZD5055 film-coated tablets with rabeprazole, overnight fasting, E (test) / AZD5055 film-coated tablets 20 mg, overnight fasting, C (reference). ○AZD5055 film-coated tablets with rabeprazole, fed, F (test) / AZD5055 film-coated tablets 20 mg with rabeprazole, overnight fasted state, C (reference).

[0135] The effects of food and acid reducers on the PK of AZD5055 were assessed using a linear mixed-effects ANOVA model with fixed effects for treatment, period, and sequence, and a random effect for participant within sequence. The analysis was performed on natural log-transformed C max , AUC last , and AUC inf It was performed using the logarithmic scale and converted back to C max , AUC last , and AUC inf Geometric means with CIs (2-sided 95%) were calculated and presented for the treatment comparisons (i.e., AZD5055 under fed conditions vs. AZD5055 under fasted conditions). Ratios of geometric means with CIs (2-sided 90%) were also estimated and presented for the treatment comparisons (i.e., AZD5055 under fed conditions vs. AZD5055 under fasted conditions).

[0136] Safety data presentation and analysis All safety data (planned and unplanned) were presented in the data listings. Continuous variables were summarized by treatment using descriptive statistics (n, mean, SD, minimum, median, maximum). Categorical variables were summarized in frequency tables (frequency and percentage) by treatment / dose group. Analysis of safety variables was based on the safety analysis set.

[0137] Protocol Deviation There were two participants with two significant protocol deviations in the treatment sequence ACDEF and three participants with four significant protocol deviations in the treatment sequence BCDEF. Significant protocol deviations are assumed not to affect any of the prespecified endpoints. Therefore, participants with significant protocol deviations were not excluded from either analysis set.

[0138] result Pharmacokinetic results The absolute bioavailability of film-coated tablets is AUC inf and AUC last Based on the results, the C values ​​for the film-coated tablets were approximately 66% and 64%. max was approximately 21% of the IV dose. The total systemic exposure to AZD5055 after administration of film-coated tablets was AUC inf and AUC last was equivalent to oral suspension administration based on C max was about 35% lower. ●C max , AUC last , and AUC inf The exposure to AZD5055 based on C was increased by 22% to 32% when administered in the fed state compared to the fasted state. However, when rabeprazole was administered, food did not affect the overall systemic exposure to AZD5055, but the C was increased compared to when fasted rabeprazole was administered. max increased by approximately 17%. When rabeprazole was administered in the fasted state, the total systemic exposure (AUC inf and AUC last ) did not change, but C max decreased by 32%. When rabeprazole was administered in the fed state, the total systemic exposure (AUC inf and AUC last ) did not change, but C max decreased by 20%.

[0139] safety results The study did not identify any significant safety or tolerability concerns and AZD5055 was generally well tolerated. This assessment was based on: There were no deaths in this study. One participant experienced an SAE in Period 3, which was assessed by the investigator as possibly related to AZD5055 (transaminases increased). ●Two participants experienced AEs (2 events) leading to discontinuation of AZD5055 after administration in Period 3 (increased transaminases and non-cardiac chest pain). Overall, 11 participants experienced any AE (20 events) during the study. Five participants experienced any AE (9 events) assessed by the investigator as possibly related to AZD5055. In total, eight participants reported at least one AE of grade 1 intensity, and four participants reported at least one AE of grade 2 intensity. No AEs of grade 3 or higher were reported. No clinically relevant trends were observed for laboratory parameters, vital signs, ECG, or physical examination. The coronavirus disease 2019 (COVID-19) pandemic did not affect the overall safety results of this trial.

[0140] References Many publications are cited above. Full citations for these references are provided below. Each of these references is incorporated herein in its entirety.

[0141] [Table 5]

Claims

1. 1. A method of treating interstitial lung disease in a subject in need thereof, comprising administering to the subject 2-[4-(2-methyl-4-pyridyl)pyrrolo[3,2-c]pyridin-1-yl]-N-(5-pyrazin-2-yl-2-pyridyl)acetamide (AZD5055). 【Chemistry 1】 at a dose of 5 to 35 mg per day.

2. 10. The method of claim 1, wherein the daily dose is 10 to 30 mg per day.

3. 3. The method of claim 1 or 2, wherein the daily dose is 15 to 25 mg per day.

4. 10. The method of claim 1, wherein the daily dose is 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, or 35 mg per day.

5. 2. The method of claim 1, wherein the daily dose is selected from the group consisting of 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, and 35 mg.

6. 10. The method of claim 1, wherein the daily dose is about 5 mg per day.

7. 10. The method of claim 1, wherein the daily dose is about 15 mg per day.

8. 8. The method of any one of claims 1 to 7, wherein AZD5055 is administered once daily (QD).

9. 8. The method of any one of claims 1 to 7, wherein AZD5055 is administered twice daily (BID).

10. 10. The method of any one of claims 1 to 9, wherein AZD5055 is administered continuously in a treatment cycle.

11. 11. A method according to any preceding claim, wherein AZD5055 is taken on an empty stomach, without food, 2 hours before and 1 hour after.

12. A method according to any preceding claim, wherein AZD5055 is taken with food.

13. 13. The method of any one of claims 1 to 12, further comprising separate, sequential or simultaneous administration of a proton pump inhibitor or a pharmaceutically acceptable salt thereof.

14. 14. The method of claim 13, wherein the proton pump inhibitor is rabeprazole.

15. 15. The method of claim 14, wherein rabeprazole is administered orally twice daily (BID) at a dose of about 10 or 20 mg.

16. The method of any one of claims 1 to 15, wherein the interstitial lung disease is idiopathic pulmonary fibrosis.

17. 2-[4-(2-methyl-4-pyridyl)pyrrolo[3,2-c]pyridin-1-yl]-N-(5-pyrazin-2-yl-2-pyridyl)acetamide (AZD5055) 【Chemistry 2】 in an amount of 2.5 to 35 mg.

18. 18. An oral dosage unit according to claim 17, comprising a daily dose of AZD5055 according to any one of claims 1 to 7.

19. 18. An oral dosage unit according to claim 17, comprising half a daily dose of AZD5055 according to any one of claims 1 to 7.

20. 20. The oral dosage unit of any one of claims 17 to 19, which is an aqueous suspension.

21. 21. The oral dosage unit of claim 20, wherein the suspension comprises one or more additional excipients selected from the group consisting of viscosity agents, sweeteners, and colorants.

22. 20. The oral dosage unit according to any one of claims 17 to 19, wherein the oral dosage unit is a tablet.

23. 23. The oral dosage unit of claim 22, wherein the tablet comprises one or more pharmaceutical excipients selected from the group consisting of diluents, compression aids, disintegrants, and glidants / lubricants.

24. 24. The oral dosage unit of claim 23, wherein a diluent is present, said diluent being a sugar or sugar-containing substance, excluding mannitol, or an inorganic compound.

25. 25. The oral dosage unit of claim 24, wherein the diluent is microcrystalline cellulose.

26. 26. An oral dosage unit according to any one of claims 23 to 25, wherein a compression aid is present and is selected from microcrystalline cellulose (MCC), xylitol, dicalcium phosphate, lactose monohydrate, and starch.

27. 27. The oral dosage unit of claim 26, wherein the compression aid is dicalcium phosphate.

28. 28. The oral dosage unit of claim 26 or 27, wherein the compression aid is 10 to 30% by weight of the tablet core.

29. 29. The oral dosage unit of any one of claims 23 to 28, wherein the lubricant / glidant is present and is glyceryl behenate.

30. 30. The oral dosage unit of claim 29, wherein the lubricant / glidant is 2-15% by weight of the tablet core.

31. An oral dosage unit according to any one of claims 23 to 30, wherein a disintegrant is present and is a compound that swells or dissolves in water.

32. 32. The oral dosage unit of claim 31, wherein the disintegrant is croscarmellose sodium.

33. 33. The oral dosage unit of claim 31 or 32, wherein the disintegrant is 2 to 15% by weight of the tablet core.

34. 34. The oral dosage unit of any one of claims 23 to 33, wherein the tablet is coated.

Images