Oral formulations of N-pyridylacetamide derivatives for treatment of interstitial lung disease

Abstract

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

Description

[0001] This specification claims the benefit of priority of U.S. Provisional Application No. 63 / 382,311, filed on November 4, 2022, the content of which is hereby incorporated by reference in its entirety for all purposes.

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

[0003] Interstitial lung diseases are a rare group of diffuse parenchymal lung disorders with high morbidity and mortality, sharing common clinical and pathophysiological features but also exhibiting diverse etiologies and prognoses (Olsen et al. 2018). ILD affects the interstitial or connective tissue matrix that separates the epithelial and endothelial barriers in the lungs. ILD is divided into five broad clinical categories: ILD associated with different primary diseases (such as sarcoidosis), ILD associated with environmental exposures (such as hypersensitivity pneumonitis), ILD induced by drugs or radiation, ILD associated with connective tissue diseases (such as scleroderma and rheumatoid arthritis), and idiopathic interstitial pneumonias (such as idiopathic pulmonary fibrosis, IPF). Although ILD is heterogeneous, they share common genetic risk factors and common downstream pathways leading to fibrogenesis.

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

[0005] The pathology of idiopathic pulmonary fibrosis is characterized by the presence of the usual interstitial pneumonia pattern and a distinctive cluster of activated (myo)fibroblasts (fibroblast foci). Although the etiology of IPF remains unclear, it is thought to be due to repetitive epithelial injury in genetically susceptible individuals that induces an abnormal wound healing response. It is characterized by excessive and abnormal epithelial repair, (myo)fibroblast activation driven by increased production of profibrotic growth factors such as TGF-β, epithelial-mesenchymal transition, interstitial collagen deposition by (myo)fibroblasts, and immune cell dysfunction, including the accumulation of profibrotic macrophages in the lungs (Richeldi 2017). Although the course of the disease can be variable, the fibrotic response in the lungs of IPF patients is often progressive, leading to progressive gas exchange impairment, respiratory failure, and death. In the absence of antifibrotic therapy, the median survival from the time of diagnosis is approximately 2 to 4 years (Ley 2011).

[0006] A proportion of patients with ILD other than IPF also develop a progressive fibrotic phenotype associated with decline in lung function, worsening symptoms and QoL, and early death. These include idiopathic nonspecific interstitial pneumonia, ILD associated with autoimmune diseases 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 ILD such as silicosis, and unclassifiable idiopathic interstitial pneumonia (Wollin 2019). The pathogenesis and clinical features of other ILD-PF are similar to those of IPF.

[0007] Currently, only two therapies have been approved for treating patients with IPF: pirfenidone and nintedanib. Both of these therapies have anti-fibrotic activity and slow the rate of decline in lung function (King 2014 and Richeldi 2014). However, both therapies are accompanied by troublesome GI side effects and many patients with IPF cannot tolerate these drugs. Nintedanib has also been approved for treating 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 subgroup of ILD patients with SSc-ILD (Khanna 2020), and has recently been approved for treating this disease. However, no approved anti-fibrotic therapy alleviates symptoms, halts the decline in lung function, or restores normal lifespan in patients with IPF or other ILD-PF. Therefore, 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 WNT ligands, which then bind to receptors, including 10 members of the Frizzled receptor family (FZD) and their co-receptors (LRP5 / 6). Binding of WNT ligands to FZD and LRP5 / 6 can trigger canonical or non-canonical WNT signaling (Baarsma and 2017).

[0009] The LEF / TCF family triggers downstream expression of pro-fibrotic genes in multiple cell culprits 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, accompanied by nuclear translocation of β-catenin and increased 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 occurs after binding of specific WNTs (such as WNT 4 and 5a) to FZD receptors, but is independent of the LRP5 / 6 co-receptor. Non-canonical WNT signaling causes activation of intracellular signaling molecules involved in planar cell polarity, calcium / calmodulin-dependent protein kinase II, and other less well-defined pathways (Baarsma and 2017). However, WNT signaling is complex, and a single WNT scan can activate both canonical and non-canonical pathways.

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

[0011] Additional support for canonical WNT signaling in IPF pathogenesis is that studies have shown that the expression of LRP-5 and LRP-6 is elevated in IPF lungs, and the LRP5 transcript level correlates with IPF progression and is negatively correlated with the lung's diffusing capacity for carbon monoxide. In addition, mice genetically lacking LRP5 are protected from bleomycin-induced pulmonary fibrosis (Lam 2014).

[0012] Noncanonical WNT signaling also contributes to the pathogenesis of IPF. It has been confirmed that transforming growth factor-β drives the secretion of noncanonical WNTs. The expression of WNT5A, a noncanonical WNT ligand, is increased in fibroblasts from patients with IPF and is strongly regulated by TGF-β (Distler 2019). WNT5B signals via FZD8 in a β-catenin-independent manner. High levels of FZD8 expression are present in IPF lungs, and the expression level correlates with disease progression (Lam 2014). Genetic silencing of FZD8 reduces profibrotic signaling in fibroblasts in vitro and bleomycin-mediated pulmonary fibrosis in mice (Spanjer 2016)

[0013] Increased WNT signaling has also been linked to the pathogenesis of other ILD-PFs (Adegunsoye 2019; Distler 2019). Preliminary gene expression studies have shown 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 demonstrated altered expression of many β-catenin target genes (matrix metalloproteinase-7, osteopontin, cyclin D1, secreted frizzled-related protein 2, peroxisome proliferator-activated receptor δ, and WISP-1) and pathway components (WNT2b, WNT5b, and WNT inhibitory factor 1). Patients with SSc-related advanced lung fibrosis have increased nuclear β-catenin accumulation in fibroblast foci in their lungs (Lam 2011).

[0014] In three independent sources of normal human lung fibroblast-derived cells, forced activation of β-catenin signaling promoted proliferation and migration, suggesting that activation of β-catenin signaling in lung fibroblasts may be a common feature of pulmonary fibrosis and contribute to the fibroproliferative and migratory activities of (myo)fibroblasts associated with the disease. Compared with non-RA-ILD patients, WNT5a protein levels were elevated in plasma samples from RA-ILD patients, and the levels were positively correlated with the plasma levels of rheumatoid factor (Yu 2019). Higher plasma levels of WNT5A were also found in patients with UIP compared with those with nonspecific interstitial pneumonia and other ILD patterns. RA-ILD disease severity was correlated with circulating WNT5a levels, as assessed by high-resolution computed tomography-UIP score (Yu 2019).

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

[0016] In some embodiments, the present invention provides a method of treating an interstitial lung disease in a subject in need thereof, the method comprising orally administering AZD5055 to the subject at a dose between 5 mg / day and 35 mg / day.

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

[0018] In some embodiments, an oral dose unit comprising an amount of AZD5055 between 2.5 mg and 35 mg is disclosed. Detailed Description

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

[0020]

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

[0022] WNT signaling makes a key contribution to the pathogenesis of ILD-PF via its activity on multiple key cell types involved in the pathogenesis of these diseases. AZD5055 is expected to inhibit 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 the quality of life and survival of patients with these diseases.

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

[0024] The synthesis of AZD5055 is described in WO2016 / 055790 (Compound ID No. 23), the content of WO2016 / 055790 is incorporated herein by reference in its entirety. In some embodiments, the free base of AZD5055 is administered to a subject. In some embodiments, crystalline AZD5055 is administered to a subject.

[0025] The term "proton pump inhibitor" refers to a class of drugs that cause a significant and long-term reduction in gastric acid production. They inhibit the H + / K +This is achieved by an 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 with the chemical name (RS)-2-([4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl)-1H-benzo[d]imidazole and the structure shown below:

[0027]

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

[0029]

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

[0031] The term "inhibit" includes a decrease in the baseline activity of a biological activity or biological 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 interstitial lung disease, such as idiopathic pulmonary fibrosis.

[0033] In some embodiments, the present invention provides a method for treating interstitial lung disease in a subject in need thereof, the method comprising orally administering AZD5055 to the subject at a dose between 5 mg / day and 35 mg / day.

[0034] Further disclosed is AZD5055 for treating interstitial lung disease, the method comprising orally administering AZD5055 at a dose between 5 mg / day and 35 mg / day. Also disclosed is the use of AZD5055 in the manufacture of a medicament for treating interstitial lung disease by oral administration of a dose between 5 mg / day and 35 mg / day.

[0035] In further embodiments, the daily dose is between 10 mg / day and 30 mg / day, or between 15 mg / day and 25 mg / day.

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

[0037] The daily dose can 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 during a treatment cycle.

[0041] The term "continuous" or "continuously" means that a therapeutic agent, such as AZD5055, is administered at regular intervals without stopping or interruption, i.e., without blank days. A "blank day" is a day on which no therapeutic agent is administered.

[0042] As used herein, "cycle", "treatment cycle", or "dosing schedule" refers to a combined treatment period that is repeated according to a regular schedule. For example, treatment can be given for one week, two weeks, or three weeks, during which AZD5055 is administered. In some embodiments, the treatment cycle is from about 1 week to about 3 months. In some embodiments, the treatment cycle is from about 5 days to about 1 month. In some embodiments, the treatment cycle is from about 1 week to about 3 weeks. In some embodiments, the treatment cycle is 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, the treatment cycle is 1 year or longer.

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

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

[0045] Taking AZD5055 with or without food will affect 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). Taking AZD5055 with food can increase AUC inf and AUC last .

[0046] In some embodiments, a method of treating a subject with interstitial lung disease in need thereof further comprises administering a proton pump inhibitor or a pharmaceutically acceptable salt thereof separately, sequentially, or simultaneously.

[0047] AZD5055 for treating interstitial lung disease is also disclosed, and the method further comprises administering a proton pump inhibitor or a pharmaceutically acceptable salt thereof separately, sequentially or simultaneously. The use of AZD5055 in the manufacture of a medicament for treating interstitial lung disease is also disclosed, and the treatment further comprises administering a proton pump inhibitor or a pharmaceutically acceptable salt thereof separately, sequentially or simultaneously.

[0048] It is expected that co - administration of AZD5055 with a proton pump inhibitor is important in patients with conditions that produce excessive gastric acid, such conditions including dyspepsia, peptic ulcer disease and gastroesophageal reflux disease. Proton pump inhibitors reduce the acidity of gastric contents, and the solubility of AZD5055 is known to be pH - dependent. Thus, it might have been expected that such combinations would require higher daily doses of AZD5055 and / or would require a change from once - daily to twice - daily dosing.

[0049] In some embodiments of these embodiments, the proton pump inhibitor is rabeprazole. In some embodiments, rabeprazole is administered orally. In some embodiments, rabeprazole is in tablet form, more particularly in delayed - release tablet form. In some embodiments, rabeprazole is administered at a dose of about 10 mg or 20 mg orally once - daily (QD) or 10 mg or 20 mg orally twice - daily (BID). 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 on an empty stomach, with no food intake two hours before and one hour after. In other embodiments, rabeprazole is taken on an empty stomach, with no food intake two hours before and one hour after, and AZD5055 is taken with food.

[0051] In some embodiments, an oral dosage unit comprising an amount of AZD5055 between 2.5 mg and 35 mg is disclosed.

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

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

[0054] The suspension may comprise additional excipients, including viscosity agents (such as sodium carboxymethylcellulose), sweeteners and colorants. In some embodiments, the viscosity agent is sodium carboxymethylcellulose and is present in an amount of 5 mg / mL of the 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, other than mannitol. For example, the diluent can be lactose, dextrin, glucose, sucrose, sorbitol. In some embodiments, the diluent is microcrystalline cellulose. From compatibility studies, it has been found that the commonly used diluent mannitol is incompatible with AZD5055. When used as a diluent, additional amounts of degradation products were 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 referred to as a binder or granulating agent) is selected from microcrystalline cellulose (MCC), xylitol, dicalcium phosphate, lactose monohydrate, and starch. In some embodiments, the compression aid is dicalcium phosphate (also known as calcium hydrogen phosphate).

[0060] In some embodiments, the compression aid is between 10 wt% and 30 wt% of the tablet core. In some of these embodiments, it is between 15 wt% and 25 wt% of the tablet core. In some embodiments, it is 22 wt% of the tablet core.

[0061] In some embodiments, the lubricant / glidant is glyceryl behenate. From compatibility studies, it has been found that the commonly used glidant silica and lubricant magnesium stearate are incompatible with AZD5055. When these are used as glidant and lubricant respectively, additional amounts of degradation products were identified.

[0062] In some embodiments, the lubricant / glidant is between 2 wt% and 15 wt% of the tablet core. In some of these embodiments, it is between 5 wt and 12 wt% of the tablet core. In some embodiments, it is 10 wt% 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. In some embodiments, the disintegrant is croscarmellose sodium.

[0064] In some embodiments, the disintegrant is between 2 wt% and 15 wt% of the tablet core. In some of these embodiments, it is between 5 wt and 12 wt% of the tablet core. In some embodiments, it is 10 wt% of the tablet core.

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

[0066] In some embodiments, the tablets are coated. The coating may comprise one or more excipients such as film formers, plasticizers, opacifiers, and colorants.

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

[0068] In some embodiments, a kit is disclosed that comprises: a first pharmaceutical composition comprising AZD5055; a second pharmaceutical composition comprising a proton pump inhibitor or a pharmaceutically acceptable salt thereof; and instructions for the combined use of the first pharmaceutical composition and the second pharmaceutical composition.

[0069] Interstitial lung disease (ILD) includes ILD associated with different primary diseases (such as sarcoidosis), ILD associated with environmental exposures (such as hypersensitivity pneumonitis), ILD induced by drugs or radiation, ILD associated with connective tissue diseases (such as scleroderma and rheumatoid arthritis), and idiopathic interstitial pneumonia (such as IPF).

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

[0071] ILDs associated with environmental exposures include hypersensitivity pneumonitis, asbestosis, and silicosis. Hypersensitivity pneumonitis (HP) is an immune-mediated lung disease triggered by the repeated inhalation of large amounts 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 silica or quartz.

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

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

[0074] In some embodiments, nintedanib treatment can be administered in parallel. Such additional treatment can be administered at the current standard of care or at a reduced dose.

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

[0076] Example

[0077] The compounds of the present application will now be further explained with reference to the following non-limiting examples.

[0078] Suspension Preparation

[0079] Component Amount (per mL) Function AZD5055 1 mg to 20 mg Active Pharmaceutical Ingredient Sodium Carboxymethylcellulose 5 mg Viscosity Agent Purified Water To 1 mL Solvent

[0080] Tablet Preparation

[0081] Component Amount - Core Function AZD5055 5 mg to 35 mg Active Pharmaceutical Ingredient Anhydrous Calcium Hydrogen Phosphate 30.8 mg Compression Aid Croscarmellose Sodium 7 mg Disintegrant Glyceryl Behenate 7 mg Lubricant

[0082] Component Amount - Core Function Microcrystalline Cellulose To 140 mg Diluent

[0083] Tablets are formed into 7 mm round, biconvex tablets by roller compaction and then coated with a coating premix of approximately 4.3 wt% to achieve a coverage of approximately 5 mg / cm 2 of coverage.

[0084] The coating premix is Aquarius TM Prime BAP312542Brown and consists of HPMC (film-forming agent), PEG (plasticizer), TiO2 (opacifier), and FeO x (colorant).

[0085] Example 1. The First Clinical Study on Safety, Tolerance and Pharmacokinetics

[0086] The study was divided into two parts - Part 1 included testing single ascending doses, while Part 2 included testing multiple ascending doses.

[0087] Part 1 included a screening period of up to 6 weeks. This was followed by a treatment period during which the subjects remained in the clinical unit from 1 day before administration of the investigational medicinal product (IMP) (Day -1) to at least 72 hours after IMP administration (Day 4). The subjects received a single oral dose of AZD5055 or placebo on Day 1. This was followed by a follow-up visit within 6 ± 1 days after the IMP dose.

[0088] Part 2 includes a screening period of up to 6 weeks. This is followed by a treatment period during which the subjects stay in the clinical unit from 1 day before IMP administration (Day -1) until at least 72 hours after the last dose (Day 19). The subjects are dosed for a total of 15 days, receiving a once-daily morning single dose of AZD5055 or placebo on Day 1 and Days 3 to 16, and no dose on Day 2. This is followed by a follow-up visit within 6 ± 1 days after the IMP dose, and an additional follow-up visit within 29 ± 2 days after the last IMP dose.

[0089] For the cohorts on the QD dosing regimen, after the screening period is the treatment period during which the subjects stay in the clinical unit from 1 day before IMP administration (Day -1) until at least 72 hours after the last dose (Day 19). The subjects are dosed for a total of 15 days, receiving a QD morning single dose of AZD5055 or placebo on Day 1 and Days 3 to 16.

[0090] For the cohorts on the BID dosing regimen, after the screening period is the treatment period during which the subjects stay in the clinical unit from 1 day before IMP administration (Day -1) until at least 72 hours after the last dose (Day 19). The subjects are dosed for a total of 15 days, receiving a morning single dose of AZD5055 or placebo on Day 1 and Day 16, and repeating the BID dosing at 12-hour (±30 minutes) intervals from Days 3 to 15.

[0091] For both cohorts, after the treatment period is 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.

[0092] Study Objectives

[0093] Primary Objectives

[0094] Part 1: SAD (Single Ascending Dose) - To evaluate the safety and tolerability of AZD5055 after oral administration of single ascending doses to healthy subjects.

[0095] Part 2: MAD (Multiple Ascending Dose) - To evaluate the safety and tolerability of AZD5055 after oral administration of multiple ascending doses to healthy subjects.

[0096] Secondary Objectives

[0097] Part 1: SAD - To characterize the PK of AZD5055 after oral administration of single ascending doses to healthy subjects.

[0098] Part 2: PK of MAD-characterized AZD5055 after multiple ascending oral doses in healthy subjects.

[0099] Exploratory Objectives

[0100] Part 1: SAD

[0101] · Evaluate target engagement in hair follicles (Cohorts 1 and 2).

[0102] · Evaluate target engagement in whole blood.

[0103] · Assess the effect of AZD5055 on bone turnover biomarkers.

[0104] · Evaluate cardiac safety by 12-lead safety electrocardiogram (ECG) and dECG, including the intent to obtain a TQT surrogate.

[0105] · Evaluate changes in a panel of renal biomarkers in urine if indicated by the 3-month preclinical toxicity study.

[0106] · Investigate the presence of AZD5055 metabolites in plasma and urine and measure metabolite levels. Results will be used to guide future studies of exposure to AZD5055 metabolites.

[0107] Part 2: MAD

[0108] · Evaluate target engagement in skin biopsies.

[0109] · Evaluate target engagement in hair follicles.

[0110] · Evaluate target engagement in whole blood.

[0111] · Explore additional exploratory biomarkers in blood samples.

[0112] · Assess the effect of AZD5055 on bone turnover biomarkers in serum samples after multiple ascending oral doses in healthy subjects.

[0113] · Evaluate cardiac safety by 12-lead safety ECG and dECG, including the intent to obtain a TQT surrogate.

[0114] · Evaluate changes in a panel of renal biomarkers in urine if indicated by the 3-month preclinical toxicity study.

[0115] · Investigate the presence of AZD5055 metabolites in plasma and urine and measure metabolite levels.

[0116] · Assess the effect of AZD5055 on CYP3A (4-β-hydroxy-cholesterol).

[0117] Clinical trials were conducted according to the above - mentioned protocol and can be summarized as follows:

[0118] Major Inclusion Criteria

[0119] The study was conducted in healthy male and female subjects of non - childbearing potential with suitable veins for intubation or repeated venipuncture. The body mass index of the subjects ranged from 18 kg / m 2 to 30 kg / m 2 (including the end values) and the body weight was at least 50 kg. In addition, for the males and females in Part 1 and only the males in Part 2, the subjects were 18 to 55 years of age. For the female subjects in Part 2, the age range was 18 to 49 years, including the end values.

[0120] In Part 1 of the study, three dose levels of AZD5055 were studied in three cohorts. Each cohort consisted of 8 subjects. Within each cohort, 6 subjects were randomly assigned to receive AZD5055 and 2 subjects were randomly assigned to receive placebo. In Part 2 of the study, three dose levels of AZD5055 were studied in three cohorts. In each cohort, 9 subjects were randomly assigned to receive AZD5055 and 3 subjects were randomly assigned to receive placebo. Subjects who had not been experimented on (i.e., those who had not participated in Part 1 of this study) were included in Part 2 of the study. One subject who was randomly assigned to receive AZD5055 in Cohort 1 did not receive AZD5055 treatment and withdrew from the study due to headache.

[0121] Evaluation Criteria

[0122] Safety Variables

[0123] Safety endpoints included adverse events; vital signs (supine blood pressure, pulse, respiratory rate, and body temperature); 12 - lead ECG, 12 - lead dECG, telemetry, physical examination, clinical laboratory evaluations (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).

[0124] Pharmacokinetic Parameters

[0125] Primary PK parameters: C max 、AUC inf and AUC last; Secondary PK parameters: including but not limited to tmax, AUC(0-12) or AUC(0-24) (parameters that are not primary parameters), t 1 / 2 λz, MRTinf, CL / F, Vz / F, Rac, TCP, Ae(t1-t2), fe(t1-t2), and CLR.

[0126] Pharmacodynamic Parameters

[0127] Change in blood 4-β-hydroxy-cholesterol level relative to baseline.

[0128] Statistical Methods

[0129] Determination of Sample Size

[0130] The sample sizes for Parts 1 and 2 of the study were selected to obtain a sufficient assessment of safety and tolerability without exposing an excessive number of subjects to the compound during this clinical development phase. Previous experience in Phase I studies indicated that the sample sizes proposed for Parts 1 and 2 of the study were sufficient to achieve the objectives of the study. To enable a sufficient analysis of the PK and safety of AZD5055, 8 evaluable subjects in the AZD5055 treatment group were selected in Part 2 (MAD) cohorts 1, 2, and 3. 8 evaluable subjects in the placebo group were selected in Part 2 (MAD) cohorts.

[0131] Presentation and Analysis of Safety Data

[0132] All safety data (planned and unplanned) are presented in the data listings. Continuous variables are summarized by treatment using descriptive statistics (n, mean, standard deviation, minimum, median, maximum). Categorical variables are summarized by treatment (Parts 1 and 2) in frequency tables (frequency and proportion). The analysis of safety variables is based on the safety analysis set. Using the Medical Dictionary for Regulatory Activities glossary, adverse events are summarized by System Organ Class (SOC) and Preferred Term (PT). In addition, lists of Serious Adverse Events (SAEs) and Adverse Events Leading to Discontinuation of the IMP (DAEs) were made, and the number of subjects with any Adverse Event (AE), SAE, DAE, and AE of severe intensity was summarized. Adverse events occurring prior to dosing were reported separately. Tables and listings of data for ECG, vital signs, AE, and clinical laboratory tests and measurements were provided.

[0133] Presentation and Analysis of Pharmacokinetic Data

[0134] No formal statistical hypothesis testing was conducted. As appropriate, descriptive statistics (including tables, listings, and graphs) were used alone to descriptively summarize the analysis of safety, tolerability, PK, and PD data by treatment / dose / study day. The preliminary dose proportionality of AZD5055 after the single dose (Day 1) in Parts 1 and 2 and the multiple doses (Day 16) in Part 2 was evaluated graphically and analyzed using the power model approach, with the logarithm of the PK parameter (AUC and C max ) on Day 1 and (AUC(0-τ) and C max ) on Day 16 as the dependent variables and the logarithm of the dose as the independent variable. For the data collected in Part 2, the time-dependence of PK was evaluated by comparing AUC(0-τ) (Day 16) with AUC (Day 1), and accumulation was evaluated by comparing AUC(0-τ) (Day 16) with AUC(0-τ) (Day 1) and comparing C max (Day 16) with C max (Day 1). The linear mixed-effects analysis of variance model used the logarithm of the above PK parameters as the response variable, with treatment, day, and treatment-by-day interaction as fixed effects. Day was considered a repeated effect within subjects.

[0135] Presentation and Analysis of Exploratory Data

[0136] Statistical analysis of plasma 4-β-hydroxy-cholesterol levels at baseline and on the last day of dosing was performed using analysis of covariance with a linear mixed model, with treatment as the fixed effect and the baseline concentration of 4-β-hydroxy-cholesterol as the covariate.

[0137] Protocol Deviations

[0138] A total of 11 significant protocol deviations were reported in 8 subjects. In one part of the study, PK urine measurements were missing for 2 subjects, 1 subject vomited within 2 hours of AZD5055 administration, and 1 subject had another protocol deviation related to urine sample collection. From these subjects, one subject was excluded from the PK analysis set (descriptive and inferential statistics) due to vomiting within 2 hours of AZD5055 administration (at / before 2 times the median tmax). In Part 2 of the study, PK plasma processing had a time-window deviation for 4 subjects, dECG measurements were missing for 2 subjects, and PK urine processing reported a time-window deviation for 1 subject. One subject was excluded from the PK analysis set due to no PK samples being available, and one subject was excluded from the PD set due to no PD samples being available. None of the reported deviations from the protocol affected the interpretation of the study results.

[0139] Results

[0140] Pharmacokinetics

[0141] After administration of an oral suspension of AZD5055 at single ascending doses of 7 mg to 40 mg, AZD5055 was rapidly absorbed. After single and multiple dose administrations, AZD5055 exposure increased approximately proportionally within the test dose range of 5 mg to 40 mg. After multiple daily doses of 5 mg to 20 mg of AZD5055, a similar median range and a similar tmax range of 1.00 to 1.30 hours were observed. The AZD5055 concentration declined in a biphasic manner, with geometric mean terminal half-life values of 9.7 to 11.4 hours after single administration and 12.2 to 17.2 hours after multiple daily administrations of AZD5055. Among subjects, the variability in the peak and extent (C max and AUC) was low (<25%) to moderate (>25%, <40%) respectively. The temporal variation in systemic exposure was expected to be minimal. Minor to moderate accumulation of AZD5055 was observed after repeated daily administration. Renal clearance of AZD5055 accounted for a small fraction of the total clearance of AZD5055. Less than 2.3% of the administered dose was recovered unchanged in urine (as AZD5055).

[0142] Pharmacodynamics

[0143] After 14 days of once-daily dosing of AZD5055, there was no effect on 4-β-hydroxy-cholesterol, indicating that AZD5055 had no significant effect on CYP3A4 activity in healthy subjects.

[0144] Safety

[0145] In Part 1, oral doses of 7 mg, 20 mg, and 40 mg of AZD5055 (n = 6 / dose level) administered as a single-dose oral suspension were well tolerated. In Part 2, AZD5055 was dosed as a single-dose oral suspension at 5 mg QD, 15 mg QD, and 20 mg QD and was well tolerated at all administered doses. These assessments were based on the following:

[0146] Part 1

[0147] · No SAE, death, or AE leading to discontinuation or withdrawal from the study of AZD5055.

[0148] · Overall, 4 (22.2%) subjects in all AZD5055 doses and 1 (16.7%) subject in the combined placebo group experienced at least one AE.

[0149] · There was no obvious trend for AEs by System Organ Class (SOC) or Preferred Term (PT). All AEs in all AZD5055 doses were reported only once.

[0150] · Overall, 3 subjects (16.7%) in all AZD5055 doses and no subjects in the pooled placebo group had at least one AE considered possibly related to AZD5055 as evaluated by the investigator. These AEs included dizziness, ventricular tachycardia, wheezing, upper abdominal pain, vomiting, and nausea.

[0151] · All AEs had a grade 1 (mild) intensity and resolved / subsided by the end of the study.

[0152] · No clinically relevant trends were observed for clinical laboratory results, vital signs, physical examinations, and ECGs.

[0153] Part 2

[0154] · There were no SAEs or deaths.

[0155] · Three AEs led to the discontinuation of AZD5055.

[0156] ο Two subjects receiving the 5 mg AZD5055 dose experienced AEs of grade 2 (moderate) intensity of ventricular tachycardia / non - sustained ventricular tachycardia, both considered possibly related to AZD5055 as evaluated by the investigator.

[0157] ο One subject receiving the 15 mg AZD5055 dose experienced an AE of grade 1 (mild) intensity of coronavirus infection, not considered that coronavirus infection was possibly related to AZD5055 as evaluated by the investigator.

[0158] · Overall, 21 subjects in all AZD5055 doses and 5 subjects in the pooled placebo group experienced at least one AE.

[0159] · There was no obvious trend for A4 by System Organ Class (SOC) or Preferred Term (PT).

[0160] · Most AEs 16 had a grade 1 (mild) intensity, and 5 subjects (among all AZD5055 doses) had AEs of grade 2 (moderate) intensity. All AEs resolved / subsided by the end of the study.

[0161] · A total of 7 AEs across all AZD5055 doses and none in the combined placebo group were considered possibly related to AZD5055 treatment as evaluated by the investigator. These AEs included dysgeusia (1), headache (3), photophobia (1), ventricular tachycardia (2), and breath odor (1).

[0162] · No clinically relevant trends were observed for clinical laboratory results, vital signs, physical examinations, and ECGs.

[0163] Example 2. The Second Clinical Study on Safety, Tolerance and Pharmacokinetics

[0164] The study included a screening period of up to 28 days and 5 cycles during which subjects will participate from Day - 1 of Cycle 1 through 72 hours after the AZD5055 dose in Cycle 5.

[0165] Cycle 1: On Day 1, subjects will receive 5 mg AZD5055 in the form of a 20 - minute IV infusion in the overnight - fasted state (Treatment A) or 20 mg AZD5055 in the form of an oral suspension in the overnight - fasted state (Treatment B).

[0166] Cycle 2: On Day 1 (Study Day 4), subjects will receive 20 mg AZD5055 film - coated tablets in the overnight - fasted state (Treatment C).

[0167] Cycle 3: On Day 1 (Study Day 8), subjects will receive a standardized high - fat breakfast 30 minutes before receiving 20 mg AZD5055 in the form of film - coated tablets (Treatment D).

[0168] Cycle 4: On Study Day 10, rabeprazole 20 mg will be administered twice daily for 3 days prior to Day 1. On Day 1 (Study Day 13), 20 mg AZD5055 film - coated tablets will be administered together with rabeprazole, and rabeprazole administration will continue twice daily (Treatment E).

[0169] Cycle 5: On Day 1 (Study Day 17), participants will receive a low - fat breakfast 30 minutes before 20 mg AZD5055 film - coated tablets are administered together with 20 mg rabeprazole. Rabeprazole will continue twice daily, with the last dose on the evening of Study Day 18 (Treatment F).

[0170] A follow - up visit or phone call will be made approximately 6 days after the last dose of AZD5055 in Cycle 5.

[0171] There will be a minimum washout period of 3 days between AZD5055 dose administrations in Cycle 1 and Cycle 2, and for subsequent study cycles, there will be a minimum washout period of 4 days between AZD5055 dose administrations. Repeated PK (pharmacokinetics) sampling will be performed from before the AZD5055 dosing until 48 hours after dosing in each cycle. After all samples have been collected and all evaluations have been performed, the subject will be discharged on Day 20 of the study (Day 4 of Cycle 5).

[0172] For single oral dose administration, 20 mg of AZD5055 was selected because it was estimated that once-daily dosing of approximately 20 mg would achieve a C 谷 (trough concentration) of 23 nmol / L, thus providing 24-hour coverage that is 3-fold the in vitro IC 50 potency assay. This exposure was predicted to cause >75% PORCN sustained inhibition across the dosing interval. In Example 1, oral doses of 7 mg, 20 mg, and 40 mg of AZD5055 (n = 6 / dose level) administered as a single-dose oral suspension were well tolerated.

[0173] Predicted human intestinal permeability is high, the estimated fraction absorbed is close to 100%, and predicted clearance is low with limited first-pass effect. Based on in vitro data, the predicted oral bioavailability of AZD5055 is 70%. Oral bioavailability observed in several animal species ranges from 40% to 60%. Based on these data, the lower limit of a reasonable value for the oral bioavailability (F) of AZD5055 was selected as 25% or 0.25. Based on the t max (time to reach C max ) observed 1 hour after the oral dose, it was estimated that approximately 75% of the dose was absorbed within 20 minutes. Therefore, a conservative estimate is that after correction for F, the C max after a 20-minute IV infusion is less than 2-fold the oral dose.

[0174] Rabeprazole was administered as an oral dose of 20 mg BID in the morning and evening. Rabeprazole pretreatment for 3 days was required before the administration of AZD5055 to achieve a pH-elevated PD (pharmacodynamics) steady state. In preclinical and clinical studies, the highest usually recommended dose of 20 mg BID did not cause any significant safety issues

[0175] Breakfast

[0176] A high-fat, high-calorie breakfast consists of: 2 fried eggs with butter; 2 strips of bacon; 2 slices of buttered toast; 112 g / 4 oz hash browns; 240 mL / 8 oz whole milk. The test meal may be substituted provided that it supplies a similar amount of calories from protein, carbohydrate, and fat and has an equivalent meal volume and viscosity.

[0177] A low-fat, low-calorie breakfast consists of: 1 hard-boiled egg; 1 packet of flavored instant oatmeal made with water; 240 mL / 8 oz milk (1% fat). The test meal may be substituted provided that it supplies a similar amount of calories from fat and has an equivalent meal volume and viscosity.

[0178] IV Infusion

[0179] Component Amount (per mL) Function AZD5055 0.50 mg Active Pharmaceutical Ingredient Sodium Sulfobutyl Ether β - Cyclodextrin 60 mg Solubilizer Anhydrous Citric Acid 0.55 mg Buffer Sodium Chloride 4.0 mg Tonicity Agent Hydrochloric Acid Q.S. to pH 5 pH Regulator Sodium Hydroxide Q.S. to pH 5 pH Regulator Water for Injection To 1.0 mL Solvent

[0180] Primary Outcome Measures

[0181] · Area under the concentration-time curve (AUC inf ) from time 0 to infinity [Time range: Days 1 to 6, 8 to 10, 13 to 15, 17 to 19]

[0182] · Area under the concentration-time curve (AUC last ) from time 0 to the last quantifiable concentration [Time range: Days 1 to 6, 8 to 10, 13 to 15, 17 to 19]

[0183] · Maximum observed concentration (C max ) [Time range: Days 1 to 6, 8 to 10, 13 to 15,

[0184] 17 to 19]

[0185] o To estimate the relative bioavailability of the AZD5055 film-coated tablet formulation and the AZD5055 oral suspension formulation.

[0186] o To estimate the absolute bioavailability of the AZD5055 oral suspension and the AZD5055 film-coated tablet formulation.

[0187] o To evaluate the effect of the proton pump inhibitor rabeprazole on the PK of AZD5055 alone and in combination with an acid reducer.

[0188] o To evaluate the effect of the proton pump inhibitor rabeprazole on the PK of AZD5055 when AZD5055 is administered with food.

[0189] Secondary Outcome Measures In the time range of Days 1 to 6, 8 to 10, 13 to 15, 17 to 19:

[0190] · Time to reach maximum observed concentration (t max )

[0191] · Terminal elimination rate constant (λz)

[0192] · Terminal elimination half-life (t 1 / 2 λz)

[0193] · Apparent total body clearance (for extravascular administration only) (CL / F)

[0194] · Total body clearance (for intravascular administration only) (CL)

[0195] · Apparent volume of distribution at the end of the dosing interval (for extravascular administration only) (Vz / F)

[0196] · Volume of distribution at the end of the dosing interval (for intravascular administration only) (Vz)

[0197] · Mean residence time (MRT)

[0198] · Absolute bioavailability (calculated as the geometric mean AUCinf of treatment B or treatment C relative to the geometric mean AUCinf of treatment A) (F)

[0199] · Absolute bioavailability (calculated as the geometric mean AUCinf of treatment B or treatment C relative to the geometric mean AUCinf of treatment A) (F rel )

[0200] · Ratio of test treatment to reference treatment based on AUCinf (calculated for treatment D vs treatment C; treatment E vs treatment C; treatment F vs treatment C; treatment F vs treatment E) (R AUC))

[0201] · Ratio of test treatment to reference treatment based on AUC inf (calculated for treatment D vs treatment C; treatment E vs treatment C; treatment F vs treatment C; treatment F vs treatment E) (RC max ))

[0202] ο To estimate the relative bioavailability of the AZD5055 film-coated tablet formulation and the AZD5055 oral suspension formulation.

[0203] ο To estimate the absolute bioavailability of the AZD5055 oral suspension and the AZD5055 film-coated tablet formulation.

[0204] ο To evaluate the effect of food on the pharmacokinetic (PK) parameters of AZD5055 in the fed and fasted states.

[0205] ο To evaluate the effect of the acid reducer rabeprazole on the PK of AZD5055 alone and in combination with an acid reducer.

[0206] ο To evaluate the effect of the acid reducer rabeprazole on the PK of AZD5055 when AZD5055 is administered in the fasting and fed states.

[0207] ο To evaluate the safety after single oral and IV doses of AZD5055 in healthy participants.

[0208] · Number of subjects with adverse events and serious adverse events [Time frame: From screening (-28 days to -2 days) to follow-up (day 23)]

[0209] ο To evaluate the safety after single oral and IV doses of AZD5055 in healthy subjects

[0210] Clinical trials were conducted according to the above protocol and can be summarized as follows:

[0211] Major Inclusion Criteria

[0212] Healthy male and female (non-fertile potential) participants aged 18 to 55 years with a body mass index (BMI) between 18 kg / m2 and 30 kg / m2 (including the endpoints).

[0213] Evaluation Criteria

[0214] Pharmacokinetic parameters - The pharmacokinetic parameters of AZD5055 include but are not limited to Cmax, AUCinf, and AUClast.

[0215] Safety variables - Safety endpoints include adverse events (AE), clinical laboratory evaluations (hematology, clinical chemistry, urinalysis, and urine albumin:creatinine ratio), vital signs and peripheral oxygen saturation (SpO2), standard 12-lead electrocardiogram, (ECG), telemetry, and physical examination.

[0216] Statistical Methods

[0217] Determination of Sample Size

[0218] Approximately 18 healthy participants were recruited to ensure that at least 15 participants completed the Phase 5 study. The proposed sample size is expected to give sufficient information about the effect of the formulation and concomitant therapy on AZD5055 exposure while exposing as few participants as possible to the study procedures. The interpretation of the results is based on the estimated geometric mean ratio (GMR) and the associated 90% confidence interval (CI) between the test and reference for AUC and Cmax.

[0219] Presentation and Analysis of Pharmacokinetic Data

[0220] List the plasma concentrations of each participant at each actual sampling time and summarize by treatment and nominal sampling time using the same descriptive statistics as for the PK parameters. The graphical representation includes 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. The pharmacokinetic variables and diagnostics for the PK analysis are listed, and for all variables except tmax, the PK variables are 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]), and these variables are summarized using n, min, median, and max. To evaluate the absolute and relative bioavailability of AZD5055, the following statistical comparisons are made for the PK analysis set:

[0221] ο AZD5055 film-coated tablets, fasted, C (test) / AZD5055 oral suspension, fasted, B (reference).

[0222] ο AZD5055 film-coated tablets, fasted, C (test) / AZD5055 infusion solution, A

[0223] (reference).

[0224] The analysis is performed using a linear mixed-effects analysis of variance (ANOVA) model, using the natural logarithm of C max , AUC inf and AUC last as the response variables; using sequence, period, and treatment as fixed effects, and participants nested within sequence as random effects. After back-transforming from the logarithmic scale, the geometric means and CIs (two-sided 95%) for C max , AUC inf and AUC last are estimated and presented.

[0225] The results are transformed back to the original scale to give estimates of the true* / geometric standard deviation (gSD) ratios and 90% CIs for these ratios. Additionally, 90% CIs for the differences are calculated and presented.

[0226] To evaluate the effects of food and antacids, the following statistical comparisons are made for the PK analysis set:

[0227] ο AZD5055 film-coated tablets 20 mg, fed state, D (test) / AZD5055 film-coated tablets 20 mg, overnight fasted state, C (reference).

[0228] ο AZD5055 film-coated tablets, taken with rabeprazole after eating, F (test)

[0229] / AZD5055 film-coated tablets, taken with rabeprazole after an overnight fast, E (reference).

[0230] ο AZD5055 film-coated tablets, taken with rabeprazole after an overnight fast, E (test)

[0231] / 20 mg AZD5055 film-coated tablets, in the overnight fasting state, C (reference).

[0232] ο AZD5055 film-coated tablets, taken with rabeprazole after eating, F (test)

[0233] / 20 mg AZD5055 film-coated tablets, in the overnight fasting state, C (reference).

[0234] The linear mixed-effects ANOVA model was used to evaluate the effects of food and acid reducer on the PK of AZD5055, with treatment, period, and sequence as fixed effects, and participants nested within sequence as random effects. The natural logarithm-transformed C max , AUC last and AUC inf were used for this analysis. After back-transforming from the logarithmic scale, the geometric means and CIs (two-sided 95%) of C max , AUC last and AUC inf were calculated and presented. In addition, the ratios of geometric means and CIs (two-sided 90%) were estimated and presented for treatment comparisons (i.e., AZD5055 under fed conditions vs. AZD5055 under fasting conditions).

[0235] Presentation and Analysis of Safety Data

[0236] 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 proportion) by treatment / dose group. The analysis of safety variables was based on the safety analysis set.

[0237] Protocol Deviations

[0238] Two participants in the treatment sequence ACDEF had two major protocol deviations, and three participants in the treatment sequence BCDEF had four major protocol deviations. No major protocol deviations were assumed to affect any of the pre-specified endpoints. Therefore, no participants with major protocol deviations were excluded from any of the analysis sets.

[0239] Results

[0240] Pharmacokinetic Results

[0241] ·Based on AUC inf and AUC last ,the absolute bioavailability of the film-coated tablets was approximately 66% and 64%. The C max of the film-coated tablets was approximately 21% of the IV dose.

[0242] ·Based on AUC inf and AUC last ,the total systemic exposure to AZD5055 after administration of the film-coated tablets was comparable to that after administration of the oral suspension. However, C max was approximately 35% lower.

[0243] ·When administered in the fed state, compared to fasting, the exposure to AZD5055 based on C max , AUC last and AUC inf increased between 22% and 32%. However, when administered with rabeprazole, food did not affect the total systemic exposure to AZD5055, and food increased C max by approximately 17% compared to fasting administration of rabeprazole.

[0244] ·When administered with rabeprazole in the fasting state, compared to AZD5055 alone in the fasting state, the total systemic exposure (AUC inf and AUC last ) did not change. However, C max decreased by 32%.

[0245] ·When administered with rabeprazole in the fed state, compared to AZD5055 alone in the fasting state, the total systemic exposure (AUC inf and AUC last ) did not change. However, C max decreased by 20%.

[0246] Safety Results

[0247] No major safety or tolerability issues were identified in this study, and AZD5055 was generally well tolerated. This assessment was based on the following:

[0248] ·There were no deaths in this study. One participant experienced an SAE in cycle 3. The SAE was evaluated by the investigator as possibly related to AZD5055 (increased transaminases).

[0249] · Two participants experienced AEs (2 events), resulting in the discontinuation of AZD5055 after dosing in Cycle 3 (increased transaminases and non - cardiac chest pain).

[0250] · Overall, 11 participants experienced any AE (20 events) during the study.

[0251] Five participants experienced any AE (9 events) evaluated by the investigator as possibly related to AZD5055.

[0252] · A total of 8 participants reported at least 1 AE of Grade 1 intensity, and 4 participants reported at least 1 AE of Grade 2 intensity. No Grade 3 or higher - grade AEs were reported.

[0253] · No clinically relevant trends were observed for laboratory parameters, vital signs, ECG, or physical examinations.

[0254] · The coronavirus disease 2019 (COVID - 19) pandemic did not affect the overall safety results of this study.

[0255] References

[0256] Numerous publications are cited above. The complete citations for these references are provided below. The entire contents of each of these references are incorporated herein.

[0257]

[0258]

Claims

1. A method for treating interstitial lung disease in a subject in need thereof, the method comprising orally administering to the subject 2-[4-(2-methyl-4-pyridinyl)pyrrolo[3,2-c]pyridin-1-yl]-N-(5-pyrazin-2-yl-2-pyridinyl)acetamide (AZD5055): in a dose between 5 mg / day and 35 mg / day.

2. The method according to claim 1, wherein the daily dose is between 10 mg / day and 30 mg / day.

3. The method according to claim 1 or claim 2, wherein the daily dose is between 15 mg / day and 25 mg / day.

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

5. The method according to 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. The method according to claim 1, wherein the daily dose is about 5 mg / day.

7. The method according to claim 1, wherein the daily dose is about 15 mg / day.

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

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

10. The method according to any one of claims 1 to 9, wherein AZD5055 is administered continuously during the treatment cycle.

11. The method according to any one of claims 1 to 10, wherein AZD5055 is taken on an empty stomach, without eating two hours before and one hour after.

12. The method according to any one of claims 1 to 10, wherein AZD5055 is taken with food.

13. The method according to any one of claims 1 to 12, the method further comprising separately, sequentially or simultaneously administering a proton pump inhibitor or a pharmaceutically acceptable salt thereof.

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

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

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

17. An oral dosage unit comprising 2-[4-(2-methyl-4-pyridyl)pyrrolo[3,2-c]pyridin-1-yl]-N-(5-pyrazin-2-yl-2-pyridyl)acetamide (AZD5055): in an amount between 2.5 mg and 35 mg.

18. The oral dosage unit according to claim 17, the oral dosage unit comprising a daily dose of AZD5055 as defined in any one of claims 1 to 7.

19. The oral dosage unit according to claim 17, the oral dosage unit comprising half of the daily dose of AZD5055 as defined in any one of claims 1 to 7.

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

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

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

23. The oral dosage unit according to 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. The oral dosage unit according to claim 23, wherein a diluent is present, and the diluent is a sugar or sugar-containing, other than mannitol, or an inorganic compound.

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

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

27. An oral dosage unit according to claim 26, wherein the compression aid is dicalcium phosphate.

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

29. An oral dosage unit according to any one of claims 23 to 28, wherein there is a lubricant / glidant and the lubricant / glidant is glyceryl behenate.

30. An oral dosage unit according to claim 29, wherein the lubricant / glidant is between 2% and 15% by weight of the tablet core.

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

32. An oral dosage unit according to claim 31, wherein the disintegrant is sodium carboxymethylcellulose cross-linked.

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

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

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