CN118302167A - Novel oral pharmaceutical compositions and dosage regimens for the treatment of progressive fibrotic interstitial lung disease - Google Patents

Abstract

The present invention relates to an oral pharmaceutical composition consisting essentially of a PDE4B inhibitor of formula III in a dose of 18mg or 9mg and optionally one or more pharmaceutically acceptable carriers or excipients, for use in the treatment of a patient suffering from one or more progressive fibrotic interstitial lung diseases (PF-ILD), wherein this oral pharmaceutical composition is administered to the patient twice daily. The invention further relates to oral pharmaceutical compositions comprising a dose of 18mg or 9mg of the PDE4B inhibitor of formula III and a therapeutically effective dose of a second active ingredient selected from the group consisting of nintedanib (nintedanib) or pirfenidone (pirfenidone), wherein the oral pharmaceutical compositions are administered to the patient twice daily.

Description

Novel oral pharmaceutical compositions and dosage regimens for the treatment of progressive fibrotic interstitial lung disease

1. Background of the invention

1.1 Phosphodiesterases and their role in fibrosis

Phosphodiesterase (PDE) mediates the hydrolysis of the second messenger cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate. PDE is encoded by a superfamily of 11 genes containing multiple genes (encoding subtype A, B, C, etc.) that also produce alternative mRNA splice variants, resulting in approximately 100 PDE isoforms. PDE4 has traditionally been associated with modulation of inflammation and modulation of immunocompetent cells, and the three selective PDE4 inhibitors currently available support the beneficial effects of PDE4 inhibitors in inflammatory and/or autoimmune diseases (Sakkas et al, 2017, curr. Med. Chem.24,3054-3067; li et al, 2018, front. Pharmacol.9, 1048). Oral roflumilast (roflumilast) as a PDE4 inhibitor of the first class Approval by the U.S. food and drug administration (u.s.food and Drug Administration) was obtained in 2011 for reducing the risk of exacerbation of COPD in patients with severe COPD associated with chronic bronchitis and having a history of exacerbations (U.S. food and drug administration, 2013,(Roflumilast)). Another compound, namely oral apremilast (apremilast)In 2014, has been approved for the treatment of psoriatic arthritis and plaque psoriasis (U.S. food and drug administration, 2017,(Apremilast)). Third PDE4 inhibitor, clenbuterol (crisaborole)Topical treatment of mild to moderate atopic dermatitis was approved in 2016 (U.S. food and drug administration, 2016, eucrisa ^TM (kriboro)). None of these drugs exhibited any preferential enzyme inhibition in the four PDE4 subtypes a-D.

Taking roflumilast as an example, the general anti-inflammatory capacity of PDE4 inhibition has been well documented (Hatzelmann et al, 2010, pulm. Pharmacol. Ther.23, 235-256), and the use of PDE4 inhibitors in a variety of inflammatory and immune mediated diseases has been widely investigated (Sakkas et al, 2017, curr. Med. Chem.24,3054-3067; li et al, 2018, front. Pharmacol.9, 1048). However, over the last decade, it has become increasingly clear that PDE4 may also play an important role in fibrosis based on animal studies and in vitro experiments assessing the functional role of PDE4 inhibitors in fibroblasts. The attenuation of pulmonary fibrosis by PDE4 inhibitors has been demonstrated under a variety of experimental conditions, the most widespread being bleomycin (bleomycin) -induced rodent fibrosis. Rolipram (rolipram) was shown to inhibit fibrosis score, hydroxyproline content and serum tumor necrosis factor-alpha (TNF-alpha) in a rat model (Pan et al, 2009,Respirology 14,975-982). In this preliminary study PDE4 inhibitors were administered since the onset of bleomycin challenge, and it is therefore not clear whether rolipram was active primarily due to inhibition of initial inflammation or inhibition of secondary fibrosis. However, a second early study in mice and rats showed that oral roflumilast has dose-dependent activity in both prophylactic and therapeutic regimens (Cortijo et al, 2009, br.j. Pharmacol.156, 534-544). In lung extracts roflumilast inhibited histologically assessed mRNA expression of fibrosis, hydroxyproline content, TNF- α, transforming growth factor- β (TGF- β), connective Tissue Growth Factor (CTGF), α1 collagen, endothelin-1 and mucin 5 ac. In bronchoalveolar lavage fluid (BALF), TNF- α, interleukin (IL) -13, TGF- β and mucin 5ac levels, lipid hydroperoxide formation and inflammatory cell (e.g., neutrophils and macrophages) influx are inhibited. In addition to fibrosis, right ventricular hypertrophy and vascular remodeling (pulmonary artery) are positively affected by roflumilast. The same group also demonstrated later that the metabolites associated with pulmonary fibrosis in bleomycin mice were regulated by roflumilast. Roflumilast reduces the content of the Amino Acids (AA) glycine and proline involved in collagen formation/structure, while pulmonary glutathione and plasma tetrahydrobiopterin increase, indicating that roflumilast alters oxidative balance (Milara et al, 2015,PLoS One 10,e0133453). Cilomilast (cilomilast), another PDE4 inhibitor, was shown to inhibit advanced pulmonary fibrosis and tended to reduce collagen levels in bleomycin mice, although no effect on TGF- β1 and collagen type (Col) 1A1 expression was found (Udalov et al, 2010,BMC Pulm.Med.10,26).

The improvement of pulmonary fibrosis by inhibition of PDE4 is not limited to the bleomycin model. In murine models in which murine pulmonary fibrosis of mice expressing the transgene diphtheria toxin receptor under the control of the murine surfactant protein C promoter targets type II alveolar epithelial cells, roflumilast reduced lung hydroxyproline content, mRNA expression of TNF- α, fibronectin (FN) and CTGF (Sisson et al, 2018, physiol. Rep.6, e 13753). Interestingly, roflumilast is active in both prophylactic and therapeutic therapies and appears to be therapeutically equivalent to pirfenidone (pirfenidone) and nilotic (nintedanib) under therapeutic therapy conditions. Furthermore, oral roflumilast can reduce pulmonary fibrosis in a chronic graft versus host disease mouse model (Kim et al 2016, exp. Hematol.44,332-341. E334). Roflumilast inhibits fibrosis, collagen deposition, hydroxyproline and TGF-beta 1 content, cellular infiltration, and mRNA expression of IL-6 and IL-1 beta. In addition, in BALF inflammatory cells (macrophages, lymphocytes, neutrophils and eosinophils), mRNA expression of IL-6, IL-1. Beta. And mononucleotidyl chemotactic protein-1 was inhibited by roflumilast. In the rabbit tuberculosis model, lung injury and fibrosis are inhibited by two PDE4 inhibitors from Celgene, namely CC-3052 (Subbian et al, 2011, am. J. Pathol.179, 289-301) and CC-11050 (Subbian et al, 2016,EBioMedicine 4,104-114). PDE4 inhibition improves antibiotic therapy and pulmonary fibrosis by positively affecting collagen deposition and mRNA expression of various matrix metalloproteinases, including metalloproteinase 12.

In addition to the lung, the beneficial effects of PDE4 inhibition on fibrosis have been demonstrated in several other organs, including skin, liver, kidney and colon. For example, rolipram and apremilast inhibited bleomycin or topoisomerase I induced skin fibrosis and chronic graft versus host disease in various preclinical mouse models of SSc (Maier et al, 2017, ann. Rheum. Dis.76, 1133-1141). This group did not find direct inhibition of PDE4 inhibition of the release of pro-fibrotic cytokines (IL-6, IL-13, TGF- β1/β2) from fibroblasts purified from peripheral blood of SSc patients and M2 macrophages, possibly due to the lack of exogenous cAMP triggers under the experimental conditions used. Rolipram was shown to inhibit renal interstitial fibrosis in a mouse unilateral ureteral occlusion-induced obstructive renal disease model (Ding et al 2017,Antioxid.Redox Signal.29,637-652). TGF-beta up-regulates PDE4A/B in vitro mouse primary tubular epithelial cells, and rolipram inhibits TGF-beta induced injury, FN expression, and granulosomal production defects. Roflumilast inhibits diethylnitrosamine-induced liver fibrosis, hydroxyproline deposition, and TGF-beta 1 expression in rats (Essam et al 2019,Life Sci.222,245-254). Likewise rolipram inhibits collagen deposition, α -smooth muscle actin (α -SMA) staining and mRNA expression, as well as TGF- β1mRNA and TNF- α protein expression, and PDE4A, B and D up-regulation in a bile duct ligation induced rat liver fibrosis model (Gobejishvili 2019). Rolipram inhibits the mRNA expression of alpha-SMA and Col1A2 in hepatic stellate cells in vitro (Gobejishvili et al, 2013, J.Pharmacol. Exp. Ther.347, 80-90). rolipram inhibits collagen and TGF- β1 in a trinitrobenzenesulfonic acid-induced rat colitis model for colonic tissue (Videla et al, 2006, j. Pharmacol.exp. Thor. 316, 940-945), and apremilast inhibits colonic fibrosis, collagen deposition and expression of fibrosis-related genes in a dextran sodium sulfate-induced mouse ulcerative colitis model (Li et al, 2019, br. J. Pharmacol.176, 2209-2226). Rolipram inhibits fibrotic responses in murine cecal abrasion models, suggesting that PDE4 inhibition may prevent intra-abdominal adhesions after surgery (Eser et al, 2012,Dis.Colon Rectum 55,345-350). adhesion is assumed to be caused by abnormal healing by laparotomy. To support this hypothesis, rolipram has been demonstrated to be active in the mouse subcutaneous or intraperitoneal polyether-polyurethane sponge implant model by inhibiting collagen and TGF- β1 deposition in the implant (Mendes et al, 2009, microvasc. Res.78, 265-271). Thus, in various animal models, the beneficial effects of selective PDE4 inhibition on fibrosis have been demonstrated, most widely occurring in the lung, but also in several other organs. While the specific objective of PDE4 inhibitors in fibrotic diseases is largely unknown, it is readily speculated that they act indirectly via inhibition of pro-inflammatory cells and mediators, and/or directly by inhibition of effector cells (fibroblasts, myofibroblasts) typical of mediated fibrosis.

Direct modulation of various fibroblast functions by PDE4 inhibitors has been demonstrated in human fibroblast lines. Kohyama et al demonstrate the direct effect of PDE4 inhibitors on fibroblasts in vitro (Kohyama et al 2004, clin. Immunol.111, 297-302). Rolipram and cilomilast inhibit FN-induced chemotaxis and contraction of collagen gels in human fetal lung fibroblasts (HFL-1). In the presence of PDE4 inhibitors, the inhibition of fibroblast function by prostaglandin E2 (PGE 2) shifts to the left, while the inhibition of endogenous PGE2 by indomethacin (indomethacin) reduces its effect (Kohyama et al, 2002,Am.J.Respir.Cell Mol.Biol.26,694-701). Inhibition of the function of the fibroblast cell line HFL-1 by cilomilast may be regulated by cytokines such as IL-1β (which up-regulates PGE2 and moves cilomilast curve to the left) or IL-4 (which down-regulates PGE2 and cilomilast curve to the right). The inhibition of HFL-1 function (FN stimulated chemotaxis and collagen gel contraction) by rolipram and roflumilast depends on the expression of cyclooxygenase 2 and the subsequent synthesis of PGE2 (Kohyama et al, 2002,Am.J.Respir.Cell Mol.Biol.26,694-701). Furthermore, TGF- β1 stimulated FN release is inhibited by PDE4 inhibitors while PGE2 release is stimulated as a positive feedback mechanism (Togo et al, 2009,Am.J.Physiol.Lung Cell Mol.Physiol.296,L959-L969). In another human fetal lung fibroblast cell line (GM 06114), roflumilast N-oxide (active metabolite of roflumilast) was shown to inhibit TNF- α stimulated intercellular adhesion molecule-1 and eosin release in the presence of PGE2, and basic fibroblast growth factor (bFGF) plus IL-1β stimulated proliferation, and TGF- β1 induced expression of α -SMA, CTGF and FN mRNA in the presence of IL-1β (Sabatini et al, 2010, pulm. Pharmacol. Ther.23, 283-291). Importantly, IL-1β up-regulates PDE4 activity.

In Normal Human Lung Fibroblasts (NHLF), the effects of PDE4 inhibitors have been described in a number of publications. TGF- β induced conversion of fibroblasts to myofibroblasts assessed by α -SMA expression showed inhibition by plasamite (piclamilast) in the presence of PGE2 (Dunkern et al, 2007, eur. J. Pharmacol.572, 12-22). In the subsequent papers, the same group showed the inhibition of IL-1. Beta. And bFGF stimulated fibroblast proliferation by piramipst and the importance of cyclooxygenase-2 and PGE2 (Selige et al, 2010, J.cell. Physiol.223, 317-326). PDE4B and PDE4A were shown to be involved in this response, and PDE4B and PDE4D were shown to be involved in TGF- β induced α -SMA expression (Selige et al, 2011, J.cell.Physiol.226, 1970-1980). Inhibition of TGF- β1-induced expression of CTGF mRNA and α -SMA protein by roflumilast in the presence of the long-acting β2-adrenergic agonist indacaterol (indacaterol) confirms the importance of cAMP triggers for regulating fibroblast function through PDE4 inhibition (TANNHEIMER et al 2012, respir. Res.13, 28). In addition, bleomycin or various other NHLF reactions stimulated by 8-epi-PGF2α (collagen synthesis, proliferation, active oxygenate and F2-isoprostane formation, NADPH oxidase 4 expression) are inhibited by roflumilast N-oxide (Vecchio et al, 2013,Mediators Inflamm.2013,745984). In another human lung fibroblast model (WI-38), TGF-beta induced mRNA expression of collagen alpha 1, CTGF and FN was inhibited by roflumilast and another PDE4 inhibitor (Compound 1) (Sisson et al, 2018, physiol. Rep.6, e 13753), and a dual selective PDE4/5 inhibitor (Compound A) (Muraki et al, 2019, biosci. Biotechnol. Biochem.83, 1000-1010) in the presence of forskolin (adelin).

Thus, a number of in vitro studies have shown that PDE4 inhibitors are capable of directly inhibiting various fibroblast functions, where endogenous or exogenous cAMP triggers are useful in the test system. While the availability of cAMP agonists may be limited under artificial in vitro conditions, it is expected that cAMP agonists, such as PGE2, adenosine, histamine or epinephrine, may be formed in diseased (inflamed, fibrotic) tissues. The importance of PDE4 under such conditions may be further enhanced by up-regulation of PDE4 activity by cytokines such as IL-1 beta.

Another interesting aspect of regulation of fibrosis, namely epithelial-mesenchymal transition, was studied in the in vitro TGF- β1 stimulated A549 human alveolar epithelial cell line. TGF-. Beta.1 stimulates up-regulation of PDE4 isoforms (PDE 4A and 4D), whereas rolipram and siRNA inhibit changes in epithelial-mesenchymal transition, such as FN and collagen mRNA expression, but not alpha-SMA mRNA (Kolosionek et al, 2009,Mol.Biol.Cell 20,4751-4765).

1.2 Progressive fibrotic interstitial lung disease (PF-ILD)

Interstitial Lung Disease (ILD) comprises a group of heterogeneous lung diseases affecting the interstitium, unlike obstructive airway diseases such as asthma or Chronic Obstructive Pulmonary Disease (COPD). Long term ILD may lead to pulmonary fibrosis, but this is not always the case. The most widely studied ILD is Idiopathic Pulmonary Fibrosis (IPF), characterized by progressive pulmonary fibrosis. non-IPF ILDs may include ILDs associated with connective tissue diseases such as those associated with rheumatoid arthritis and other autoimmune diseases, systemic sclerosis (SSc-ILDs) and polymyositis/dermatomyositis, as well as those associated with chronic sarcoidosis, chronic allergic pneumonia, idiopathic nonspecific interstitial pneumonia, and exposure related diseases such as asbestos lung and silicosis (Cottin et al eur. Respir. Rev.28,180100; kolb, m. and Vasakova, m. (2019), respir. Res.20, 57). Up to 40% of ILD patients may develop a progressive fibrotic phenotype.

Progressive fibrotic ILD is associated with high mortality rates with a median post-diagnosis survival estimate of 2-5 years in IPF patients (Raghu, g., chen, s.y., yeh, w.s., maroni, b., li, q, lee, y.c., and Collard,H.R.(2014).Idiopathic pulmonary fibrosis in US Medicare beneficiaries aged 65years and older:incidence,prevalence,and survival,2001-11.Lancet Respir.Med.2,566-572). progression of fibrotic ILD reflected in various parameters including decreased lung function, decreased motor ability, deteriorated quality of life, cough and dyspnea, acute exacerbation and increased morphological abnormalities (Cottin et al, eur. Rev.28,180100,2019; kolb and Vasakova,2019, respir. 20, 57.) in IPF patients, with a force-activated (FVC) mortality predictor, and with an acute exacerbation associated with extremely high mortality rates, while corticoid and/or immunosuppressive drugs are sometimes used outside of single approval to treat progressive fibrotic ILD, slowing down current follow-up therapies for f-up as well as flunii.p.v. 28,180100,2019, kolb and Vasakova,2019, respir. 20, 57) in IPF patients, with a unique approval for advanced treatment of flunix disease (e. 35, 2014, U.35, 2014),(Nintedanib)), and was approved in europe and japan since 2015 (European medicines agency (European MEDICINES AGENCY), 2021b,(Nifanib)), whereas pirfenidone was approved in japan in 2008, was approved in europe in 2011 (european drug administration, 2021a, esbriet (pirfenidone)), and was approved in the united states in 2014 (united states food and drug administration, 2019,(Pirfenidone)). Lung transplantation is the only treatment that is possible for curing IPF, and the medical need for IPF and other progressive fibrotic ILDs remains high.

However, for patients with IPF with mild or moderate impaired FVC (50% predictive value), both the currently approved drugs pirfenidone and nilamide only reduce FVC decline, consistent with a slowing of disease progression, but neither can stop or even reverse or cure the symptoms of IPF (Tzouvelekis et al Ther. Clin. Risk Management 2015,11,359-370).

Nevertheless, both treatment options with pirfenidone or with nilotic showed significant beneficial effects in slowing the progression of IPF disease.

The most significant side effects associated with nilotic and pirfenidone are gastrointestinal events, particularly diarrhea, nausea, vomiting, abdominal pain, loss of appetite and weight. If gastrointestinal side effects occur, management is generally by discontinuing therapy, reducing doses, or symptomatic treatment of gastrointestinal side effects (see Mazzei et al, ther. Adv. Respir. Dis.2015, volume 9 [3], pages 121-129).

Because of these "additive gastrointestinal side effects" of pirfenidone on the one hand and nilamide on the other hand, it is not common to use a combination of pirfenidone and nilamide for the combination treatment of IPF. Studies have shown that combined treatment with pirfenidone and nidazole results in increased gastrointestinal side effects, especially diarrhea, nausea, vomiting and upper abdominal pain (Vancheri et al, ,nintedanib with Add-on pirfenidone in Idiopathic Pulmonary Fibrosis:Results of the INJOURNEY Trial.Am J Respir Crit Care Med.2017,, preprinted electronic version).

Thus, since the two active agents pirfenidone and nilamide for treating IPF, which have been approved heretofore, do not prevent or cure IPF when administered alone, but only slow the progression of IPF disease to a certain percentage (Tzouvelekis et al, cher. Risk Management 2015,11,359-370), and since nilamide and pirfenidone additionally exhibit significant gastrointestinal side effects, which accumulate when the two compounds are combined, there remains a significant medical need for improved methods of IPF/PF-ILD treatment, particularly improved methods of IPF/PF-ILD treatment, which combine improved therapeutic efficacy (compared to standard care treatment) with acceptable tolerability/safety (particularly in terms of gastrointestinal side effects).

1.3 Patent literature

In addition to the approved PDE4 inhibitors roflumilast and apremilast, there are a number of patent applications based on other PDE4 inhibitors with improved properties that have been published:

pteridines as PDE4 inhibitors in WO 2006/056607, WO 2006/058869, WO 2006/058868 and WO 2006/058867.

Piperazine as PDE4 inhibitor in WO 2006/111549, WO 2007/118793 and WO 2009/050242And dihydrothienopyrimidines.

Piperidinedihydrothienopyrimidines as PDE4 inhibitors in WO 2009/050248 and WO 2013/026797.

PDE 4-inhibitors having the formula: i is a kind of

Formula II

And in particular of formula III

Which is the R-enantiomer of the compound of formula II,

Have been disclosed in WO 2013/026797. PDE4 inhibitors of formulas I, II and III have been shown to preferentially inhibit PDE4B subtype.

WO2019/081235 discloses a combination of nildanib and a PDE4 inhibitor of formula III, which shows a synergistic overadditive effect on fibroblast proliferation in an in vitro assay using human lung fibroblasts.

Thus, neither WO 2013/026797 nor WO 2019/081235 discloses oral compositions and/or dosage regimens of PDE4 inhibitors of formula III that combine both: excellent therapeutic efficacy (alone and in combination with standard of care therapy, either nidanib therapy or pirfenidone therapy) and acceptable tolerability/safety profile for human PF-ILD/IPF patients, particularly acceptable adverse gastrointestinal events/side effects.

However, only oral compositions with dosages and dosage regimens combining both of the following can cause sufficient patient compliance and provide successful PF-ILD/IPF treatment by the patient: on the one hand, satisfactory therapeutic efficacy is achieved for the treatment of PF-ILD, preferably IPF, and on the other hand acceptable tolerability/safety.

Accordingly, the problem of the present invention is to provide an oral composition comprising a PDE4 inhibitor of formula III in a suitable dose and dosage regimen, which combines both: satisfactory therapeutic efficacy for treating PF-ILD patients, preferably IPF patients, will result in an acceptable tolerability/safety profile of adequate patient compliance.

This problem of the present invention is solved by the results of a 12 week clinical trial (phase II) in an IPF patient which evaluates the efficacy, safety and tolerability of the PDE4 inhibitor of formula III alone or in combination with standard of care IPF treatment (with either nidulans or pirfenidone), thereby yielding a novel oral pharmaceutical composition comprising the PDE4 inhibitor of formula III

The dosage is 18mg or 9mg for use in the treatment of a patient with PF-ILD, preferably for use in the treatment of a patient with IPF, wherein the oral pharmaceutical composition is administered twice daily (b.i.d.), or preferably for use in the treatment of a patient with PF-ILD.

In a preferred embodiment, the PDE4 inhibitor of formula III is administered to PF-ILD patients, preferably to IPF patients, at a dose of 18mg twice daily.

Disclosure of Invention

2.1 Detailed description of the invention.

In a first aspect, the present invention relates to an oral pharmaceutical composition comprising a PDE4B inhibitor of formula III

A dose of 18mg or 9mg for use in the treatment of one or more progressive fibrotic interstitial lung diseases (PF-ILD), wherein the oral pharmaceutical composition is administered to a patient twice daily.

In a preferred embodiment, the PDE4 inhibitor of formula III is administered to PF-ILD patients, preferably to IPF patients, at a dose of 18mg twice daily.

In a preferred embodiment of the above oral pharmaceutical composition, the one or more progressive fibrotic interstitial lung diseases (PF-ILD) is Idiopathic Pulmonary Fibrosis (IPF).

In a further preferred embodiment of the above oral pharmaceutical composition, the oral pharmaceutical composition is a film coated tablet.

In another aspect, the present invention relates to an oral pharmaceutical composition consisting essentially of:

PDE4B inhibitors of formula III

The dosage is 9mg

Optionally one or more pharmaceutically acceptable carriers or excipients

For use in treating a patient suffering from one or more progressive fibrotic interstitial lung diseases (PF-ILD), more preferably suffering from Idiopathic Pulmonary Fibrosis (IPF), wherein the oral pharmaceutical composition is administered to the patient twice daily.

In a more preferred embodiment, the present invention relates to an oral pharmaceutical composition consisting essentially of:

PDE4B inhibitors of formula III

The dosage is 18mg

Optionally one or more pharmaceutically acceptable carriers or excipients

For the treatment of one or more progressive fibrotic interstitial lung diseases (PF-ILD), more preferably for the treatment of Idiopathic Pulmonary Fibrosis (IPF), wherein the oral pharmaceutical composition is administered to a patient twice daily.

Accordingly, these oral pharmaceutical compositions consist essentially of a PDE4B inhibitor of formula III in a dose of 18mg or 9mg and optionally one or more pharmaceutically acceptable carriers or excipients, administered twice daily, preferably as film coated tablets.

In another preferred embodiment, the present invention relates to an oral pharmaceutical composition comprising

PDE4B inhibitors of formula III as the sole active agent,

The dosage is 9mg

Optionally one or more pharmaceutically acceptable carriers or excipients

For use in treating a patient suffering from one or more progressive fibrotic interstitial lung diseases (PF-ILD), more preferably suffering from Idiopathic Pulmonary Fibrosis (IPF), wherein the oral pharmaceutical composition is administered to the patient twice daily.

In another preferred embodiment, the present invention relates to an oral pharmaceutical composition comprising

PDE4B inhibitors of formula III as sole active agents

The dosage is 18mg

Optionally one or more pharmaceutically acceptable carriers or excipients

For use in treating a patient suffering from one or more progressive fibrotic interstitial lung diseases (PF-ILD), more preferably suffering from Idiopathic Pulmonary Fibrosis (IPF), wherein the oral pharmaceutical composition is administered to the patient twice daily.

Accordingly, these oral pharmaceutical compositions comprising a PDE4B inhibitor of formula III as the sole active agent at a dose of 9mg or 18mg as described above, optionally with one or more pharmaceutically acceptable carriers or excipients, are preferably film coated tablets.

In a second aspect, the invention relates to the use of a PDE4B inhibitor of formula III

For the manufacture of an oral pharmaceutical composition consisting essentially of 18mg or 9mg and optionally one or more pharmaceutically acceptable carriers or excipients, for use in the treatment of a patient suffering from progressive fibrotic interstitial lung disease (PF-ILD), wherein the oral pharmaceutical composition is administered to the patient twice daily.

In a preferred embodiment of the above use, the PDE4B inhibitor of formula III is administered to PF-ILD patients, preferably to IPF patients, at a dose of 18mg twice daily.

In a preferred embodiment of the use of a PDE4B inhibitor of formula III as described above for the manufacture of an oral pharmaceutical composition consisting essentially of a dose of PDE4B inhibitor of formula III of 18mg or 9mg and optionally one or more pharmaceutically acceptable carriers or excipients, for the treatment of a patient suffering from PF-ILD, the progressive fibrotic interstitial lung disease (PF-ILD) being Idiopathic Pulmonary Fibrosis (IPF).

In a further preferred embodiment of the use of a PDE4B inhibitor of formula III as described above for the manufacture of an oral pharmaceutical composition consisting essentially of a dose of PDE4B inhibitor of formula III of 18mg or 9mg and optionally one or more pharmaceutically acceptable carriers or excipients for the treatment of a patient suffering from PF-ILD, the oral pharmaceutical composition is a film coated tablet.

In a third aspect, the present invention relates to an oral pharmaceutical composition comprising

18Mg or 9mg of PDE4B inhibitors of the formula III

Therapeutically effective doses of Nidamib, and

Optionally one or more pharmaceutically acceptable carriers or excipients

For use in treating a patient suffering from progressive fibrotic interstitial lung disease (PF-ILD), wherein the oral pharmaceutical composition is administered to the patient twice daily.

In a preferred embodiment, the present invention relates to an oral pharmaceutical composition comprising

18Mg or 9mg of PDE4B inhibitors of the formula III

And

150Mg of Nidaminib, and

Optionally one or more pharmaceutically acceptable carriers or excipients

For use in treating a patient suffering from progressive fibrotic interstitial lung disease (PF-ILD), wherein the oral pharmaceutical composition is administered to the patient twice daily.

In another preferred embodiment, the present invention relates to an oral pharmaceutical composition comprising

18Mg or 9mg of PDE4B inhibitors of the formula III

And

100Mg of Nidaminib, and

Optionally one or more pharmaceutically acceptable carriers or excipients

For use in treating a patient suffering from progressive fibrotic interstitial lung disease (PF-ILD), wherein the oral pharmaceutical composition is administered to the patient twice daily.

In another preferred embodiment of the above oral pharmaceutical composition, the progressive fibrotic interstitial lung disease (PF-ILD) to be treated is Idiopathic Pulmonary Fibrosis (IPF).

In a fourth aspect, the invention relates to the use of a PDE4B inhibitor of formula III

For the manufacture of an oral medicament comprising 18mg or 9mg of a PDE4B inhibitor of formula III, in combination with a separate oral medicament comprising a therapeutically effective dose of nilamide cloth as background treatment, for the treatment of a patient suffering from progressive fibrotic interstitial lung disease (PF-ILD), wherein the oral medicament comprising 18mg or 9mg of a PDE4B inhibitor of formula III is administered to the patient twice daily.

In a preferred embodiment, the invention relates to the use of PDE4B inhibitors of formula III

For the manufacture of an oral medicament comprising 18mg or 9mg of a PDE4B inhibitor of formula III, for use in combination with a separate oral medicament comprising 150mg of nilamide for the treatment of a patient suffering from progressive fibrotic interstitial lung disease (PF-ILD), as background treatment, wherein the oral medicament comprising the PDE4B inhibitor of formula III is administered to the patient twice daily.

In another preferred embodiment, the invention relates to the use of PDE4B inhibitors of formula III

For the manufacture of an oral medicament comprising 18mg or 9mg of a PDE4B inhibitor of formula III, for use in combination with a separate oral medicament comprising 100mg of nilamide for the treatment of a patient suffering from progressive fibrotic interstitial lung disease (PF-ILD), as background treatment, wherein the oral medicament comprising the PDE4B inhibitor of formula III is administered to the patient twice daily.

In a preferred embodiment, the above oral medicament is for the treatment of Idiopathic Pulmonary Fibrosis (IPF).

In a fifth aspect, the present invention relates to an oral pharmaceutical composition comprising

18Mg or 9mg of PDE4B inhibitors of the formula III

A therapeutically effective amount of pirfenidone, and

Optionally one or more pharmaceutically acceptable carriers or excipients

For use in treating a patient suffering from progressive fibrotic interstitial lung disease (PF-ILD), wherein the oral pharmaceutical composition is administered to the patient twice daily.

In a preferred embodiment, the above oral pharmaceutical composition is for the treatment of Idiopathic Pulmonary Fibrosis (IPF).

In a sixth aspect, the invention relates to the use of a PDE4B inhibitor of formula III

For the manufacture of an oral medicament comprising 18mg or 9mg of a PDE4B inhibitor of formula III, for use in combination with a separate oral medicament comprising a therapeutically effective dose of pirfenidone as a background treatment for treating a patient suffering from progressive fibrotic interstitial lung disease (PF-ILD), wherein this oral medicament comprising a PDE4B inhibitor of formula III is administered to the patient twice daily.

Accordingly, progressive fibrotic interstitial lung disease (PF-ILD) is preferably Idiopathic Pulmonary Fibrosis (IPF).

Accordingly, a therapeutically effective dose of pirfenidone in the oral drug alone (as background treatment) is preferably a daily dose between 801mg and 2403 mg.

In a seventh aspect, the invention relates to a kit for treating a patient suffering from progressive fibrotic interstitial lung disease (PF-ILD), comprising:

A first pharmaceutical composition or dosage form comprising 18mg or 9mg of a PDE4B inhibitor of formula III

And optionally one or more pharmaceutically acceptable carriers and/or excipients

And

A second pharmaceutical composition or dosage form comprising a dose of either 100mg or 150mg of nidanib

And

Optionally one or more pharmaceutically acceptable carriers and/or excipients,

Wherein the first pharmaceutical composition and the second pharmaceutical composition are administered twice daily.

In a preferred embodiment, the above kit is for use in the treatment of Idiopathic Pulmonary Fibrosis (IPF).

In another preferred embodiment of the above kit, the first pharmaceutical composition or dosage form is administered simultaneously, concurrently, sequentially, alternately or separately with the second pharmaceutical composition or dosage form.

In an eighth aspect, the invention relates to a kit for treating a patient suffering from progressive fibrotic interstitial lung disease (PF-ILD), comprising:

A first pharmaceutical composition or dosage form comprising 18mg or 9mg of a PDE4B inhibitor of formula III

And optionally one or more pharmaceutically acceptable carriers and/or excipients

And

A second pharmaceutical composition or dosage form comprising a therapeutically effective dose of pirfenidone

And

Optionally one or more pharmaceutically acceptable carriers and/or excipients,

Wherein the first therapeutic composition or dosage form is administered twice daily.

In a preferred embodiment of the above kit, the kit is for treating a patient suffering from Idiopathic Pulmonary Fibrosis (IPF).

In another preferred embodiment of the above kit, the first pharmaceutical composition or dosage form is administered simultaneously, concurrently, sequentially, alternately or separately with the second pharmaceutical composition or dosage form.

In another preferred embodiment of the above kit, the second pharmaceutical composition or dosage form comprises pirfenidone at a dose of 267mg and administered three times daily, or at a dose of 534mg and administered three times daily, or at a dose of 801mg and administered three times daily.

In another preferred embodiment of the above kit, the second pharmaceutical composition or dosage form comprises pirfenidone at a daily dose of between 801mg and 2403 mg.

2.2 Accompanying drawings

Figure 1 depicts the mean (SE) of the adjustment of the Force Vital Capacity (FVC) of the "AF-free group" with respect to the change in baseline [ ml ]. For the "AF-free group", the difference in FVC change from baseline between the "compound of formula III" (= "active group") and the "placebo group" after 12 weeks of treatment was 101.7ml (MMRM).

The curve depicting the data points in solid triangles represents the group where "compound of formula III" has been obtained (this means "active group"), while the dashed line depicting the data points in open triangles represents the group where "placebo" has been obtained.

Figure 2 depicts the adjusted mean (SE) of the change in Forced Vital Capacity (FVC) from baseline [ ml ] for the complete "AF group" ("nidanib as anti-fibrotic background drug group" + "pirfenidone as anti-fibrotic background drug group"). For the complete "AF group", the difference in FVC change from baseline between the "compound of formula III" (= "active group") and the "placebo group" after 12 weeks of treatment was 80.4ml (MMRM).

The curve depicting the data points in solid triangles represents the group where "compound of formula III" has been obtained (this means "active group"), while the dashed line depicting the data points in open triangles represents the group where "placebo" has been obtained.

FIG. 3 depicts the mean (SE) of the variation [ ml ] of Forced Vital Capacity (FVC) from baseline for the fraction of Nitanib as anti-fibrotic background drug in the "AF group" that has been obtained ("Nitanib as anti-fibrotic background drug group"). For the fraction of nildanib that had been obtained as an anti-fibrotic background drug in the "AF group", the difference in FVC change from baseline between the "compound of formula III" (= "active agent group") and the "placebo group" after 12 weeks of treatment was 105.43ml (MMRM).

The curve depicting the data points in solid triangles represents the group where "compound of formula III" has been obtained (this means "active group"), while the dashed line depicting the data points in open triangles represents the group where "placebo" has been obtained.

Figure 4 depicts the adjusted mean value (SE) of the change in Forced Vital Capacity (FVC) from baseline [ ml ] of pirfenidone as part of the anti-fibrotic background drug in "AF group" ("pirfenidone as anti-fibrotic background drug group"). For the fraction of pirfenidone that had been obtained in the "AF group" as anti-fibrotic background drug, the difference in FVC change from baseline between the "compound group of formula III" (= "active agent group") and the "placebo group" after 12 weeks of treatment was 61.30ml (MMRM).

The curve depicting the data points in solid triangles represents the group where "compound of formula III" has been obtained (this means "active group"), while the dashed line depicting the data points in open triangles represents the group where "placebo" has been obtained.

Fig. 5 depicts the adjusted mean (SE) of the change in Forced Vital Capacity (FVC) from baseline [ ml ] for "aggregate AF background" (= "no AF group" +complete "AF group"). For "pooled AF background", the difference in FVC change from baseline between "compound of formula III" (= "active group") and "placebo group" after 12 weeks of treatment was 88.38ml (MMRM).

The curve depicting the data points with filled circles represents the group that obtained "compound group of formula III" (meaning "active group") and the dashed line depicting the data points with open circles represents the group that obtained "placebo".

Fig. 6 depicts the adjusted mean (SE) of changes in Forced Vital Capacity (FVC) from baseline [ ml ] at week 12 (MMRM), for the complete "AF group" (= "anti-fibrosis"), the "no AF group" (= "no anti-fibrosis") and the "aggregate AF background" (= "all patients").

3. Clinical trial

3.1 Detailed description of clinical trials

The study was open to Idiopathic Pulmonary Fibrosis (IPF) adults at least 40 years of age at recruitment. Persons taking IPF standard drugs (including anti-fibrotic drugs) may continue to take the study throughout the duration of the study.

The aim of this study was to find out whether PDE4 inhibitors of formula III

Can slow down the deterioration of lung function. The participants were about 4 months in the study. During this time, they were treated about 7 times at the study site. Initially, they were at the study site every 2 weeks. After 1 month of treatment, they were at the study site every 4 weeks.

The participants were randomly divided into 2 groups ("active group" and "placebo group"). A tablet comprising 12mg of the compound of formula III and a tablet comprising 6mg of the compound of formula III ("active agent tablet" yielding an 18mg single dose, see table 1) are orally administered to a first group of patients twice daily (b.i.d.). A 12mg placebo tablet and a 6mg placebo tablet (both without active ingredient, see table 1) were orally administered twice daily (b.i.d.) to a second group of patients. Placebo tablets look like tablets of the active ingredient (=compound of formula III).

Table 1: composition of "active agent tablet" and "placebo tablet" administered in clinical trial (12 mg and 6mg of "active agent tablet" or "placebo tablet" administered one at a time, twice daily)

The "active group" and "placebo group" were further assigned to two different background drug groups: "AF group" ("anti-fibrosis background drug group") and "AF-free group" ("non-fibrosis background drug group"). Patients belonging to the "AF-free group" did not acquire an anti-fibrotic background drug of either nilamide or pirfenidone during the trial (according to approved dosages and dosage regimens) (this means that 18mg doses of PDE4B inhibitor b.i.d (=twice daily) or placebo b.i.d (twice daily) of formula III were administered alone), and patients belonging to the "AF-group" acquired an anti-fibrotic background drug of either nilamide or pirfenidone during the trial (this means that 18mg doses of PDE4B inhibitor b.i.d (=twice daily) or placebo b.i.d (twice daily) of formula III were administered in combination with either nilamide or pirfenidone). The combination of both nilamide and pirfenidone is not allowed in "AF group" as background drug.

Participants were tested for lung function ("Forced Vital Capacity (FVC)") at study visit. The results of the changes in lung function tests were compared for the "active" and "placebo" groups (within "AF" and "no AF"). The doctor also regularly checks the general health of the participants.

The study recruited 147 IPF patients meeting the following inclusion criteria:

patients with age > 40 years when informed consent was signed.

Diagnosis: IPF, based on 2018ATS/ERS/JRS/ALAT guidelines, was confirmed by researchers based on chest High Resolution Computed Tomography (HRCT) scans taken within 12 months after the 1 st visit and if available, surgical lung biopsy.

And

The pattern of interstitial pneumonia (UIP) or suspected UIP HRCT, consistent with IPF clinical diagnosis, was confirmed by a central assessment (CENTRAL REVIEW) prior to visit 2,

If HRCT finds an indeterminate IPF, local validation can be done by (historical) biopsy

Stabilize for at least 8 weeks prior to visit 1.

Patient must:

No treatment with either nidulance or pirfenidone (combination of nidulance plus pirfenidone is not allowed) at least 8 weeks before visit 1

Or alternatively

Stabilization with nintedanib or pirfenidone at least 8 weeks prior to visit 1 and intended to remain stable in this background treatment after randomization

Stabilization treatment is defined as individual and general tolerating therapy of pirfenidone or nilamide, (combination of nilamide plus pirfenidone is not allowed)

The Forced Vital Capacity (FVC) at the 1 st visit is not less than 45% of the predicted normal value

Lung carbon monoxide diffusion capacity (DLCO) (corrected for hemoglobin [ Hb ] [1 st visit ]) at visit 1 is ≡25% to <80% of predicted normal.

Written informed consent signed and dated according to ICH-GCP and local legislation prior to entry into the trial.

For participating IPF patients, the following exclusion criteria apply:

related airway obstruction at visit 1 (bronchodilator first second forced expiratory volume (FEV 1)/Forced Vital Capacity (FVC) < 0.7).

Other clinically significant pulmonary abnormalities, according to the opinion of the investigator.

Acute exacerbation of IPF (determined by the investigator) within 4 months prior to and/or during screening.

Lower respiratory tract infections requiring antibiotics occur within 4 weeks prior to visit 1 and/or during screening.

Major surgery performed within 3 months prior to visit 1 or planned to be performed during the trial (major surgery based on the evaluation of the investigator). (allowed on the migration list).

Any recorded history of active or suspected malignancy or malignancy within 5 years prior to visit 1, with the exception of appropriately treated basal cell carcinoma of the skin, "in-monitor" prostate cancer or cervical carcinoma in situ.

Evidence of active infection (chronic or acute) based on clinical or laboratory findings at visit 1 or visit 2.

Any suicidal behavior (i.e., actual attempt, interrupted attempt, aborted attempt, or preparatory action or behavior) over the past 2 years.

Patients were diagnosed with SARS-CoV-2 within 4 weeks prior to visit 1 and/or during screening.

Further exclusion criteria apply.

The trial was a randomized, double-blind, placebo-controlled, parallel group study. During the 12 weeks of the study, the lung function of all participating IPF patients was monitored by measuring the change in Forced Vital Capacity (FVC) from baseline ("primary outcome measure"). At 12 weeks of the treatment period and one week after the treatment period (time frame: up to 13 weeks), all participating IPF patients had been monitored for Treatment Emergency Adverse Events (TEAE) ("secondary outcome measure").

3.2 Phase II clinical trial results:

3.2.1 population

Of 147 patients, all patients who had previously stopped trial medication were from the "active agent group", namely "AF group" 10/49 (20.4%) and "no AF group" 5/49 (10.4%).

The most common cause of premature withdrawal is adverse events, accounting for 100%10/10 of the withdrawal of the "AF group" and 60%3/5 of the withdrawal of the "no AF group" (see Table 2).

Table 2: summary of clinical trial

Table 3 shows that the time since the diagnosis of IPF was longer in the "AF group" (4.33 years) relative to the "no AF group" (2.54 years) and a balance was maintained between placebo control arm (arm) and active arm.

Table 3: demographic of treated patients: time since diagnosis

Table 4 shows that IPF patients in the "AF group" used nilamide as a background drug more than pirfenidone ("53.1% nilamide and 46.9% pirfenidone in the active group" and 68% nilamide and 32% pirfenidone in the "placebo group"). In addition, table 4 shows that the time elapsed since IPF diagnosis for IPF patients from "AF group" was longer (4.6 years for "active group" and 3.9 years for "placebo group") compared to "no AF group" patients (2.7 years for "active group" and 2.2 years for "placebo group").

Table 4: characterization of patients receiving treatment in different groups

3.2.2 Results regarding efficacy of PDE4 inhibitors of formula III

3.2.2.1 Results of "no AF group

Mean value estimation (mixed model repeat measurement, MMRM) was adjusted:

The IPF patient "no AF group" obtained a tablet containing 18mg of the compound of formula III twice daily (= "active group") or a placebo tablet containing no active ingredient twice daily (here "placebo tablet" is not distinguished in terms of appearance, smell, taste, etc. from "active tablet" containing 18mg of the compound of formula III). Patients in the "no AF group" did not acquire standard of care background drug for treatment of IPF during the 12 week study period (this means no nilamide background drug and pirfenidone background drug). Patients for each test were tested for lung function at regular intervals at each study visit. From the results of these pulmonary function tests, the change from baseline in FVC (in ml) at different time points in the study was determined (see figure 1). Patient data from lung function tests at various time points over a 12 week study period were analyzed by Mixed Model Repeat Measurement (MMRM). MMRM is a well established Longitudinal data analysis method that allows for the use of a set of repeated measurements of a patient during the estimation process (Fitzmaurice et al, "Longitudinal DATA ANALYSIS", chapman & Hall/CRC, new York (2009)).

Change in FVC from baseline from study start to week 12: the "placebo group" was 95.62ml and the "active group" was +6.10ml, resulting in a difference in FVC from baseline of 101.72ml between the "active group" and the "placebo group from study start to week 12 (see table 5, figures 1 and 6). Although the change in FVC of the "placebo group" from baseline was substantially reduced (meaning that IPF disease was substantially progressed in these untreated patients) during the 12 week study period, the change in FVC of the "active group" (PDE 4 inhibitor of formula III that had been obtained at 18mg daily dose) remained stable or even slightly increased over the same 12 week study period (see fig. 1 and 6). Thus, a twice daily 18mg dose of PDE4 inhibitor of formula III shows an impressive therapeutic efficacy for IPF patients without the standard of care background drug of nilamide or pirfenidone during the 12 week treatment period.

Table 5: "AF-free group" mean (SE) of the adjustment of FVC (ml) baseline changes at 12 weeks (MMRM)

3.2.2.2 Results for "AF group

Adjusting mean value estimation (MMRM):

IPF patients of "AF group" obtained tablets containing 18mg of compound of formula III twice daily (= "active group") or placebo tablets of similar appearance without active ingredient twice daily (= "placebo group"). In addition, patients in the "AF group" received standard of care background drug for treatment of IPF during the 12 week study period (this means that either the nilamide background drug was in approved dose/dose regimen or the pirfenidone background drug was in approved dose/dose regimen, the combination of nilamide and pirfenidone not being allowed as background drug). Patients for each test were tested for lung function at regular intervals at each study visit. From the results of these pulmonary function tests, the change from baseline in FVC (in ml) at different time points in the study was determined (see figure 2). Patient data from lung function tests at various time points over a 12 week study period were analyzed by Mixed Model Repeat Measurement (MMRM).

Change in FVC from baseline from study start to week 12: the "placebo group" was 77.7ml and the "active group" was +2.72ml (see table 6, fig. 2 and 6), resulting in a difference in FVC from baseline of 80.42ml between "active group" and "placebo group" from study start to week 12. Whereas during the 12 week study period the "placebo group" ("placebo group" of "AF group") only acquired the antifibrotic background drug, which means that only the variation of FVC of nilamide or only pirfenidone from baseline was reduced (which means that the IPF disease progressed in these patients taking the antifibrotic background drug alone), the "active agent group" (combination of PDE4 inhibitor of formula III with nilamide or pirfenidone, having acquired an 18mg dose twice daily) of FVC remained stable or even slightly increased over the same 12 week study period. Thus, the combination of the PDE4 inhibitor of formula III twice daily with an anti-fibrotic background drug (nilamide or pirfenidone) at a dose of 18mg shows an impressive improved therapeutic efficacy over a treatment period of 12 weeks compared to the therapeutic efficacy in IPF patients treated with the same anti-fibrotic background drug alone.

This 80.42ml change in FVC from baseline between "active" and "placebo" in "AF group" was less than 101.72ml for "no AF group" at week 12. However, this is understandable, since in the "AF group" the anti-fibrotic background drug using either nilamide or pirfenidone should also be responsible for a certain therapeutic basal effect.

Table 6: mean (SE) for the adjustment of FVC (ml) baseline variation at week 12 (MMRM) of the "AF group

However, when the results of the "AF group" were analyzed alone by the type of anti-fibrotic background drug administered to the patient (this means that the "nilamide background drug group" within the "AF group" was separated from the "pirfenidone background drug group"), a trend was observed for higher therapeutic efficacy in combination with 18mg of PDE4 inhibitor of formula III administered twice daily for the group to obtain nilamide as background drug compared to the group to obtain pirfenidone as background drug.

Such trends can be concluded from the data summarized in table 7: here, the difference in the adjustment average between the change from baseline to week 12 between the "active group" and the "placebo group" was calculated to be 105.43ml according to the test data for the group having acquired nilamide as the background drug, and the difference in the adjustment average between the change from baseline to week 12 between the "active group" and the "placebo group" was calculated to be only 61.30ml according to the test data for the group having acquired pirfenidone as the background drug (see table 7).

If either niloticb or pirfenidone is not distinguished as background drug, the difference in the mean adjustment between the change from baseline to week 12 between the "active" and "placebo" groups is determined to be 80.42ml (compare see table 6) -one value in between.

The progression of the change in FVC from baseline over the 12 week treatment period can be derived from figure 3 for "nilanib as background drug group" and figure 4 for "pirfenidone as background drug group".

Table 7: differences between FVC (ml) baseline variation (SE)/nintedanib background drug and pirfenidone background drug at 12 weeks (MMRM) for "AF group

Thus, data from clinical trials indicate that the twice daily administration of 18mg of PDE4 inhibitor of formula III in combination with nidazole (according to approved dosages and dosage regimens) may have better therapeutic efficacy than the twice daily administration of 18mg of PDE4 inhibitor of formula III in combination with pirfenidone (according to approved dosages and dosage regimens).

3.2.2.3 Results of "background therapy of the set" ("no AF group" + "AF group")

Adjusting mean value estimation (MMRM):

The combined results of "no AF group" and "AF group" are as shown in fig. 5 or 6 or summarized in table 8.

Whereas FVC of the "placebo group" (whether an anti-fibrotic background drug is obtained or not, depending on whether the patient is in the "AF-free group" or the "AF group") steadily decreases over the course of the 12-week study period, the "active agent group" (PDE 4 inhibitor of formula III, which has been obtained either alone or in combination with an anti-fibrotic background drug of nilamide or pirfenidone, is given twice daily, depending on whether the patient is in the "AF-free group" or the "AF group") remains stable or even slightly increases over the same 12-week study period.

If all results are considered (this means "no AF group" + "AF group" result), the change in FVC from baseline to week 12 is-4.59 ml in the "active group" and-83.79 ml in the "placebo group". If all results are considered (this means the result of "no AF group" + "AF group"), the change in FVC to week 12 compared between "active group" and "placebo group" from baseline is calculated to be 88.38ml.

Table 8: adjusted mean (SE) of FVC (ml) baseline changes at week 12 (MMRM) for "pooled background therapy" (= "no AF group" + "AF group")

3.2.3 Results regarding safety/tolerance of PDE4 inhibitors of formula III

In the "active agent group," 67% of patients experienced Adverse Events (AEs): the "no AF group" was 64.6%, and the "AF group" was 73.5%. In the "placebo group," 60% of patients experienced AE: the "no AF group" was 52%, and the "AF group" was 68% (see table 9). In all test groups, only 8.8% of patients experienced AEs leading to withdrawal of the test drug, 7.5% experienced serious adverse events (see table 10), and 2 patients (meaning 1.4%) experienced AEs leading to death (both in the "active agent group", one due to Covid-19 pneumonia, one due to unproven vasculitis cases).

Table 9: general overview of adverse events during clinical trials

Table 10: general overview of serious adverse events during clinical trials

* The deadly event is shown in bold

The most commonly reported Adverse Event (AE) was gastrointestinal disease, with diarrhea being the most common AE (diarrhea was observed in more than 10% of all patients) (see table 11).

In both the "AF group" and the "AF-free group" an increased frequency of adverse event diarrhea compared to the respective "placebo group" was observed in the corresponding "active agent group", wherein the compound of formula III was administered in combination with the anti-fibrotic background drug or alone. Three patients from "active agent group" stopped treatment due to AE diarrhea, all males ≡65 years old from "AF group" who received the nilamide background treatment.

In the "AF-free group," diarrhea reporting frequency of the "active group" (16.7%) was approximately twice that of the corresponding "placebo group" (8%) (see table 11). In the "AF group", diarrhea reporting frequency of the "active group" (30.6%) was also approximately twice that of the corresponding "placebo group" (16.0%) (see table 11).

However, the overall level of diarrhea reported for "AF group" was also increased compared to "no AF group" (see table 11, in "placebo group" 16% diarrhea compared to 8% diarrhea in "no AF group", in "compound of formula III", 30.6% diarrhea in "AF group" compared to 16.7% diarrhea in "no AF group").

Thus, the inhibitor of formula IIIPDE4 administered at a dose bid of 18mg appears to result in an increased frequency of AE diarrhea, and the anti-fibrotic background drug, particularly the nindaanib background drug, appears to significantly contribute to an increased frequency of diarrhea case reports in the "AF group" (compared to the "no AF group").

However, all diarrhea cases reported in "AF group" and "no AF group" were non-severe adverse events (see table 10).

Most reported diarrhea events were mild, except for two cases of moderate diarrhea (2.1%) and one case of severe diarrhea (1.0%), which occurred in both men and the "active" group of "AF group" receiving the nilamide background treatment. In addition, a 64 year old female developed a severe diarrhea in the "placebo group" of the "AF group" receiving the nilamide background treatment.

Overall, the AE most commonly reported to cause withdrawal was diarrhea (n=4), all of which were part of the "AF group" and receiving the nilotics background.

Among the diarrhea cases reported in all treatment arms, no dehydration cases associated with diarrhea were observed.

In all arms of treatment, no hypokalemia cases were reported.

Except for gastrointestinal disorders (particularly diarrhea), all treatment arms ("AF group" and "AF-free group", "active group" and "placebo group") reported only a single adverse event, without any specific pattern (see table 11).

Table 11: adverse Events (AE) frequently reported during clinical trials

3.2.3.2 Results regarding the safety/tolerance of PDE4 inhibitors of formula III in "AF group" (separated by type of anti-fibrotic background treatment)

If the results with respect to the frequency of AE "gastrointestinal disorders", in particular with respect to the frequency of AE "diarrhea", are compared, on the one hand, for the complete "AF group" (as shown in table 11), and on the other hand, for the fraction of the "AF group" obtained with nilamide as an anti-fibrotic background drug ("nilamide background drug group") and the fraction of the "AF group" obtained with pirfenidone as an anti-fibrotic background drug ("pirfenidone background drug group") (as shown in table 14), it is clear that the frequency of "pirfenidone background drug group" shows AE "gastrointestinal disorders" is significantly lower:

Of the "Compound arms of formula III" of the complete "AF group", 36.7% of patients experienced gastrointestinal disorders (see Table 11)

In the "Compound arm of formula III" of "Nidamib background drug subgroup", 46.2% of patients experienced gastrointestinal disorders (see Table 14)

And

Of the "Compound arms of formula III" of the "pirfenidone background drug subgroup", only 26.1% of patients experienced gastrointestinal disorders (see Table 14)

Comparable results can be found from the individual "placebo group" of the "AF group":

In the "placebo arm" of the complete "AF group", 32.0% of patients experienced gastrointestinal disorders (see table 11)

In the "placebo arm" of the "nildanib background drug subgroup", 41.2% of patients experienced gastrointestinal disorders (see table 14)

And

Of the "placebo arms" of the "pirfenidone background drug subgroup," only 12.5% of patients experienced gastrointestinal disorders (see table 14).

If the AE "diarrhea" condition is analyzed, the exact same trend can be observed

For "compound arm of formula III":

In the "compound arm of formula III" of the complete "AF group", 30.6% of patients experienced diarrhea (see table 11)

In "Compound arm of formula III" of "Nidamib background drug subgroup", 46.2% of patients experienced diarrhea (see Table 14)

And

Of the "Compound arms of formula III" of the "pirfenidone background drug subgroup", only 13.0% of patients experienced diarrhea (see Table 14)

And for the respective "placebo arm":

in the "placebo arm" of the complete "AF group", 16.0% of patients experienced diarrhea (see table 11)

In the "placebo arm" of the "nildanib background drug subgroup", 23.5% of patients experienced diarrhea (see table 14)

And

In the "placebo arm" of the "pirfenidone background drug subgroup", even 0% of patients experienced diarrhea (see table 14).

In the case of using pirfenidone as an anti-fibrotic background drug (compared to nilanib as an anti-fibrotic background drug), this trend of lower tendency for AE gastrointestinal disorders, in particular AE diarrhea, is also supported by table 15, where the frequency/percentage shows adverse events leading to discontinuation of the test drug. As is evident from Table 15, in the "AF group" of the "active agent group" ("Compound of formula III"), 18mg of the b.i.d. Compound of formula III in combination with Nidamib as the background drug resulted in

4 Cases (15.4%) of test treatments for interruption due to AE gastrointestinal disorders

And

3 (11.5%) Trial treatments were discontinued due to diarrhea AE,

While 18mg of the b.i.d. compound of formula III in combination with pirfenidone as background drug resulted in no interruption of the experimental treatment at all (see table 15). In all arms of treatment using pirfenidone as background drug (meaning in the respective "active and" placebo "groups), there was no record of discontinuation of the trial treatment due to any gastrointestinal AE (see table 15). Thus, combination therapy using 18mg of a compound of formula III and pirfenidone (at approved doses) as background therapy may be associated with reduced frequency and severity of AE gastrointestinal disorders, particularly AE diarrhea, as compared to 18mg of a combination therapy of a compound of formula III and nintenib (at approved doses) as background therapy.

Table 12: background drug is an adverse event summary in "AF group" of nildanib:

Table 13: summary of the background drug "AF group" adverse events for pirfenidone:

table 14: adverse Events (AE) frequently reported during clinical trials

Table 15: gastrointestinal disorders resulting in discontinuation of trial treatment

4. Conclusion(s)

The results of the clinical trial "no AF group" support the following assumptions: administration of PDE4 inhibitors of formula III twice daily (b.i.d.) at a dose of 18mg without anti-fibrotic background drug significantly slowed FVC decline in IPF patients for a treatment period of 12 weeks ("no AF group": for "compound of formula III (=active agent) group"), FVC change from baseline after 12 weeks was +6.1ml, for the respective "placebo group", FVC change from baseline after 12 weeks was-95.6 ml, see table 5, fig. 1).

For the "no AF group", this resulted in a difference of 101.72ml in the adjusted mean of the change in FVC from baseline between the "active group" and the "placebo group" to week 12, supporting the following assumptions: PDE4 inhibitors of formula III administered twice daily to PF-ILD/IPF patients at a dose of 18mg without anti-fibrosis background treatment showed a higher therapeutic efficacy for treating PF-ILD patients, preferably IPF patients (see table 5, fig. 1).

On the other hand, only 1 patient (2.1%) in the "active group" experienced gastrointestinal disorders leading to interruption of the trial compared to no patient (0%) in the "placebo group" of the "no AF group" (see table 15).

The results of this section, "AF group having acquired nilamide as an anti-fibrotic background drug" support the following hypothesis: PDE4 inhibitors of formula III administered at a dose of 18mg twice daily (b.i.d.) in combination with nilamide as an anti-fibrotic background drug significantly slowed FVC decline in IPF patients for a treatment period of 12 weeks compared to treatment with nilamide alone ("AF group using nilamide as background drug: for" compound of formula III (=active agent) group ", FVC change from baseline after 12 weeks is +23.41ml; FVC change from baseline after 12 weeks is-82.01 ml for the respective" placebo group "(see table 7, fig. 3)).

For the "AF group having acquired nilotics as an anti-fibrotic background drug", this resulted in a difference in the adjusted mean value of the change in FVC from baseline between "active group" and "placebo group" to week 12 of 105.43ml (see table 7, fig. 3).

This supports the following assumptions: the combination of 18mg PDE4 inhibitor of formula III and nidanib (administered according to approved dosages and dosage regimens) administered twice daily may lead to very high therapeutic efficacy.

On the other hand, compared to no patients (0%) in the "placebo group" of the "AF group using nildarinib as an anti-fibrosis background drug", 4 patients (15.4%) in the "active group" experienced gastrointestinal disorder as AE causing discontinuation of the trial treatment, and 3 of these 4 patients experienced AE diarrhea causing discontinuation of the trial treatment (see table 15).

The results of "AF group having obtained pirfenidone as an anti-fibrotic background drug" support the following hypothesis: the 18mg PDE4 inhibitor of formula III administered twice daily (b.i.d.) in combination with pirfenidone as an anti-fibrotic background drug significantly slowed the FVC decline in IPF patients for a treatment period of 12 weeks compared to treatment with pirfenidone alone ("AF group with pirfenidone as background drug": for "compound of formula III (=active agent) group", change in FVC relative to baseline after 12 weeks is-18.67 ml; change in FVC relative to baseline after 12 weeks is-80.06 ml for the respective "placebo group" (see table 7, fig. 4)).

For the "AF group that had obtained pirfenidone as an anti-fibrotic background drug", this resulted in a difference of 61.30ml in the adjusted mean value of the change in FVC from baseline between the "active group" and the "placebo group" to week 12 (see table 7, fig. 4).

On the other hand, none of the patients in the "active" group "of the AF group" using pirfenidone as an anti-fibrotic background drug "experienced gastrointestinal disorders leading to discontinuation of the trial (see table 15).

At the same time, twice daily (b.i.d.) administration of 18mg of PDE4 inhibitor of formula III increases the frequency of adverse events "gastrointestinal disorders", and in particular the frequency of AE "diarrhea" in all treatment arms (in "AF-free" and "AF-free").

However, in the "AF group", the frequency and severity of reported adverse events of gastrointestinal disorders, and in particular of reported adverse events of diarrhea, are largely dependent on the type of anti-fibrotic background drug used. Adverse events of gastrointestinal disorders, particularly diarrhea, were less frequently recorded and resulted in less frequent discontinuation of the trial treatment in IPF patients who had obtained pirfenidone as an anti-fibrotic background drug than IPF patients who had obtained nilotic as an anti-fibrotic background drug (see tables 14 and 15).

Adverse events of gastrointestinal disorders, particularly diarrhea, were more frequently recorded in IPF patients who had acquired nilotics as an anti-fibrotic background drug, and in some cases also resulted in discontinuation of the trial treatment (see tables 14 and 15). However, IPF patients who have acquired nilamide as an anti-fibrotic background drug express better therapeutic efficacy than IPF patients who have acquired pirfenidone as an anti-fibrotic background treatment.

Thus, the results presented for phase II trial, "AF group with nildanib as anti-fibrotic background treatment" support the following hypothesis: the 18mg twice daily dose of PDE4 inhibitor of formula III in combination with the background treatment of nilotica (according to the doses and dosage regimen approved for nilotica (preferably 150mg b.i.d. or 100mg b.i.d.)) may result in excellent therapeutic efficacy as well as acceptable tolerability and safety profile (leading to acceptable patient compliance). Thus, a combination of Nidamib and a PDE4 inhibitor of formula III administered at a dose of 18mg twice daily may be particularly suitable for PF-ILD/IPF patients who have no predisposition or predisposition to gastrointestinal disorders, particularly diarrhea, or whose PF-ILD-ILD/IPF treatment history has heretofore had no problems caused by gastrointestinal disorders, particularly diarrhea.

Thus, the results presented for phase II trial "AF group with pirfenidone as anti-fibrotic background treatment" support the following hypothesis: PDE4 inhibitors of formula III in combination with pirfenidone background treatment (in accordance with dosages and dosage regimens approved for pirfenidone, preferably resulting in dosages and dosage regimens of between 801mg and 2403mg daily), at twice daily 18mg doses, may result in satisfactory therapeutic efficacy as well as excellent tolerability and safety profiles (resulting in excellent patient compliance). Thus, a combination of pirfenidone and PDE4 inhibitors of formula III administered at a dose of 18mg twice daily may be particularly suitable for PF-ILD/IPF patients who have no predisposition or predisposition to gastrointestinal disorders, particularly diarrhea, or whose PF-ILD-ILD/IPF treatment history has heretofore had no problems caused by gastrointestinal disorders, particularly diarrhea.

Claims (18)

1. An oral pharmaceutical composition consisting essentially of:

18mg PDE4B inhibitor of formula III

And optionally one or more pharmaceutically acceptable carriers or excipients,

For use in treating a patient suffering from one or more progressive fibrotic interstitial lung diseases (PF-ILD), wherein the oral pharmaceutical composition is administered to the patient twice daily.

2. The oral pharmaceutical composition of claim 1, wherein the one or more progressive fibrotic interstitial lung disease (PF-ILD) is Idiopathic Pulmonary Fibrosis (IPF).

3. The oral pharmaceutical composition of at least one of claims 1 or 2, wherein the oral pharmaceutical composition is a film coated tablet.

4. Use of a PDE4B inhibitor of formula III for the preparation of an oral pharmaceutical composition for the treatment of a patient suffering from progressive fibrotic interstitial lung disease (PF-ILD), said oral pharmaceutical composition consisting essentially of 18mg of said PDE4B inhibitor of formula III and optionally one or more pharmaceutically acceptable carriers or excipients

Wherein the oral pharmaceutical composition is administered to the patient twice daily.

5. The use of a PDE4B inhibitor according to claim 4 according to formula III, wherein said progressive fibrotic interstitial lung disease (PF-ILD) is Idiopathic Pulmonary Fibrosis (IPF).

6. PDE4B inhibitor of formula III according to at least one of claims 4 or 5, wherein the oral pharmaceutical composition is a film-coated tablet.

7. An oral pharmaceutical composition comprising

A dose of 18mg of PDE4B inhibitor of formula III as the sole active agent

And optionally one or more pharmaceutically acceptable carriers or excipients,

For use in treating a patient suffering from progressive fibrotic interstitial lung disease (PF-ILD), wherein the oral pharmaceutical composition is administered to the patient twice daily.

8. The oral pharmaceutical composition of claim 7, wherein the progressive fibrotic interstitial lung disease (PF-ILD) is Idiopathic Pulmonary Fibrosis (IPF).

9. The oral pharmaceutical composition of at least one of claims 7 or 8, which is a film coated tablet.

10. Use of a PDE4B inhibitor of formula III for the preparation of an oral pharmaceutical composition for the treatment of a patient suffering from progressive fibrotic interstitial lung disease (PF-ILD), wherein the oral pharmaceutical composition comprises a dose of 18mg of the PDE4B inhibitor of formula III as sole active agent, and optionally one or more pharmaceutically acceptable carriers or excipients

Wherein the oral pharmaceutical composition is administered to the patient twice daily.

11. The use of a PDE4B inhibitor according to claim 10 of formula III, wherein said progressive fibrotic interstitial lung disease (PF-ILD) is Idiopathic Pulmonary Fibrosis (IPF).

12. The PDE4B inhibitor of formula III according to at least one of claims 10 or 11, wherein said oral pharmaceutical composition is a film coated tablet.

13. A method of treating a patient suffering from progressive fibrotic interstitial lung disease (PF-ILD), comprising the steps of: administering to said patient twice daily an oral pharmaceutical composition comprising a PDE4B inhibitor of formula III in a dose of 18mg as sole active agent

And optionally one or more pharmaceutically acceptable carriers or excipients.

14. The method of claim 13, wherein the progressive fibrotic interstitial lung disease (PF-ILD) is Idiopathic Pulmonary Fibrosis (IPF).

15. The method of at least one of claims 13 or 14, wherein the oral pharmaceutical composition is a film coated tablet.

16. A method of treating a patient suffering from progressive fibrotic interstitial lung disease (PF-ILD), comprising the steps of: administering to the patient twice daily an oral pharmaceutical composition consisting essentially of: 18mg of PDE4B inhibitor of formula III

And optionally one or more pharmaceutically acceptable carriers or excipients.

17. The method of claim 16, wherein the progressive fibrotic interstitial lung disease (PF-ILD) is Idiopathic Pulmonary Fibrosis (IPF).

18. The method of at least one of claims 16 or 17, wherein the oral pharmaceutical composition is a film coated tablet.