Patent Description:
Prolonged ILD may result in pulmonary fibrosis, but this is not always the case.

Therefore ILD also include the so-called Progressive Fibrosing Interstitial Lung Diseases (PF-ILDs).

In Progressive Fibrosing Interstitial Lung Diseases (PF-ILD) the response to lung injury in fibrosing ILDs includes the development of fibrosis which becomes progressive, self-sustaining and independent of the original clinical association or trigger. It is postulated that, at this stage, targeted anti-fibrotic therapy is required to slow the progression of the disease.

Based on the similarity in both, their biologic and clinical behaviors i.e. self-sustaining fibrosis and progressive decline in lung function and early mortality, it is considered justified to group patients with PF-ILD together regardless of the original ILD diagnosis.

The number of patients with the different fibrosing ILDs e.g. idiopathic non-specific interstitial pneumonia (iNSIP) or chronic hypersensitivity pneumonitis (CHP), is similar to or lower than the number of patients with IPF; the number of patients with progressive phenotype within each group, while still significant, is even lower. Therefore grouping patients with PF-ILD together is considered the only feasible way to provide efficacious therapies for all patients with progressive fibrosing interstitial lung disease.

A patient suffers from PF-ILD in case that a physician diagnosed for this patient an Interstitial Lung Disease (ILD) and that additionally at least one of the following criteria for Progressive Fibrosing Interstitial Lung Disease are fulfilled within <NUM> months after the first visit at physician's despite treatment with unapproved medications used in clinical practice to treat ILD as assessed by the physician (Unapproved medications used in the clinical practice to treat ILD include but are not limited to corticosteroids, azathioprine, mycophenolate mofetil (MMF), n-acetylcysteine (NAC), rituximab, cyclophosphamide, cyclosporine, tacrolimus):.

Examples of PF-ILDs are Idiopathic pulmonary fibrosis (IPF), Idiopathic Non-Specific Interstitial Pneumonia (iNSIP), Hypersensitivity Pneumonitis (HP), Unclassifiable Idiopathic Interstitial Pneumonias, Rheumatoid Arthritis ILD (RA-ILD), Sjögren's syndrome ILD, Systemic Lupus Erythematous ILD (SLE-ILD), Polymyositis and Dermatomyositis ILD (PM/DM-ILD), Mixed Connective Tissue Disease ILD (MCTD-ILD), Systemic Sclerosis ILD (SSc-ILD), other Connective Tissue Disease ILDs (CTD-ILD), Sarcoidosis, Asbestosis, Silicosis.

The most prominent PF-ILDs are Idiopathic Pulmonary Fibrosis (IPF) and Systemic Sclerosis Interstitial Lung Disease (SSc-ILD). Idiopathic Pulmonary Fibrosis (IPF) is a PF-ILD for which no obvious cause can be identified (which is the definition for "idiopathic") and which is associated with typical findings both radiographic (basal and pleural based fibrosis with honeycombing) and pathological (temporally and spatially heterogeneous fibrosis, histopathologic honeycombing and fibroblastic foci).

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic irreversible and ultimately fatal lung disease characterized by a progressive fibrosis in the interstitium in the lung, leading to a decreasing lung volume and progressive pulmonary insufficiency. IPF is also characterized by a specific histopathologic pattern known as usual interstitial pneumonia (UIP) (<NPL>. The lung functions in patients with lung fibrosis either caused by IPF or any other PF-ILD is determined as forced vital capacity (FVC).

The term IPF means scarring of lung tissue and is the cause of worsening dyspnea (shortness of breath). IPF is usually associated with a poor prognosis with a median survival time of <NUM>-<NUM> years after diagnosis. IPF is believed to be the result of an aberrant wound healing process including/involving abnormal and excessive deposition of collagen (fibrosis) in the pulmonary interstitium with minimal associated inflammation (<NPL>).

Fibroblasts play a central role in the pathogenesis of fibrotic processes that are common to ILDs, PF-ILDs and IPF, and several factors influence their proliferation and their extracellular matrix (ECM) synthesis. In ILDs, these mesenchymal cells have an increased activity with respect to proliferation, migration, extracellular matrix (ECM) synthesis and response to fibrogenic cytokines. The increased deposition of ECM from activated fibroblasts (called "myofibroblasts") contributes to the stiffening of the lung tissue and the destruction of alveolar oxygen exchange area which results in progressive dyspnea and eventually death.

Based on the similarity in both the underlying pathophysiology and clinical course of PF-ILD and IPF, it is anticipated that therapeutically active agents which target fundamental processes in progressive lung fibrosis in IPF will elicit comparable therapeutic effects in PF-ILD.

In <NUM>, the US Food and Drug Administration (FDA) approved the first drugs for the treatment of IPF in the US: Nintedanib (OFEV) by Boehringer Ingelheim Pharmaceuticals Inc. and Pirfenidone (ESBRIET) by InterMune Inc. Pirfenidone had already been approved for the treatment of IPF in Europe, Japan and several other countries at that time and Nintedanib was approved as a treatment for IPF in Europe in January <NUM>.

Consequently, the standard treatments of IPF today are either Pirfenidone treatment (<CIT> B) or Nintedanib treatment (<CIT>; P05-<NUM>)
(https://consultqd. clevelandclinic. org/<NUM>/<NUM>/pirfenidone-and-nintedanib-novel-agents-in-the-treatment-of-idiopathic-pulmonary-fibrosis/).

However, in patients with IPF having a mild or moderate impairment of FVC (≥<NUM> % predicted), both presently approved medicaments Pirfenidone and Nintedanib, can only reduce the decline in FVC, consistent with a slowing of disease progression, but both are not able to stop or even reverse or heal the symptoms of IPF (<NPL>).

Nevertheless, both treatment-options, either with Pirfenidone or with Nintedanib, show significant beneficial effects in slowing down IPF disease progression.

The most prominent side effects associated with both, Nintedanib and Pirfenidone, are gastrointestinal events, particularly diarrhea, nausea, vomiting, abdominal pain, decreased appetite and a decreased body weight. In case that gastrointestinal side effects arise, they are usually managed either by treatment interruption, dose reduction or symptomatic treatment of the gastrointestinal side effects (see <NPL>).

Due to these "accumulative gastrointestinal side effects" of Pirfenidone on the one hand and of Nintedanib on the other hand a combination treatment for IPF by a combination of Pirfenidone and Nintedanib is not frequently used. Investigations have shown that a combination treatment with Pirfenidone and Nintedanib leads to increased gastrointestinal side effects, in particular to diarrhoea, nausea, vomiting, and upper abdominal pain (<NPL>, Epub ahead of print).

Consequently, due to the fact that both active agents which are so far approved for the treatment for IPF, Pirfenidone and Nintedanib, are - when administered alone - not able to stop or to heal IPF, but instead can only slow down the IPF disease progression to a certain percentage (<NPL>), and due to the fact that additionally both Nintedanib and Pirfenidone show significant gastrointestinal side effects which accumulate when both compounds are combined, there is still a significant medical need for improved medicaments for IPF treatment/PF-ILD treatment, in particular for improved combination treatments/ combination medicaments comprising as a first combination partner either one of the approved medicaments in IPF Nintedanib or Pirfenidone (with proven efficacy in IPF treatment) and a second other suitable combination partner which is active in IPF/PF-ILD treatment with acceptable tolerability (but which is different from Pirfenidone or Nintedanib). Hereby, it would be extraordinarily beneficial to provide a new medicament combination with a good/improved therapeutic efficacy and with an acceptable tolerability, in particular with regard to gastrointestinal side effects.

Consequently, it was the problem of the instant invention to provide a new combination treatment/ combination medicament for PF-ILD treatment/IPF treatment, comprising as a first combination partner one of the presently approved medicaments in IPF, either Nintedanib or Pirfenidone, and a second combination partner (which is different from Nintedanib or Pirfenidone), whereby this combination treatment /combination medicament is improved compared to the PF-ILD/IPF treatment with the first combination partner alone.

This problem was solved by providing a combination treatment/ combination medicament for PF-ILD treatment/IPF treatment, comprising as a first combination partner a therapeutically effective amount of Nintedanib or a pharmaceutically acceptable salt thereof and as a second combination partner a therapeutically effective amount of a PDE4B-inhibitor of formula I
<CHM>.

Hereby the second combination partner is preferably a therapeutically effective amount of a PDE4B-inhibitior of formula II
<CHM>
or of formul a III
<CHM>.

This above-mentioned new combination treatment/combination medicament for PF-ILD treatment/IPF treatment, comprising as a first combination partner Nintedanib and as a second combination partner a PDE4B-inhibitor of formula I, preferably a PDE4B-inhibitor of either formula II or III, particularly a PDE4B-inhibitor of either formula III, shows an improved therapeutic efficacy in PF-ILD/IPF-treatment compared to treatment with Nintedanib alone or compared to treatment with the above PDE4B-inhibitor alone.

Experiments A) and B) as described in Chapter <NUM> (Experimental Data) have experimentally shown that the combination comprising the PDE4B-inhibitor of formula III and Nintedanib shows.

This above-mentioned combination treatment/combination medicament for PF-ILD treatment, particularly for IPF-treatment, of the invention comprising as a first combination partner Nintedanib and as a second new combination partner a PDE4B-inhibitor of formula I, preferably a PDE4B-inhibitor of either formula II or III, particularly a PDE4B-inhibitor of formula III, further shows an acceptable tolerability in PF-ILD-treatment.

"Acceptable tolerability" means in this context that the tolerability of the treatment with the combination of Nintedanib with the PDE4B-inhibitor of formula I, preferably of formulas II and III, particularly of formula III, is better than the tolerability of the combination Nintedanib and Pirfenidone, preferably only slightly worse, more preferable not significantly worse compared to treatment with Nintedanib alone and should therefore be well-tolerated by the patient.

Nintedanib, the compound of formula A (free base),
<CHM>
is described in <CIT> (<CIT>).

<CIT> (<CIT>) discloses the monoethanesulphonate salt of this compound of formula A; further salt forms are presented in <CIT> (<CIT>).

Furthermore, <NPL> ff. also discloses that Nintedanib shows an anti-fibrotic effect in human lung fibroblasts derived from patients with idiopathic pulmonary fibrosis due to its anti-proliferative capacity and due to its effect on the extracellular matrix.

<CIT> further discloses a method of synthesizing Nintedanib.

Nintedanib is a highly potent, orally bioavailable inhibitor of vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs) and fibroblast growth factor receptors (FGFRs). It binds competitively to the adenosine triphosphate (ATP) binding pocket of these receptors and blocks intracellular signalling. In addition, Nintedanib inhibits Fms-like tyrosine-protein kinase <NUM> (Flt <NUM>), lymphocyte-specific tyrosine-protein kinase (Lck), tyrosine-protein kinase lyn (Lyn) and proto-oncogene tyrosine-protein kinase src (Src) (<NPL>). Recently, it was discovered that nintedanib also inhibits colony stimulating factor <NUM> receptor (CSF1R) (<NPL>).

Nintedanib was shown to be able to inhibit or attenuate cellular proliferation, contributing to angiogenesis (<NPL>), as well as lung fibroblast proliferation, migration (<NPL>) and transformation to myofibroblasts (<NPL>. ) contributing to lung fibrosis (e.g. IPF), SSc-ILD and RA-ILD. Furthermore, it revealed anti-fibrotic and antiinflammatory activity in lung fibrosis models (<NPL>; <NPL>). Additionally Nintedanib demonstrated the ability to inhibit fibroblast migration, proliferation and transformation to myofibroblasts in SSc cellular models, to attenuate skin and lung fibrosis in SSc and SSc-ILD animal models (<NPL>, <NPL>, EPub ahead of print), to reduce lung fibrosis in RA-ILD animal models (<NPL>) and to attenuate lung fibrosis in a chronic mouse model of allergic lung impairment resembling aspects of HP (<NPL> EPub ahead of print).

Pharmaceutical dosage forms comprising Nintedanib are disclosed in <CIT> (<CIT>) and in <CIT> (<CIT>). Also, a dry powder formulation for inhalation has been described (<NPL>).

The use of Nintedanib for the treatment of a large variety of diseases, between many others also the use for the treatment of fibrotic diseases is described in <CIT>.

Nintedanib as a single treatment for idiopathic pulmonary fibrosis is usually dosed twice daily with <NUM> (twice daily with <NUM> for patients with mild hepatic impairment).

Further, <CIT> discloses that Nintedanib may be combined with a large variety of different combination partners. Between many other combinations partners <CIT> also proposes to combine Nintedanib with PDE4-inhibitors such as for example Roflumilast.

However, in contrast to Nintedanib (which has been approved for the treatment of IPF in the meantime) the PDE4-inhibitor Roflumilast (originally disclosed in <CIT> B) has never been neither developed nor approved for the treatment of proliferative fibrotic diseases such as PF-ILD or IPF in particular. Instead, Roflumilast was in the meantime approved for the treatment of chronic obstructive pulmonary disease (COPD) only which is a respiratory disease that does not involve any fibrotic symptoms. Also other PDE4-inhibitors such as for example Apremilast (originally disclosed in <CIT>) that appeared on the market in the following years have never been considered for being developed or for being approved for the treatment of proliferative fibrotic diseases such as PF-ILD or for IPF in particular, but instead Apremilast was approved for the treatment of psoriasis only (a skin disease).

Additionally to Roflumilast and Apremilast - many further patent applications drawn on other PDE4/PDE4B-inhibitors with improved properties were published:.

Furthermore, <CIT> discloses that structurally similar PDE4B-inhibitors like the ones of formulas I, II and III are suitable to treat diabetes mellitus or a microvascular or macrovascular complication of diabetes mellitus.

Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.

As used herein, "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.

The terms "treatment" and "treating" as used herein embrace both therapeutic, i.e. curative and/or palliative, and preventive, i.e. prophylactic, treatment.

Therapeutic treatment refers to the treatment of patients having already developed one or more of said conditions in manifest, acute or chronic form. Therapeutic treatment may be symptomatic treatment in order to relieve the symptoms of the specific indication or causal treatment in order to reverse or partially reverse the conditions of the indication or to stop or slow down progression of the disease.

Preventive treatment ("prevention") refers to the treatment of patients at risk of developing one or more of said conditions, prior to the clinical onset of the disease in order to reduce said risk.

The terms "treatment" and "treating" include the administration of one or more active compounds in order to prevent or delay the onset of the symptoms or complications and to prevent or delay the development of the disease, condition or disorder and/or in order to eliminate or control the disease, condition or disorder as well as to alleviate the symptoms or complications associated with the disease, condition or disorder.

The term "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents the particular disease or condition, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease or condition, or (iii) prevents or delays the onset of one or more symptoms of the particular disease or condition described herein.

The instant application refers to a combination of a therapeutically effective amount of a PDE4B-inhibitor of formula I
<CHM>.

In a preferred embodiment of the above-mentioned combination said PDE4B-inhibitor of formula I is administered in a dose that will lead to an estimated human free fraction of the compound of formula I between <NUM> nMol/L to <NUM> nMol/L, more preferred between <NUM> nMol/L to <NUM> nMol/L.

In a preferred embodiment of the above-mentioned combination the Progressive Fibrosing Interstitial Lung Disease is Idiopathic Pulmonary Fibrosis (IPF) or systemic Sclerosis ILD (SSc-ILD).

In another preferred embodiment of the above-mentioned combination the above-mentioned PDE4B-inhibitor of formula I is administered simultaneously, concurrently, sequentially, successively, alternately or separately with the tyrosine kinase inhibitor selected from the group consisting of Nintedanib and a pharmaceutically acceptable salt thereof.

In a further preferred embodiment of the above-mentioned combination said tyrosine kinase inhibitor is Nintedanib in the form of its monoethanesulfonate.

In another further preferred embodiment of the above-mentioned combination said tyrosine kinase inhibitor is Nintedanib in the form of its monoethanesulfonate and is administered in a dose that will lead to an estimated human free fraction of Nintedanib monoethanesulfonate between <NUM> nMol/L to <NUM> nMol/L, more preferred between <NUM> nMol/L to <NUM> nMol/L.

In a more preferred embodiment of the above-mentioned combination said PDE4B-inhibitor of formula I is selected from the group consisting of the compound of formula II
<CHM>.

In a particularly preferred embodiment of the above-mentioned combination said PDE4B-inhibitor of formula I is the compound of formula III
<CHM>
or a pharmaceutically acceptable salt thereof.

In another particularly preferred embodiment of the above-mentioned combination said PDE4B-inhibitor of formula I is the compound of formula III and is administered in a dose that will lead to an estimated human free fraction of the compound of formula III between <NUM> nMol/L to <NUM> nMol/L, more preferred between <NUM> nMol/L to <NUM> nMol/L.

Furthermore, the instant application refers to a PDE4B-inhibitor of formula I
<CHM>.

In a preferred embodiment the above-identified Progessive Fibrosing Interstitial Lung Disease (PF-ILD) is either idiopathic pulmonary fibrosis (IPF) or systemic sclerosis ILD (SSC-ILD), more preferred IPF.

In another preferred embodiment the above-mentioned PDE4B-inhibitor of formula I is administered simultaneously, concurrently, sequentially, successively, alternately or separately with the tyrosine kinase inhibitor selected from the group consisting of Nintedanib and a pharmaceutically acceptable salt thereof.

In a further preferred embodiment the above-mentioned tyrosine kinase inhibitor is Nintedanib in the form of its monoethanesulfonate.

In another further preferred embodiment the above-mentioned tyrosine kinase inhibitor is Nintedanib in the form of its monoethanesulfonate and is administered in a dose that will lead to an estimated human free fraction of Nintedanib monoethanesulfonate between <NUM> nMol/L to <NUM> nMol/L, more preferred between <NUM> nMol/L to <NUM> nMol/L.

In a more preferred embodiment the above-mentioned PDE4B-inhibitor of formula I is selected from the group consisting of the compound of formula II
<CHM>.

In a particularly preferred embodiment the above-mentioned PDE4B-inhibitor of formula I is the compound of formula III
<CHM>
or a pharmaceutically acceptable salt thereof.

In another particularly preferred embodiment the above-mentioned PDE4B-inhibitor of formula I is the compound of formula III and is administered in a dose that will lead to an estimated human free plasma fraction of the compound of formula III between <NUM> nMol/L to <NUM> nMol/L, more preferred between <NUM> nMol/L to <NUM> nMol/L.

Further, the instant application refers to a tyrosine kinase inhibitor selected from the group consisting of Nintedanib and pharmaceutically acceptable salts thereof for its combined use together with a therapeutically effective amount of a PDE4B-inhibitor of formula I
<CHM>.

In a preferred embodiment the above one or more Progressive Fibrosing Interstitial Lung Diseases (PF-ILDs) will be either idiopathic pulmonary fibrosis (IPF) or systemic sclerosis ILD (SSC-ILD, more preferred IPF.

In another preferred embodiment the above-mentioned tyrosine kinase inhibitor is administered simultaneously, concurrently, sequentially, successively, alternately or separately with the PDE4B-inhibitor of formula I.

In another further preferred embodiment the tyrosine kinase inhibitor is Nintedanib in the form of its monoethanesulfonate and is administered in a dose that will lead to an estimated human free fraction of Nintedanib monoethanesulfonate between <NUM> nMol/L to <NUM> nMol/L, more preferred between <NUM> nMol/L to <NUM> nMol/L.

In another embodiment the instant application refers to a pharmaceutical composition comprising:.

In a preferred embodiment the application refers to the above-mentioned pharmaceutical composition, wherein said tyrosine kinase inhibitor is Nintedanib in the form of its monoethanesulfonate.

In another further preferred embodiment of the above-mentioned pharmaceutical composition said tyrosine kinase inhibitor is Nintedanib in the form of its monoethanesulfonate and is administered in a dose that will lead to an estimated human free fraction of Nintedanib monoethanesulfonate between <NUM> nMol/L to <NUM> nMol/L, more preferred between <NUM> nMol/L to <NUM> nMol/L.

In a preferred embodiment the instant application refers to the above-mentioned pharmaceutical composition, wherein said PDE4-B-inhibitor of formula I is selected from the group consisting of the compound of formula II
<CHM>.

In a particularly preferred embodiment the instant application refers to the above-mentioned pharmaceutical composition, wherein said PDE4-B-inhibitor of formula I is the compound of formula III
<CHM>
or a pharmaceutically acceptable salt thereof.

In another particularly preferred embodiment the instant application refers to the above-mentioned pharmaceutical composition, wherein said PDE4-B-inhibitor of formula I is the compound of formula III in a dose that leads to an estimated human free plasma fraction of the compound of formula III between <NUM> nMol/L and <NUM> nMol/L, preferably between <NUM> nMol/L and <NUM> nMol/L.

In a further embodiment the instant application refers to a kit comprising:.

In a preferred embodiment the application refers to the above-identified kit is for use in a method of treating one or more Progressive Fibrosing Interstitial Lung Diseases (PF-ILDs).

In a more preferred embodiment the application refers to the above-identified kit is for use in a method of treating either idiopathic pulmonary fibrosis (IPF) or systemic sclerosis ILD (SSc-ILD).

In another preferred embodiment the application refers to the above-identified kit is for use in a method of treating one or more PF-ILDs, wherein said first pharmaceutical composition or dosage form is to be administered simultaneously, concurrently, sequentially, successively, alternately or separately with the second pharmaceutical composition or dosage form.

In a further preferred embodiment the application refers to above-identified kit, wherein said tyrosine kinase inhibitor of the second pharmaceutical composition or dosage form is Nintedanib in the form of its monoethanesulfonate.

In another further preferred embodiment the above-mentioned kit said tyrosine kinase inhibitor is Nintedanib in the form of its monoethanesulfonate and is administered in a dose that will lead to an estimated human free fraction of Nintedanib monoethanesulfonate between <NUM> nMol/L to <NUM> nMol/L, more preferred between <NUM> nMol/L to <NUM> nMol/L.

In a more preferred embodiment the application refers to above-identified kit, wherein said first pharmaceutical composition or dosage form comprises a PDE4B-inibitor of formula I selected from the group consisting of the compound of formula II
<CHM>.

In a particularly preferred embodiment the application refers to above-identified kit, wherein said first pharmaceutical composition or dosage form comprises the PDE4B inhibitor compound of formula III
<CHM>
or a pharmaceutically acceptable salt thereof.

In another particularly preferred embodiment the instant application refers to the above-mentioned kit, wherein said PDE4-B-inhibitor of formula I in the first pharmaceutical composition or dosage form is the compound of formula III in a dose that leads to an estimated human free plasma fraction of the compound of formula III between <NUM> nMol/L and <NUM> nMol/L, preferably <NUM> nMol/L and <NUM> nMol/L.

In a particularly preferred embodiment the application refers to any of the above-identified kits, further comprising.

In another particularly preferred embodiment the application refers to any of the above-identified kit, further comprising.

Concentration-dependent inhibition of TGF-β-stimulated α-SMA protein expression of human lung fibroblasts from patients with IPF by the compound of formula III (filled circles, black line; IC<NUM> = <NUM> nMol/L) or a combination of the compound of formula III with <NUM> nMol/L Nintedanib (empty circles, grey line; IC<NUM> = <NUM> nMol/L).

□ represents the measured inhibition of α-SMA protein expression of the fibroblasts in the presence of <NUM> Nintedanib alone which showed no inhibitory effect.

Data are presented ± SEM of n = <NUM> donors. Data were normalized to untreated (non-stimulated) control cells (=<NUM>% inhibition) and to TGF-β-treated cells (=<NUM>% inhibition).

Concentration-dependent inhibition of TGF-β-stimulated α-SMA protein expression of human lung fibroblasts from patients with IPF by Apremilast (filled circles, black line; IC<NUM> = <NUM>µMol/L) or a combination of Apremilast with <NUM> nMol/L Nintedanib (empty circles, grey line; IC<NUM> = <NUM>µMol/L).

□ represents the measured inhibition of α-SMA protein expression of the fibroblasts in the presence of <NUM> Nintedanib alone which showed no inhibitory effect.

Data are presented ± SEM of n = <NUM> donors. Data are normalized to untreated (non-stimulated) control cells (=<NUM>% inhibition) and to TGF-β treated cells (=<NUM>% inhibition).

Concentration-dependent inhibition of TGF-β-stimulated α-SMA protein expression of human lung fibroblasts from patients with IPF by Roflumilast N-Oxide (filled circles, black line ; IC<NUM> = <NUM> nMol/L) or a combination of Roflumilast N-Oxide with <NUM> nMol/L Nintedanib (empty circles, grey line; IC<NUM> = <NUM> nMol/L).

Data are presented ± SEM of n = <NUM> donors. Data are normalized to untreated (non-stimulated) control cells (=<NUM>% inhibition) and TGF-β treated cells (=<NUM>% inhibition).

Concentration-dependent inhibition of FGF plus IL-1β-stimulated proliferation of human lung fibroblasts from patients with IPF by the compound of formula III (filled circles, black solid line; IC<NUM> = <NUM> nMol/L) or a combination of the compound of formula III with <NUM> nmol/L Nintedanib (empty circles, grey solid line; IC<NUM> = <NUM> nMol/L). The calculated additive curve of the combination of both drugs is represented by the empty triangles and the dashed line.

□ represents the FGF plus IL-1β-stimulated proliferation of human lung fibroblasts from patients with IPF by <NUM> Nintedanib alone.

Data are presented ± SEM of n = <NUM> donors. Data are normalized to untreated (non-stimulated) control cells (=<NUM>% inhibition) and to FGF + IL-1β treated cells (=<NUM>% inhibition).

Concentration-dependent inhibition of FGF plus IL-1β-stimulated proliferation of human lung fibroblasts from patients with IPF by Apremilast (filled circles, black solid line; IC<NUM> = <NUM>µMol/L ) or a combination of Apremilast with <NUM> nMol/L Nintedanib (empty circles, grey solid line; IC<NUM> = <NUM>µMol/L). The calculated additive curve of the combination of both drugs is represented by the empty triangles and the dashed line.

Concentration-dependent inhibition of FGF plus IL-1β-stimulated proliferation of human lung fibroblasts from patients with IPF by Roflumilast N-Oxide (filled circles, black solid line; IC<NUM> = <NUM> pMol/L) or a combination of Roflumilast N-Oxide with <NUM> nMol/L Nintedanib (empty circles grey solid line; IC<NUM> = <NUM> pMol/L).

The calculated additive curve of the combination of both drugs is represented by empty triangles and a dashed line.

Pathogenesis of fibrotic processes that are common to ILDs, PF-ILDs and IPF are presently not completely understood.

The main characteristics of IPF are changes in epithelial and mesenchymal cells as well as the interaction between these cells whereas it is currently believed that inflammatory processes play only a minor role [<NPL>]. One widely accepted hypothesis to explain the mechanisms in IPF pathogenesis postulates that an injury of the alveolar epithelium results in an excessive wound healing response with overshooting release of growth and transcription factors and cytokines subsequent activation and transformation of fibroblasts to the secreting myofibroblast phenotype resulting in excessive production of extracellular matrix (ECM) proteins, [<NPL>]. The fibroblast focus, a typical histological feature of IPF, is a specific aggregate of cells, especially of fibroblasts and of myofibroblasts, covered by injured and hyperplastic epithelium, and ECM produced by myofibroblasts [<NPL>]. Studies have revealed that IPF patients with a high number of fibroblast foci have a shortened survival [<NPL>]. In addition, the extent of expression of alpha smooth muscle actin (α-SMA), as a marker of myofibroblasts, in the lungs of IPF-patients, has been shown to be negatively associated with patient survival [Waisberg DR, Parra ER, Barbas-Filho JV, Fernezlian S, Capelozzi VL]. Increased fibroblast telomerase expression precedes myofibroblast alpha-smooth muscle actin expression in idiopathic pulmonary fibrosis [<NPL>].

Current paradigms of pathogenesis of fibrotic processes suggest that following exposure to endogenous or exogenous stimuli, the lung epithelium initiates an injury response resulting in the production of soluble factors such as Transforming Growth Factor beta-<NUM> (TGF-β1), platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF), and cytokines including interleukin-<NUM> (IL-<NUM>) and interleukin-<NUM> (IL-<NUM>). These substances promote recruitment of inflammatory cells and mesenchymal activation which causes expansion of tissue resident post-embryonic fibroblasts which are thought to give rise to activated myofibroblasts. These cells are central to the process of wound healing but, if unmodulated, deposit excessive ECM and destroy normal lung architecture. During normal wound healing, myofibroblasts are transiently activated and direct production of granulation tissue by producing ECM and exerting traction forces. Once healing is achieved, granulation tissue is resorbed and myofibroblasts undergo programmed cell death to restore normal tissue architecture and function [<NPL>]. Disruptions at any stage in this process could cause tissue pathology. When the healing response is insufficient, as is seen in acute respiratory distress syndrome, a pathology dominated by acute injury and diffuse alveolar damage ensues. However, when the healing phase dominates, the tissue milieu shifts towards fibrosis and remodeling and a pathology dominated by the dysregulated accumulation of scar tissue is seen. Fibroblasts and activated myofibroblasts are believed to be central to this process [<NPL>].

In a further level, fibroblasts and myofibroblasts in IPF demonstrate a pathologic phenotype characterized by uncontrolled proliferation and survival. These cells accumulate in lung interstitium where they deposit excessive amounts of collagen-I rich ECM and ultimately organize into the fibroblastic foci described above. As these regions expand and become juxtaposed to the alveolar space, they appear to first rupture and then ultimately destroy the alveolar basement membrane [<NPL>].

This expansion is largely attributed to the resistance to programmed cell death that has been described for primary fibroblasts obtained from IPF lung tissue [<NPL> and <NPL>]. Several possible mechanisms are proposed for this observation including abnormalities in apoptotic pathways, aberrant Wnt signaling [<NPL>], and defective autophagy [<NPL>].

However, a number of well characterized cytokines, including TGF-β, have been either found in injured lungs or had been produced by inflammatory cells removed from the lung. Further, in an animal model of pulmonary fibrosis, TGF-β production was increased prior to collagen synthesis and was mainly produced by alveolar macrophages. In advanced idiopathic pulmonary fibrosis extensive TGF-β deposition can be detected by immunohistochemical staining, primarily in epithelial cells in areas of lung regeneration and remodelling. This suggests that the pathogenesis of the progressive fibrosis characteristic of lung diseases such as ILDs, PF-ILDs and IPF may be an aberrant repair process (see <NPL> and <NPL>.

From this background information on fibrosis it is clear that the pathology of fibrotic processes underlying ILDs, PF-ILDs and in particular IPF can be divided into " three different levels of pathogenesis of fibrotic processes", whereby the chronological order especially of the second and the third level is not yet fully understood and could also partially take place in parallel.

In a first level of fibrotic processes, following exposure to endogenous or exogenous stimuli, the lung epithelium usually initiates an injury response resulting in the production of soluble factors such as Transforming Growth Factor beta-<NUM> (TGF-β1), cytokines and of pro-fibrotic mediators/fibrotic markers such as for instance procollagen, fibronectin and MCP-<NUM>.

Then, in a second level of pathogenesis of fibrotic processes, these profibrotic mediators/fibrotic markers promote mesenchymal activation which causes expansion of tissue resident post-embryonic fibroblasts which are thought to give rise to myofibroblasts, an activated form of fibroblasts. These myofibroblasts are central to the process of wound healing, but if unmodulated, they produce excessive amounts of extracellular matrix material and collagen/scar tissue. This "myofibroblast phenotype" is further characterized by a strong α-smooth muscle actin (α-SMA) expression. The transformation/activation of fibroblasts into myofibroblast, which strongly express α-SMA protein, forms the second level of pathogenesis of fibrotic processes common to ILDs, PF-ILDs and IPF.

Consequently quantification of the α-smooth muscle actin (α-SMA) protein expression is a suitable measurement for the extent of transformation/activiation of fibroblasts into myofibroblasts which corresponds to the second level of pathogenesis of fibrotic processes common to ILDs, PF-ILDs and IPF.

The third level of pathogenesis of fibrotic processes common to ILDs, PF-ILDs and IPF is characterized by uncontrolled proliferation/cell division and survival of fibroblasts and myofibroblasts, probably by their resistance to programmed cell death. Proliferating fibroblasts and myofibroblasts accumulate in lung interstitium where they deposit excessive amounts of collagen-I rich ECM and ultimately organize into the fibroblastic foci.

Quantification of cell division (for instance by quantification of incorporation of BrdU into the DNA of proliferating fibroblasts) is a suitable measurement for the extent of proliferation of fibroblasts which corresponds to the third level of pathogenesis of fibrotic processes common to ILDs, PF-ILDs and IPF.

Lung fibroblasts of IPF-patients (IPF-LF cells) grown in <NUM>-well plates were incubated for <NUM> with different concentrations of the PDE4 inhibitors "Compound of formula III", "Apremilast" or "Roflumilast-N-Oxide" or with a combination of each of the aforementioned PDE4-inhibitiors with Nintedanib.

After compound incubation cells were stimulated with the assay-relevant stimulus and incubated for the assay -relevant time in the presence of the test compounds.

α-SMA protein was determined by a Western-replacement assay (MSD) using monoclonal anti smooth muscle actin antibodies.

BrdU incorporated in the DNA of proliferating cells was determined by ELISA.

BrdU is an analog of the DNA precursor thymidine. In proliferating cells, the DNA has to be replicated before the division can take place. If BrdU is added to the cell culture, proliferating cells will incorporate it into their DNA just like they would incorporate thymidine. The amount of BrdU in the DNA of cells can be detected with specific anti-BrdU fluorescent antibodies followed by flow cytometry or by cellular ELISA with monoclonal antibodies against BrdU.

IPF-lung fibroblasts (passage <NUM> to <NUM>) were seeded in <NUM>-well cell culture plates at <NUM> cells/well with <NUM>µL/well FBM + supplements. <NUM> after seeding the cells were washed once with FBM medium without supplements and starved for <NUM>.

In experiment A1) the PDE4B-inhibitor of formula III was used as a" test compound".

In experiment A2) Apremilast was used as a" test compound".

In experiment A3) Roflumilast-N-oxide was used as a" test compound".

All "test compounds" (the PDE4B-inhibitor of formula III, Apremilast or Roflumilast) were prepared 1000x in <NUM> mmol/L HCl or DMSO and a <NUM>:<NUM> dilution series was performed (in <NUM> mmol/L HCl or DMSO). To obtain 2x concentrated compound-medium a <NUM>:<NUM> dilution (<NUM>µl of the 1000x dilution was added to <NUM>µl FBM plus <NUM> nmol/L PGE2) was prepared.

<NUM> after seeding, the medium was aspirated and FBM (<NUM>µl per well) was added. After <NUM> incubation at <NUM>, <NUM>µl medium containing 2x concentrated compounds (at different concentrations) plus 2x concentrated PGE2 (<NUM> nmol/L) was added for <NUM>. Final concentration for PGE2 was <NUM> nmol/L.

<NUM> after test compound pre-incubation (<NUM>µL), <NUM>µl of 20x concentrated TGF-β was added and the cells stimulated for <NUM> at a temperature of <NUM>.

For this purpose the TGF-β stock solution (<NUM>µg/mL reconstituted in <NUM> mmol/L sterile HCL) was diluted <NUM>:<NUM> in starvation medium to reach a concentration of <NUM> ng/mL. <NUM>µL of this TGF-β medium or starvation medium was added to indicated wells. The test compound concentration was maintained during the stimulation. The final TGF-β concentration was <NUM> ng/mL.

<NUM> after stimulation supernatants were removed and stored at -<NUM> for further experiments. Cells were washed once with ice cold PBS and <NUM>µl RIPA buffer containing 1x protease inhibitor was added per well. Lysates were incubated for <NUM> minutes on ice before stored at -<NUM>.

After thawing, <NUM>µl of each lysate was transferred to the membrane of the multi-array <NUM> well plate (MSD) and incubated for <NUM> at room temperature with gentle shaking. After the incubation time, plates were washed <NUM> times with <NUM>µl 1x Tris-wash buffer (MSD) and <NUM>µl of <NUM>% blocking buffer was added for <NUM>. After blocking, plates were washed <NUM> times with <NUM>µl 1x Tris-wash buffer and <NUM>µl of the antibody solution (per plate <NUM> <NUM>% blocking buffer, <NUM> 1x Tris-wash buffer, <NUM>µl anti-α-SMA antibody (<NUM>:<NUM>), <NUM>µl goat anti-mouse sulfo-tag antibody (<NUM>:<NUM>) was added for <NUM>. After AB-incubation plates were washed <NUM> times with <NUM>µl 1x Tris-wash buffer and <NUM>µl of 1x MSD read buffer was added per well. Plates were measured with Sector Imager (MSD).

IPF-lung fibroblasts (passage <NUM> to <NUM>) were seeded in <NUM>-well cell culture plates at <NUM> cells/well with <NUM>µL/well FBM + supplements. <NUM> after seeding the cells were washed once with FBM medium without supplements and then kept in this medium for <NUM> starvation.

In experiment B1) the PDE4B-inhibitor of formula III was used as a" test compound".

The dashed line with the empty triangles represents the "calculated additive curve" of a combination treatment of <NUM> nMol/L Nintedanib with the corresponding concentration of the PDE4B-inhibitor of formula III.

In experiment B2) Apremilast was used as a" test compound".

The dashed line with the empty triangles represents the "calculated additive curve" of a combination treatment of <NUM> nMol/L Nintedanib with the corresponding concentration of Apremilast.

In experiment B3) Roflumilast-N-oxide was used as a" test compound".

The dashed line with the empty triangles represents the "calculated additive curve" of a combination treatment of <NUM> nMol/L Nintedanib with the corresponding concentration of Roflumilast-N-oxide.

All test compounds were prepared 1000x in <NUM> mmol/L HCl or DMSO and a <NUM>:<NUM> dilution series was performed (in <NUM> mmol/L HCl or DMSO). To obtain 1x concentrated compound medium <NUM>µl of the 1000x DMSO dilution was added to <NUM>µl FBM.

<NUM> after seeding, medium was removed by suction and <NUM>µl compound- or starvation medium was added for <NUM>.

<NUM> after test compound pre-incubation (<NUM>µL), <NUM>µl of 10x concentrated FGF plus IL-1β was added and the cells were stimulated for <NUM> at a temperature of <NUM>.

For this purpose the FGF and IL-1β stock solutions (<NUM>µg/mL and <NUM>µg/mL respectively) were diluted in starvation medium to reach a concentration of <NUM> ng/mL and <NUM> pg/mL for FGF and IL-1β respectively. <NUM>µL of this stimulus medium or starvation medium was added to the indicated wells. The test compound concentration was maintained during the stimulation.

The final FGF concentration was <NUM> ng/mL. The final IL-1β concentration was <NUM> pg/mL.

Proliferation was determined by a colorimetric immunoassay for the quantification of cell proliferation, based on the measurement of BrdU incorporation during DNA synthesis.

The assay was carried out according to the manufacturer's instructions.

<NUM> after stimulation a <NUM>:<NUM> dilution of BrdU in starvation medium (resulting concentration <NUM>µmol/L) was performed and <NUM>µl added per well (end-concentration per well <NUM>µmol/l). About <NUM> later the BrdU medium was removed by suction. Cells were fixed and denatured for <NUM> at room temperature with FixDenat reagent. The reagent was removed by tapping and the anti-BrdU-POD working solution was added (incubation time: <NUM>). The plate was washed three times with <NUM>µL washing buffer before incubation with substrate solution for about <NUM>. The reaction was stopped by adding <NUM> mol/L H<NUM>SO<NUM> to the substrate solution and plates were read at <NUM> in a photometer (EnVision <NUM> Multilabel reader, PerkinElmer).

x-fold of unstimulated control was calculated from optical density readings (OD) for BrdU assay or from MSD units (α-SMA assay).

The % inhibition-value was calculated from the x-fold of unstimulated control.

In each of the experiments for the different donors all inhibition values were determined in duplicates or triplicates.

Means of blanks were subtracted from all values.

The IC<NUM> -values of stimulated cells were determined as follows: <MAT>.

Non-linear regression of log (inhibitor concentration) versus % inhibition-value was calculated using three parameter fitting with variable slope of the Graph Pad Prism Software package.

To calculate the additive effect of the compound of formula III, Apremilast or Roflumilast-N-Oxide combined with Nintedanib the following formula was used <MAT>.

The test compounds Compound of formula III, Apremilast, Roflumilast-N-Oxide, and Nintedanib were dissolved in DMSO and stored at -<NUM>. A serial dilution of <NUM> concentrations was prepared before each experiment.

FBM (fibroblast basal medium, Lonza, Cat. No: CC-<NUM>) supplemented with insulin, FGF-<NUM>, <NUM> % FBS, GA-<NUM> (all in FGM-<NUM> SingleQuots, Lonza, Cat. No. CC-<NUM>).

FBM plus <NUM> ng/mL rhTGF-β and <NUM> nmol/L PGE2.

FBM plus <NUM> ng/mL rhbFGF plus <NUM> pg/mL rhIL-1β.

The more a specific active agent tends to inhibit the TGF-β-stimulated α-SMA protein expression of human lung fibroblasts of IPF patients, the more this active agent will have a therapeutic effect in the second level of pathogenesis of fibrotic processes which is the transition of fibroblasts into myofibroblasts.

Consequently in this Experiment A) mimicking the second level of fibrotic processes the effect of.

on the TGF-β-stimulated α-SMA protein expression of human lung fibroblasts of IPF patients was experimentally determined.

Whereas Nintedanib - administered alone - in the concentration <NUM> nMol/L showed in this experiment no inhibitory effect on TGF-β-stimulated α-SMA protein expression of human lung fibroblasts (supporting the fact that Nintedanib in this concentration alone shows no therapeutic effect on the second level of pathogenesis of fibrotic processes (see □ in <FIG> and <FIG>: Inhibition was ≤<NUM>) , all tested PDE4-inhibitors (the compound of formula III, Apremilast and Roflumilast-N-oxide ) - when administered alone and also when administered together with Nintedanib in the fixed concentration of <NUM> nMol/L - showed - at least in certain concentrations - a concentration-dependent inhibition on TGF-β-stimulated α-SMA protein expression of human lung fibroblasts which supports a certain therapeutic effect of all these PDE4-inhibitors in the second level of pathogenesis of fibrotic processes (the activation to myofibroblasts).

From these results it can be concluded that PDE4-inhibitors - at least in certain concentration ranges - have the potential to show a concentration-depending therapeutic effect on the "fibroblast to myofibroblast transition/activation", an event that represents the second level of pathogenesis of fibrotic processes which are common to ILDs, particularly to PF-ILDs, whereas Nintedanib in the concentration <NUM> nMol/L alone does not show a therapeutic effect on this very same "second level of pathogenesis" according to this experiment.

Consequently PDE4-inhibitors show in relation to Nintedanib a so-called "complementary effect" or "supplementary effect" on the "fibroblast to myofibroblast transition/activation " (= second level of pathogenesis of fibrotic processes). Therefore an administration of Nintedanib together with a PDE4B-inhibitor of formula III will show a superior effect on therapeutic efficacy compared to the IPF-treatment with for instance Nintedanib alone.

If you compare the measured inhibition on the TGF-β-stimulated α-SMA protein expression of human lung fibroblasts for the compound of formula III (<FIG>), for Apremilast (<FIG>) and for Roflumilast-N-oxide (<FIG>), it is obvious that only for the compound of formula III (<FIG>) the complete concentration/inhibition curve is located at inhibitions of "above zero", whereas for instance for Apremilast and in particular for Roflumilast-N-oxide" low PDE4-inhibitor concentrations (either alone or in combination with Nintedanib)" lead to "negative inhibitions of TGF-β-stimulated α-SMA protein expression" (supporting the absence of a therapeutic effect on the second level of fibrotic processes for Apremilast and in particular for Roflumilast-N-oxide at these lower concentrations (whereas the compound of formula III seems to show a positive inhibition of TGF-β-stimulated α-SMA protein expression in all tested concentrations).

The more a specific active agent tends to inhibit proliferation of cultured human lung fibroblasts of IPF patients, the more this active agent will have a therapeutic effect in the third level of pathogenesis of fibrotic processes which is fibroblast proliferation.

on the proliferation of human lung fibroblasts of IPF patients was experimentally determined in Experiment B).

In this experiment B) mimicking the third level of pathogenesis of fibrotic processes (the "fibroblast proliferation"), Nintedanib administered alone in the concentration <NUM> nMol/L already showed a clear inhibitory effect on human lung fibroblasts proliferation (see inhibition data points symbolized by o in <FIG>, <FIG>).

However, the results of Experiments B1) in <FIG>, B2) in <FIG> and B3) in <FIG> show that not only Nintedanib alone has an inhibitory effect on fibroblast proliferation, but that also PDE4-inhibitors such as the compound of formula III (see filled circles and black solid curve in B1, <FIG>)), Apremilast (see filled circles and black solid curve in B2, <FIG>)) and Roflumilast-N-oxide (see filled circles and black solid curve in B3 in <FIG>)) show in general a concentration-dependent inhibitory effect on fibroblast proliferation and therefore seem to have a therapeutic effect on fibroblast proliferation (third level of pathogenesis of fibrotic processes).

Since obviously both Nintedanib in the fixed concentration of <NUM> nMol/L and the tested PDE4-inhibitors concentration-dependently show an inhibitory effect on fibroblast proliferation, a simple "additive effect" for the inhibition of fibroblast proliferation by the combination of <NUM> nMol/L Nintedanib and the corresponding PDE4-inhibitor in its respective concentration should be expected.

In <FIG>, <FIG> the dashed curves with the empty triangles represent these "calculated additive combination curves" which were calculated from the simple "addition" of the measured inhibition-value for <NUM> nMol/L Nintedanib plus the measured inhibition -value for the corresponding PDE4-inhibitor alone in variable concentrations.

However, the grey solid curves with the empty circles in <FIG>, <FIG> represent the "experimentally measured inhibition-curves for the combinations comprising <NUM> nMol/L Nintedanib and the corresponding PDE4-inhibitor in variable concentrations".

Surprisingly, in <FIG> which shows the results of Experiment B1) the "experimentally measured inhibition curve of fibroblast proliferation" for the combination of Nintedanib with the compound of formula III (solid grey line, empty circles) is "significantly shifted to the left" (that means towards lower concentrations of the compound of formula III) compared to the corresponding "calculated additive inhibition curve" for the combination of Nintedanib with the compound of formula III (dashed curve with empty triangles).

This significant "left-shift" is a clear indicator for an "overadditive synergistic effect" of the combination of <NUM> nMol/L Nintedanib with the compound of formula III. This experimentally observed "overadditive synergistic effect" for the combination of Nintedanib and the compound of formula III was completely surprising, in particular because this synergistic overadditive effect does not seem to be a "class effect".

<FIG> shows the results of the corresponding Experiment B2), wherein the compound of formula III was exchanged by Apremilast. <FIG> shows that the "experimentally measured inhibition curve" for the combination of Nintedanib with Apremilast (solid grey line, empty circles) is not shifted to the left, but instead is even slightly shifted to the right (that means to higher Apremilast concentrations) compared to the corresponding "calculated additive inhibition curve" for the combination of Nintedanib with Apremilast (dashed curve with empty triangles). Such a "right-shift" would theoretically even be an indicator for a "less than additive inhibition of fibroblast proliferation" (an "anti-synergistic effect") by the combination of Nintedanib and Apremilast. However, this rather slight right-shift of the "measured Nintedanib/Apremilast combination curve" compared to the "calculated Nintedanib/Apremilast combination curve" is more or less within the error bars and therefore not statistically relevant. Consequently, for the combination of Nintedanib with Apremilast more or less a normal "addititve effect" as expected could be experimentally observed.

<FIG> shows the results of the corresponding Experiment B3), wherein the compound of formula III was exchanged by Roflumilast-N-oxide. <FIG> shows that the "experimentally measured inhibition curve" for the combination of Nintedanib with Roflumilast-N-oxide (solid grey line, empty circles) is also shifted to the right instead to the left compared to the corresponding "calculated additive inhibition curve" for the combination of Nintedanib with Roflumilast-N-oxide (dashed curve with empty triangles). Such a "right-shift" is an indicator for a "less than additive inhibition of fibroblast proliferation" (anti-synergistic effect) for the combination of Nintedanib and Roflumilast-N-oxide. This "right-shift" of the "measured Nintedanib/Roflumilast combination curve" compared to the "calculated Nintedanib/Roflumilast combination curve" is only for very high Roflumilast-N-oxide concentration beyond the error bar ranges. Consequently for the combination of Nintedanib with Roflumilast-N-oxide also a more or less "additive effect" as expected could be experimentally determined.

This "overadditive synergistic effect" on the inhibition of fibroblast proliferation which was exclusively observed for the combination of Nintedanib with the compound of formula III is also reflected in the large differences of the IC<NUM>-values calculated for the concentration/inhibition curves.

Here the IC<NUM>-value for the inhibition curve measured for the compound of formula III administered alone is compared to the IC<NUM>-value for the inhibition curve measured for the combination of the compound of formula III with Nintedanib <NUM>-fold larger (<NUM> nMol/L /<NUM> nMol/L = <NUM>).

In contrast to that, the corresponding differences in the IC<NUM>-values for the inhibition curves measured for the other PDE4-inhibitors Apremilast and Roflumilast-N-oxide administered alone compared to the inhibition curve measured for the corresponding PDE4-inhibitor/Nintedanib combinations were much smaller (<NUM>,<NUM>-fold larger for Apremilast, <NUM>,<NUM>-fold smaller for Roflumilast-N-oxide).

This experimentally determined "overadditive synergistic effect" on the inhibition of fibroblast proliferation which was exclusively observed for the combination of the compound of formula III with Nintedanib obviously does not seem to be a "class effect", since none of the other tested PDE4-inhibitors Apremilast or Roflumilast showed in combination with Nintedanib a corresponding similar "overadditive synergistic effect", but instead only the expected "additive inhibitory effect" (Nintedanib/Roflumilast-N-oxide showed at large Roflumilast-N-oxide-concentrations even a "less than additive inhibitory effect").

Consequently the combination of Nintedanib with the PDE4B-inhibitor of formula III shows due to the experimentally observed overadditive synergistic inhibitory effect on fibroblast proliferation surprisingly a clearly improved therapeutic efficacy for the treatment of PF-ILD-patients not only compared to treatment with the individual single agents, but also compared to the alternative combinations Nintedanib/Roflumilast-N-oxide and Nintedanib/Apremilast.

Consequently Experiments A) and B) have experimentally shown that the combination comprising the PDE4B-inhibitor of formula III and Nintedanib shows.

Another additional advantage the combination of the PDE4B-inhibitor of formula III with Nintedanib obviously shows compared to other PDE4-inhibitor /Nintedanib combinations (such as for instance Roflumilast-N-oxide /Nintedanib) is its relatively good tolerability (in particularly with respect to gastrointestinal side effects).

It is known that Nintedanib and also Pirfenidone - the presently two only approved therapeutic agents for the treatment of IPF - show both significant gastrointestinal side effects such as diarrhea, nausea, vomiting, weight loss etc. which is the main reason why Nintedanib and Pirfenidone are usually not combined due to their additive and therefore more frequent gastrointestinal side effects.

In contrast to Nintedanib and Pirfenidone, the PDE4B-inhibitor of formula III has been shown to be relatively free of the PDE4-inhibitor-typical gastrointestinal side effects such as diarrhea in a corresponding rat experiment (see <CIT> Chapter <NUM>: Experiments of "gastric emptying" and "intestinal transit" and Fig. 2a (gastric emptying) and 2b (intestinal transit)). In these experiments it could be shown that a rising amount of Example compound No. <NUM> (which is identical to the PDE4B-inhibitor of formula III in the present application) had basically no effect on the gastric emptying and on the intestinal transit of a test meal in the rat compared to non-treated rats.

However, in similar "gastric emptying" and "intestinal transit" experiments the alternative PDE4-inhibitor Roflumilast has shown a clear trend to show gastrointestinal side effects.

Additionally, it is also well known from clinical trials that Roflumilast (which is only authorized for the treatment of COPD) shows significant gastrointestinal side effects in human COPD-patients such as diarrhea, nausea, weight loss.

In http://www. com/daliresp-drug. htm it is disclosed that Roflumilast given to COPD-patients in a dose of <NUM>µg daily lead.

Claim 1:
A combination of a therapeutically effective amount of a PDE4B-inhibitor of formula I
<CHM>
wherein Ring A is a <NUM>-membered aromatic ring which may optionally comprise one or two nitrogen atoms and
wherein R is Cl and
wherein R may be located either in the para-, meta- or ortho-position of Ring A,
wherein S* is a sulphur atom that represents a chiral center
or a pharmaceutically acceptable salt thereof
and a therapeutically effective amount of a tyrosine kinase inhibitor selected from the group consisting of Nintedanib and pharmaceutically acceptable salts thereof
for use in the treatment of one or more Progessive Fibrosing Interstitial Lung Disease.