HK1130019A - Treatment of early stage idiopathic pulmonary fibrosis - Google Patents

Description

Treatment of early stage idiopathic pulmonary fibrosis

Technical Field

The present invention relates to the use of an endothelin receptor antagonist (hereinafter ERA) for the treatment of early idiopathic pulmonary fibrosis (hereinafter IPF or early IPF).

Background

Idiopathic Pulmonary Fibrosis (IPF), also known as cryptogenic fibrotic alveolitis, is a clear clinical disease and falls within the scope of Interstitial Lung Disease (ILD). IPF is a progressive disease characterized by the presence of the tissue structure of the Usual Interstitial Pneumonia (UIP) on surgical lung biopsies. IPF is used to represent a chronic inflammatory disease that leads to parenchymal fibrosis. However, recent evidence suggests an abnormal wound healing mechanism with progressive extracellular matrix accumulation, reduced fibroblast-myoblast death, continuous epithelial apoptosis and abnormal epidermal reimplantation. Progressive fibrotic tissue deposited in the interstitial regions of the lung results in decreased lung compliance and decreased gas exchange.

The onset of symptoms is usually gradual and patients complain of dry cough, shortness of breath at the beginning of exercise, followed by shortness of breath at rest. Pallor disease, cor pulmonale and peripheral edema can be observed in the later stages of the disease.

The presence of a surgical lung biopsy reveals the tissue appearance of UIP, and a definitive diagnosis of IPF requires the following aspects (American thoracic society: diagnostic and treatment. American Thoracic Society (ATS) and European Respiratory Society (ERS). Am J Respir Crit Care Med 2000; 161: 646-64):

1) excluding other causes of the ILD's,

2) abnormal lung function studies, which included evidence: limitation of lung capacity and/or impaired gas exchange or reduced carbon monoxide Dispersion (DLCO),

3) abnormalities on conventional chest X-ray or High Resolution Computed Tomography (HRCT) scans.

Diagnostic criteria for IPF without surgical lung biopsy necessitate a correlation between all clinical and radiological features.

According to the LeadDiscovery (2006), idiopathic pulmonary fibrosis (hereinafter IPF) is a devastating, cruel progressive and fatal disease for which current treatments are poorly effective.

The prevalence and exact nature of the occurrence of IPF has not been reported at present. The prevalence is considered to be 3-6 per 100000 cases, but may be as high as 13-20 per 100000 cases. Prevalence is higher in older adults (two-thirds of patients over the age of 60 years) and men. Median survival time after biopsy to confirm IPF was less than 3 years.

No treatment has been shown to improve survival or quality of life in patients with IPF. Current treatment is still based on the previous assumption that IPF is an inflammatory process with simultaneous pulmonary fibrosis changes. Thus, it relates to anti-inflammatory therapies, including corticosteroid, immunosuppressive, cytotoxic agents (e.g. azathioprine, cyclophosphamide) or a combination of both. However, because of the marginal effects and serious side effects of current treatments, as well as the concomitant renewed understanding of the pathogenesis of IPF, novel treatment regimens are highly desirable. The goal of anti-fibrotic treatments is to reduce matrix deposition or increase collagen breakdown, and many agents including colchicine, D-penicillamine, interferon gamma, and pirfenidone (pirfenidone) are currently under investigation. Lung transplantation has been shown to be a viable option for some IPF patients.

The neurohormone endothelin-1 (ET-1) belongs to the family of 21-amino-acid peptides released from the endothelium and is one of the most potent known vasoconstrictors. ET-1 also promotes fibrosis, cell proliferation and alterations, and is pro-inflammatory. ET-1 can regulate matrix production and turnover by altering fibroblast metabolism to stimulate collagen synthesis or reduce interstitial collagenase production. Activation of the paracrine pulmonary ET system has been demonstrated in animal models of pulmonary fibrosis. ET-1 is also associated with human IPF. ET-1 is increased in airway epithelial cells and type II epithelial cells in IPF patients compared to control subjects and non-idiopathic fibrosis patients.

ET-1 is therefore a major contributing factor in the pathogenesis of IPF.

High Resolution Computed Tomography (HRCT) and traditional Computed Tomography (CT) are currently the best non-invasive tools for lung function testing, both to assess the extent of the disease and to try to delineate its progressive stage. The typical IPF at the onset of disease is mainly represented by ground-glass density (ground-glass) shadows on CT scans with little or no cells. The ground glass density imaged the gas cell filled with macrophages corresponding to alveolar septal fibrotic tissue, interstitial inflammation. In the later stages, the ground glass will be replaced by more mesh shadows and cells. The latter corresponds to lung destruction with bronchiectasis that communicates with the closest airway. Honeycomb lesions tend to slowly enlarge over time (King Jr. TE. Iophathic Interfacial tissues in Interfacial Lung Disease, 4 th edition, 701786, Schwartz, King, eds 2003 BC Decker Inc Hamilton-London).

The cells can be half-measured at the HRCT at the lobe level or in 5 increments of regions with scale sizes 0-5 or 0-100 (Lynch DA et al Am J Respir CritCare Med 2005172488-.

The early stages of IPF can be best characterized by the following features: the presence of no or few cells on the HRCT or CT scan, and the presence of frosting on one or both lungs, but are not limited to these features. Early IPF can be more accurately defined as IPF with no or few cells at the time of disease diagnosis. In rare cases, HRCT does not show ground glass density shadows and/or honeycombs and/or meshes. However, early IPF can also be diagnosed by common diagnostic tools, such tools not being limited to e.g. magnetic resonance imaging, broncho-alveolar lavage, lung biopsy for tissue evaluation (e.g. surgical, transtracheal or transmediastinal).

In addition, early IPF can also be diagnosed by a cardiopulmonary exercise test.

Although low or no cells are visible on the HRCT scan, cells are still visible on the tissue section.

The term "low cells" or "few cells" means that the cells are present in less than 25% of the entire lung field. In another embodiment, the term "low cells" or "few cells" means that the cells are present in less than 10% of the entire lung field.

According to LeadDiscovery (2006), diagnosing early IPF patients remains a significant challenge.

Bosentan (Bosentan)Is an oral treatment for PAH (grade III and IV in the us, grade III in europe). Bosentan is a dual endothelin receptor antagonist, with endothelin ET_AAnd ET_BBoth receptors have affinity, thereby preventing the deleterious effects of ET-1. Bosentan binding to ET with ET-1_AAnd ET_BCompetition at the receptor, with ET_AThe receptor (Ki ═ 4.1-43nM) has a specific ET_BThe receptor (Ki 38-730nM) had slightly higher affinity.

In a clinical study (BUILD-1), the efficacy of bosentan in Idiopathic Pulmonary Fibrosis (IPF) patients was evaluated in 2003. The study did not show an effect on the first endpoint of motor ability. However, bosentan demonstrated efficacy at a secondary endpoint associated with death or disease progression, providing a strong theoretical basis for mortality/morbidity studies at stage III of IPF.

The full analysis of the BUILD-1 study presented at the American Thoracic Society (ATS) conference (2006.05.23) included an assessment of the therapeutic efficacy of bosentan in patients who had undergone lung biopsy (n ═ 99) as evidence of IPF. This BUILD-1 finding demonstrated IPF was unexpected in lung-biopsies and further bosentan clinical evaluation confirmed this indication. Phase III mortality and morbidity studies (BUILD-3 studies) in patients with biopsy-proven IPF began in the end of 2006 and are still ongoing.

WO2004/105684 describes a combined NAC, SAPK and bosentan for IPF. However, no early IPF is mentioned in this publication.

WO2005/110478 describes a combination of pirfenidone or a pirfenidone analog and bosentan for IPF. Furthermore, WO2005/110478 describes combined IFN- γ and bosentan for IPF. However, no early IPF is mentioned in this publication.

Surprisingly, we found that this effect of bosentan was limited in early IPF patients. Therefore bosentan is useful for the treatment of early IPF. Additional experiments have been performed to demonstrate that other ERA are also useful for treating early IPF.

Disclosure of Invention

The invention relates to the use of an endothelin receptor antagonist or a pharmaceutical composition comprising an endothelin receptor antagonist and either pirfenidone or interferon-gamma for the preparation of a medicament for the treatment of early stage idiopathic pulmonary fibrosis.

An additional embodiment of the present invention relates to the above use, wherein the endothelin receptor antagonist is a dual endothelin receptor antagonist or a mixed endothelin receptor antagonist.

An additional embodiment of the present invention relates to the use as described above, wherein the endothelin receptor antagonist is a selective endothelin receptor antagonist that selectively binds to ET_AOn the receptor.

An additional embodiment of the present invention relates to the use as described above, wherein the endothelin receptor antagonist is a selective endothelin receptor antagonist that selectively binds to ET_BOn the receptor.

A further embodiment of the present invention relates to the use as described above, wherein the endothelin receptor antagonist is selected from table 1.

An additional embodiment of the present invention relates to the use described above, wherein the endothelin receptor antagonist is selected from the group consisting of darussentan (daruentan), ambrisentan (ambrisentan), atrasentan (atrasentan), sitaxsentan (sitaxsentan), avosentan (avosentan), TBC-3711, tezosentan (tezosentan), clasentan (clazosentan), propyl-sulfamic acid {5- (4-bromo-phenyl) -6- [2- (5-bromo-pyrimidin-2-yloxy) -ethoxy ] -pyrimidin-4-yl } -amide and bosentan.

An additional embodiment of the present invention relates to the use as described above, wherein the endothelin receptor antagonist is selected from the group consisting of darussan, ambrisentan, sitaxsentan, avosentan, TBC-3711, propyl-sulfamic acid {5- (4-bromo-phenyl) -6- [2- (5-bromo-pyrimidin-2-yloxy) -ethoxy ] -pyrimidin-4-yl } -amide and bosentan.

A further embodiment of the present invention relates to the use as described above, wherein the endothelin receptor antagonist is bosentan.

A further embodiment of the invention relates to the use as described above, wherein no or minimal cells are present on the HRCT or CT scan.

A further embodiment of the invention relates to the use as described above, wherein the alveoli are present in less than 25% of the total lung field on the HRCT or CT scan.

A further embodiment of the invention relates to the use as described above, wherein the cells on the HRCT or CT scan are present in less than 10% of the entire lung field.

A further embodiment of the invention relates to the use as described above, wherein the frosted glass density shadow may be any percentage between above 0 and 80% of the lung fields.

An additional embodiment of the present invention relates to the use as described above, wherein bosentan is administered to the patient at a daily dose of 125mg, with or without a lower initial dose.

An additional embodiment of the present invention relates to the use as described above, wherein the bosentan is administered to the patient at a daily dose of 250mg, with or without a lower initial dose.

The present invention relates to the use of an endothelin receptor antagonist alone or in combination with interferon-gamma (e.g., interferon gamma-1 b) or pirfenidone for the manufacture of a medicament for the treatment of early IPF.

Pirfenidone and interferon-gamma (e.g., interferon gamma-1 b) can be purchased commercially or can be synthesized according to methods known in the art.

Early IPF can be described as a disease stage in which the cells on the HRCT or CT scan are absent or minimal. In one embodiment of the invention, the cells are present in less than 10% of the entire lung field. In a preferred embodiment, the alveoli are present in less than 8%, alternatively less than 5%, alternatively less than 3%, alternatively less than 2% of the total lung field, when expressed as a proportion of 0-100%. Most preferably, the cells are present in less than 1% of the entire lung field. In a further embodiment, the cells are present in a fraction of less than 3, preferably in a fraction of less than 2, most preferably in a fraction of less than 1, when expressed as a ratio of 1 to 5.

An additional feature is the presence of frosted glass density shadows in one or both lung fields, but is not limited to these features. The degree of devitrification in early IPF may be any percentage between 0 and 80% of the lung field, preferably greater than 2% to 80% (akira m, et al, anatomical pulmonary fibrosis: regression of pathological anatomy-section CT Radiology 1993189: 687-.

While IPF still cannot be diagnosed with a very positive clinical/radiological profile expressed as an ATS/ERS consensus clinical guideline, a lung biopsy is typically performed to exclude or identify early IPF (see: American thoracic society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus patient maintenance. American Thoracic Society (ATS) and European Respiratory Society (ERS). Am J respiratory Crit Care Med 2000; 161: 646-64).

Endothelin Receptor Antagonist (ERA):

as noted above, endothelin receptor antagonists encompass a wide range of structures and are useful in the methods of the present invention, alone or in combination. Non-limiting examples of endothelin receptor antagonists useful in the present invention include those endothelin receptor antagonists disclosed below. The reference endothelin receptor antagonists identified below are incorporated herein in their entirety.

Endothelin-1 is a potent angiogenic depressant and smooth muscle mitogen that is overexpressed in plasma and lung tissue of patients with pulmonary hypertension and pulmonary fibrosis. There are two endothelin receptors: ET_AAcceptors and ET_BReceptors, which play distinctly different roles in regulating blood vessel diameter. In chronic conditions, the pathological effects of ET-1 may be mediated by ET_AAnd ET_BBoth receptors.

Two types of ERA have been developed: double ERA (which blocks ET)_AAnd ET_BBoth receptors) and selective ERA (which blocks ET only)_AReceptor).

Dual endothelin receptor antagonists (also known as mixed endothelin receptor antagonists) block ET_AAnd ET_BBoth receptors. Bosentan (bosentan)Is the first FDA approved ERA (see US5292740 or US 5883254; incorporated herein by reference in its entirety).

Selective ERA over ET_BBinding of receptor to ET_AOn the receptor. Generally, there are selective ERA such as sitaxentan, atrasentan, avosentan, ambrisentan (BSF208075) and TBC3711 in clinical trials.

The synthesis of ambrisentan is described in US5932730 and US 5969134.

The synthesis of propyl-sulfamic acid {5- (4-bromo-phenyl) -6- [2- (5-bromo-pyrimidin-2-yloxy) -ethoxy ] -pyrimidin-4-yl } -amide is described in WO 2002/53557.

TABLE 1

Also included in table 1 are the following ERA:

atrasentan, avosentan, tezosentan, clavulan and propyl-sulfamic acid {5- (4-bromo-phenyl) -6- [2- (5-bromo-pyrimidin-2-yloxy) -ethoxy ] -pyrimidin-4-yl } -amide.

The amount of endothelin receptor antagonist used in the treatment and dosing regimen of the methods of the present invention will also depend upon a variety of factors including the age, weight, sex, and medical condition of the subject, the severity of the pathological condition, the route and frequency of treatment, and the particular endothelin receptor antagonist used, and thus can vary widely. A suitable daily dose for administration to a subject is about 0.001 to 100mg/kg body weight, or about 0.005 to about 60mg/kg body weight, or about 0.01 to about 50mg/kg body weight, or about 0.015 to about 15mg/kg body weight, or about 0.05 to about 30mg/kg body weight, or about 0.075 to 7.5mg/kg body weight, or about 0.1 to 20mg/kg body weight, or about 0.15 to 3mg/kg body weight.

The amount of endothelin receptor antagonist administered to a human subject is typically from about 0.1 mg to about 2400mg, or from about 0.5 mg to about 2000mg, or from about 0.75 mg to about 1000mg, or from about 1mg to about 1000mg, or from about 1.0 mg to about 600mg, or from about 5mg to about 500mg, or from about 5.0 mg to about 300mg, or from about 10mg to about 200mg, or from about 10.0 mg to about 100 mg. The daily dose may be administered from one to six times per day.

In a preferred embodiment, bosentan is administered to a subject in a daily dose of about 62.5mg twice daily, or 125mg twice daily, for an adult patient.

Endothelin receptor antagonists and their pharmaceutically usable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations may be administered orally, e.g. orally (e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions), by inhalation, nasally (e.g. nasal spray) or rectally (e.g. in the form of suppositories). However, the administration can also be accomplished parenterally, for example intramuscularly or intravenously (for example in the form of injection solutions).

Endothelin receptor antagonists and their pharmaceutically usable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants to produce tablets, coated tablets, dragees, hard and soft gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as adjuvants for tablets, dragees, hard gelatine capsules.

Suitable coadjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc. Suitable coadjuvants for the manufacture of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.

Suitable coadjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils.

Suitable coadjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols.

In addition, the pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may still contain other therapeutically valuable substances.

Test part/organism:

the findings on bosentan may be extrapolated to other endothelin receptor antagonists described above, since endothelin-1 (ET-1) has been shown to play a central role in the development of fibrosis, and thus drugs for targeting and inhibiting the effects of ET-1 would be effective in treating early stage fibrosis.

Indeed, at the systemic level, transgenic mice overexpressing ET-1 develop a fibrotic (pulmonary and renal) phenotype. This fibrosis is a direct consequence of the ET-1 action, since there is no associated increase in blood pressure (1, 2). Also at the cellular and biochemical level, endothelin is an intermediate mediator of fibrosis (3). The chemotaxis and proliferation of ET-1 fibroblasts increases the synthesis and production of different extracellular matrix proteins such as laminin, collagen and fibrin, while inhibiting collagenase activity. ET-1 also induces the expression of other profibrotic factors, such as connective tissue growth factor and transforming growth factor beta (TGF-. beta.). ET-1 also enhances the pro-inflammatory effector, nuclear factor-. kappa.B (NF-. kappa.B). In the rat lung model of fibrosis (bleomycin-induced), the elevation of ET-1 levels, prior to the increase in collagen content, and its localization within the established fibrosis, provides further evidence of a profibrotic effect of ET-1 in the pathogenesis of early stages of bleomycin-induced pulmonary fibrosis (20).

Bosentan prevents the onset of fibrosis by antagonizing the pro-fibrotic properties of ET-1 (3). Bosentan in cell culture reduced collagen synthesis, increased collagenase expression, inhibited extracellular matrix deposition (4) and reduced NF- κ B expression (5). Bosentan in living organisms is therefore an anti-fibrotic agent effective in different animal models of fibrosis (6-11).

Since ET-1 is the central agent of fibrosis, the finding on bosentan also suggests that all other endothelin receptor antagonists. For example, bosentan and another endothelin receptor antagonist, PD156707, in cell culture attenuate fibroblast proliferation due to ET-1 in human fibroblasts (12), increase matrix metalloproteinase-1 (collagenase) production (4), and reduce the ability to infect collagen matrices (13). Another endothelin receptor antagonist BQ-123 decreases fibrin synthesis induced by ET-1 or angiotensin II in rat mesangial cells (14). Another antagonist, PED-3512-PI, increased collagenase activity induced by ET-1 and ET-3 in rat cardiac fibroblasts (15).

In an in vivo model of fibrosis, the endothelin receptor antagonist FR 139317 attenuates the expression of collagen, laminin and TGF- β mRNA in the kidneys of diabetic rats (16). Daloxatan decreased norepinephrine-induced aortic changes and collagen accumulation in fibrosis (17). Other endothelin receptor antagonists reduce cardiac fibrosis in models of heart failure and hypertension (18, 19).

Assays for evaluating the anti-fibrotic Properties of bosentan and other endothelin receptor antagonists Test set-up

The assay was performed on the mouse embryonic fibroblast cell line Swiss 3T3(Deutsche Sammlung fur Mikroorganismen und Zellen, DSMZ ACC 173). Cells are starved for 24h in serum-free medium or in medium containing 0.5% serum, followed by 24h of endothelin-1 at a given concentration of about 50% or preferably 80% of its maximal effect, in the presence of either an excipient or an increasing concentration of an antagonist or a combination of an antagonist and pirfenidone.

Fibroblast proliferation was assessed by using MTS reagents, excluding potential cytotoxic effects (21). New synthetic collagen of fibroblast is measured³H-proline incorporation was assessed (22).

Several endothelin receptor antagonists have been tested according to the above test methods.

And (3) test results:

in this early stage fibroblastic cell culture model using Swiss 3T3 mouse embryonic fibroblastsConcentration-dependent effects of ET-1 on newly synthesized collagen were measured and 0.24nM of EC was produced₅₀(ET-1 concentration giving 50% of the maximum effect). Use 1nM (EC)₈₀) To assay the antagonist activity of the endothelin receptor antagonists mentioned below on ET-1 induced newly synthesized collagen. Figure 1 shows a representative dose-response curve for selected test compounds. The seven tested endothelin receptor antagonists are summarized in table 2.

We can conclude that: all of the tested antagonists fully antagonized ET-1-induced neosynthesis of collagen to baseline values with IC of 59nM to 369nM₅₀The value is obtained.

TABLE 2

Collagen-induced IC on ET-1 by New Synthesis of different ERAs in 3T3 fibroblasts₅₀Value (n)>＝2)

TABLE 2

IC50 values (n.gtoreq.2) for ET-1 induced novel synthesis of collagen by different ERAs in 3T3 fibroblasts

Compound (I)	IC50(nM)
		Bosentan (bosentan)	214
Compound 1	114
		Ambrisentan (ambrisentan)	79
Dalusutant	221
		TBC3711	59
Sitaxsentan	369
		Avostan	330

The compound 1 ═ propyl-sulfamic acid {5- (4-bromo-phenyl) -6- [2- (5-bromo-pyrimidin-2-yloxy) -ethoxy ] -pyrimidin-4-yl } -amide

Next, the effect of the combination of pirfenidone (Sigma P-2116) and bosentan on ET-1 induced neosynthesis of collagen was tested. For this purpose, fibroblasts were treated with vehicle, bosentan (1 μ M), pirfenidone (1mM) or bosentan and pirfenidone in combination for 24h, followed by determination of newly synthesized collagen. FIG. 2 shows the effect of different combinations of compounds on ET-1 induced new synthesis of collagen.

The results indicate that 1 μ M bosentan alone reversed ET-1 induced neosynthesis of collagen to baseline, while pefenidone alone had a 55% inhibitory effect on neosynthesis collagen. The combination of the two compounds had an additive effect on the newly synthesized collagen, resulting in a decrease to 33% below the baseline synthesis value.

Clinical evidence

The BUILD1 study was a multicenter, randomized, double-blind, placebo-controlled phase II/III study performed in IPF patients. The goal of this study was to demonstrate that bosentan improves exercise performance in IPF patients by a 6 minute walk test (6MWT) distance assessment. The second objective of this study was to demonstrate that bosentan delays the time to death or treatment failure, improves Pulmonary Function Tests (PFT), dyspnea and quality of life, and is safe and well tolerated in such patient populations. Treatment failure was defined as worsening of PFT or the appearance of acute IPF dyspnea. PFT deterioration is defined as the occurrence of 2 of the following 3 criteria:

strong vital capacity (FVC) decreased by more than or equal to 10% from baseline

The dispersion of carbon monoxide (DLCO) decreased by 15% or more from baseline.

O at rest₂Saturation (blood gas) drops by 4% or more from baseline, or alveolar capillary O₂Gradient (A-a PO)₂) The increase from baseline was ≧ 8 mmHg.

The method mainly comprises the following steps: IPF diagnosis was determined by surgical lung biopsy or according to ATS/ERS compliance criteria (see above) for <3 year duration. The majority of the criteria are that FVC ≧ 50% of the predicted value and DLCO ≧ 30% of the predicted value.

A total of 158 patients were randomized for treatment with bosentan (n-74) or placebo (n-84). A total of 154 randomized patients received at least one dose of study drug and had a postbasal value of at least one effective primary endpoint (bosentan: n-71, placebo: n-83). After one screening period (≦ 4 weeks), eligible patients were randomly assigned to bosentan or placebo (1:1), started 1 day 2 oral bosentan 62.5mg or matched placebo, and increased on week 4 to reach the target dose for the remaining treatment period (1 day 2 125mg or matched placebo) unless decreased downward for tolerability reasons. The planned treatment cycle 1 is 12 months. Patients were evaluated at regular intervals up to the end of cycle 1 (month 12) and up to the end of the study (i.e., when the last patient was at his/her final visit). The 6MWT and lung function tests were evaluated at each visit.

Patients in the entire treatment group included 154 randomized patients who had received at least one dose of study drug and had a postbaseline value of at least one effective primary endpoint (bosentan: n-71, placebo: n-83). Treatment groups generally matched well with demographic and baseline disease characteristics.

Although bosentan did not show an increase in the first endpoint of the 6MWT at the cycle 1 endpoint, BUILD-1 showed a positive and clinically relevant trend in potency of bosentan in preventing clinical exacerbations. The most important clinical finding was the trend of the treatment effect on the PFT score at the end of cycle 1 (which was a predetermined secondary end point), defined as the appearance of death or treatment failure (worsening of PFT or acute dyspnea), 36.1% for the placebo group and 22.5% for the bosentan group, corresponding to a relative hazard ratio of 0.62, p-0.0784. PFT scores were achieved primarily by varying FVC and DLCO.

Post hoc subgroup population analyses (Post hoc healthcare analyses) were performed to determine which population class would show the best therapeutic effect on the PFT score. Age, gender, location, baseline walking test, or pulmonary function test did not predict the effect of any particular bosentan treatment. Surprisingly, as can be seen in table 3, 99 patients who underwent surgical lung biopsy to establish IPF diagnosis showed dramatic statistically significant therapeutic effects with a relative risk ratio of 0.32, (95% Confidence Interval (CI) 0.14-0.74).

TABLE 3

Generation by sturlor on data stores of 31MAR06-14DEC05

Ro47-0203, protocol: AC-052-320

Table PFTP _ EOP1_ BIO _ T: fraction of PFT at the end of cycle 1

Analysis and setting: all patients were treated and surgical lung biopsy was performed

(Page 1/1)

In contrast, 58 patients (not diagnosed by Surgical Lung Biopsy (SLB)) showed no therapeutic effect (relative hazard ratio 1.36, 95% CI 0.70-2.65). Whether this result is only fortuitous can be determined by comparing the baseline characteristics of these 2 patient subgroups.

As shown in Table 4, the only significant difference was that the SLB patients were older than the SLB patients. There were no parameters tested for lung function to indicate that one group was more severely ill than the other.

TABLE 4

Yr: year; percent: a percentage of a predetermined value; TLC: total lung volume; RV: residual gas amount; FEV 1: forced expiratory volume in 1 second.

As shown in Table 5, the only significant difference was that the SLB patients were older than the SLB patients. The lung function test was well balanced between the 2 groups.

TABLE 5

^*Safe population for which one bosentan patient was not evaluated for post-baseline efficacy

Yr: year; percent: a percentage of a predetermined value; TLC: total lung volume; RV: residual gas amount; FEV 1: forced expiratory volume in 1 second.

The only logical interpretation that exists is that there are differences in HRCTs for these 2 groups. Before a focused reading of all available CTs, the following assumptions were established.

Three possible explanations were examined as to why patients with SLB had better therapeutic effect than patients without SLB:

patients undergoing surgical lung biopsy have little or no cellulite

Patients undergoing surgical lung biopsy have less extensive fibrosis and are therefore more difficult to make a definitive CT diagnosis

Patients with surgical lung biopsy had more pronounced glassification abnormalities than other patients

Based on these considerations, we set forth the following assumptions:

the extent of cellulite in IPF is a predictor of unresponsiveness to treatment.

The extent of the devitrification abnormality is predictive of the response to treatment.

The analysis is performed by a single radiologist unaffected by the grouping. Each patient CT was scored from the hives and the ground glass from 3 regions (i.e., upper, middle, and lower regions) of each lung. The increase in HC and ground glass was rounded to 5% upwards.

Figure 3 summarizes radiology findings from 143 available HRCT scans from BUILD-1 patients. Regardless of whether SLB is required to establish a diagnosis of IPF, the pre-explained assumptions are confirmed: the presence of ground glass or the absence of alveoli is a clear predictor of the therapeutic effect of bosentan and of the main distribution of abnormalities (comparison of the sub-pleural versus diffusion or of the axial periphery versus others).

We then looked at the score for cellulite (HC) versus the effect of treatment. Regardless of whether SLB was required to enter the BUILD1 study, FIG. 4 shows that HC scores are correlated with therapeutic efficacy (relative risk). The same inverse observation was made for the amount of ground glass on the baseline HRCT. The graph shows that the maximum therapeutic effect of bosentan is achieved in patients with: the patient's HC score is 0-10% of the total lung field and/or when a frosted glass fraction occurs in the patient. The figure also shows that the maximum therapeutic effect of bosentan is achieved in patients with: the patient's HC score is up to 25% of the total lung field and/or when a frosted glass fraction occurs in the patient. This therapeutic effect can also be obtained on background IPF treatments such as interferon gamma 1b, pipfenidone, imatinib (imatinib), tumor necrosis factor alpha antagonists such as etanercept and N-acetyl cysteine.

In summary, BUILD1 data analysis demonstrated that the dual endothelin receptor antagonist bosentan was primarily effective in preventing clinical exacerbations in IPF patients with early disease, low or no hives on HRCT lung scans.

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Claims (14)

1. Use of an endothelin receptor antagonist, or a pharmaceutical composition comprising an endothelin receptor antagonist and pirfenidone or interferon-gamma, for the preparation of a medicament for the treatment of early stage idiopathic pulmonary fibrosis.

2. The use according to claim 1 wherein said endothelin receptor antagonist is a dual endothelin receptor antagonist or a mixed endothelin receptor antagonist.

3. The use according to claim 1, wherein said endothelin receptor antagonist is a selective endothelin receptor antagonist that selectively binds to ET_AOn the receptor.

4. The use according to claim 1, wherein said endothelin receptor antagonist is a selective endothelin receptor antagonist that selectively binds to ET_BOn the receptor.

5. The use according to any one of claims 1-4 wherein said endothelin receptor antagonist is selected from the group consisting of Table 1.

6. The use according to any one of claims 1 to 5, wherein said endothelin receptor antagonist is selected from the group consisting of darussan, ambrisentan, atrasentan, sitaxentan, avosentan, TBC-3711, tezosentan, clasentan, propyl-sulfamic acid {5- (4-bromo-phenyl) -6- [2- (5-bromo-pyrimidin-2-yloxy) -ethoxy ] -pyrimidin-4-yl } -amide and bosentan.

7. The use according to any one of claims 1-6, wherein said endothelin receptor antagonist is selected from the group consisting of darussan, ambrisentan, sitaxsentan, avosentan, TBC-3711, propyl-sulfamic acid {5- (4-bromo-phenyl) -6- [2- (5-bromo-pyrimidin-2-yloxy) -ethoxy ] -pyrimidin-4-yl } -amide and bosentan.

8. Use according to any one of claims 1 to 7 wherein the endothelin receptor antagonist is bosentan.

9. Use according to any one of claims 1 to 8, wherein the cells on the HRCT or CT scan are absent or minimal.

10. Use according to any one of claims 1 to 9, wherein the cells on the HRCT or CT scan are present in less than 25% of the entire lung field.

11. Use according to any one of claims 1 to 10, wherein the cells on the HRCT or CT scan are present in less than 10% of the entire lung field.

12. Use according to any one of claims 1 to 11, wherein the frosted glass density shadow may be any percentage between above 0 and 80% of the lung fields.

13. Use according to claim 8, wherein bosentan is administered to the patient at a daily dose of 125mg, with or without a lower initial dose.

14. Use according to claim 8, wherein bosentan is administered to the patient at a daily dose of 250mg, with or without a lower initial dose.