Cyclosporine formulations for use in treatment of bronchiolitis obliterans syndrome (BOS)

Abstract

To provide a composition for use in prevention of bronchiolitis obliterans syndrome (BOS) in a double lung transplanted patient, or for the treatment of BOS or for prevention or delay of progression of BOS in a double lung transplanted patient being diagnosed with BOS.SOLUTION: The present invention provides a composition comprising liposomal cyclosporine A (L-CsA), which is administered to a patient by inhalation of the composition in an aerosolized form comprising a therapeutically effective dose of cyclosporine A.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition comprising cyclosporine A (CsA) for use in the prevention of bronchiolitis obliterans syndrome (BOS) in bilateral lung transplant patients or for treating or preventing or delaying the progression of BOS in bilateral lung transplant patients who have been diagnosed with BOS. [Background technology]

[0002] Lung transplantation has become an effective treatment option for a variety of chronic and end-stage lung diseases. Lung preservation techniques have been developed over time, resulting in satisfactory short-term results (Hachem RR, Trulock EP. Bronchiolitis obliterans syndrome: pathogenesis and management. Semin Thorac Cardiovasc Surg 2004;16:350-355). Immunosuppression is an important post-transplant intervention, usually consisting of a triple therapy regimen including systemic cyclosporine A (CsA) or tacrolimus, azathioprine or mycophenolate mofetil, and corticosteroids (Knoop C,et al. Immunosuppressive therapy after human lung transplantation. Eur Respir J 2004;23:159-171).

[0003] Both single and bilateral lung transplants are possible. Bilateral lung transplants are indicated in cases of cystic fibrosis, primary pulmonary hypertension, alpha-1 antitrypsin deficiency, emphysema with global dysfunction, frequent severe infections, and idiopathic pulmonary fibrosis with complications from repeated infections.

[0004] Despite systemic immunosuppressive therapy with cyclosporine or tacrolimus, azathioprine or mycophenolate mofetil, and corticosteroids, chronic rejection after lung transplantation remains a serious pulmonary complication accounting for 30% of lung transplant deaths, thus warranting evaluation of new therapeutic options.

[0005] The development of bronchiolitis obliterans syndrome (BOS), the primary cause of pulmonary chronic graft dysfunction, is the leading cause of morbidity and mortality in long-term lung transplant survivors and remains a major limitation to long-term survival after lung transplantation. It occurs in 60-70% of transplant recipients who survive 5 years. The median time to onset of BOS is approximately 18 months. Although the pathogenesis of BOS is multifactorial and incompletely understood, chronic rejection resulting from an immune-dependent response (acute rejection episodes) is believed to be the primary cause of BOS after lung transplantation (Moffatt-Bruce S., “Invited commentary”, Ann Thorac Surg. 2009 Sep; 88(3): 964-5. doi: 10.1016 / j.athoracsur.2009.06.014), despite the use of systemic calcineurin inhibitors for immunosuppression (Lacono AT, et al. A randomized trial of inhaled cyclosporine in lung-transplant recipients. N Engl J Med 2006; 354: 141-150). Once chronic rejection has occurred, airway damage is progressive and irreversible, and patients ultimately die of graft failure or pneumonia.

[0006] Currently, no satisfactory therapeutic options are available for the effective treatment of BOS after bilateral lung transplantation. Augmentation of immunosuppression using drugs commonly used for high doses of basic immunosuppression has proven ineffective and is temporarily associated with a high incidence of adverse events over time due to increased drug burden. Although immunosuppressive antibodies can be useful in preventing acute lung graft rejection, therapeutic attempts to treat chronic rejection have yielded disappointing results. From the point of view of pathological mechanisms, this is comprehensive, since acute lung graft rejection is essentially a vasculitis that begins with an adverse reaction against the epithelium of the blood vessels. In contrast, although all details are still not fully understood, there is agreement that chronic lung rejection is a bronchiolitis rather than a vasculitis, since the cause is in the lung lumen, i.e., the bronchioles. Thus, systemically administered drugs are required to cross the capillary-alveolar barrier. Photopheresis is frequently chosen as a last resort for patients with advanced stage BOS and is performed for psychological rather than medical reasons. Therefore, new therapies to prevent and treat chronic lung graft rejection, especially after bilateral lung transplantation, are highly desirable.

[0007] Currently, median survival is 4.6 years for single lung transplant recipients and 6.6 years for double lung transplant recipients. This differential survival has been shown to be associated with a significant delay in the development of BOS after double lung transplantation compared with single lung transplantation (Hadjiliadis D, et al. Is transplant operation important in determining posttransplant risk of bronchiolitis obliterans syndrome in lung transplant recipients? Chest 2002;122:1168-1175).

[0008] Successful prevention of BOS, or delay of its progression if BOS has already been diagnosed, has been identified as a major requirement for improving lung transplant outcomes.

[0009] It has been suggested that the most important cause of BOS is the activation of T lymphocytes by major histocompatibility antigens or immune-dependent mechanisms (Soubani AO, Uberti JP. Bronchiolitis obliterans following haematopoietic stem cell transplantation. Eur Respir J 2007;29:1007-1019; Halloran PF,et al. The “injury response”: A concept linking nonspecific injury, acute rejection, and long-term outcomes. Transplant Proc 1997;29:79-81). From systemic application, it is well known that CsA blocks T lymphocyte proliferation by inhibiting the phosphatase activity of the enzyme calcineurin, and reduces the expression of several cytokine genes (e.g., interleukin [IL]-2) that are normally induced by T cell activation.

[0010] While most solid organ transplants are inaccessible to local immunotherapy, lung transplants are an exception due to their inherent communication with the external environment, making inhalation a treatment option.

[0011] It has been proposed that local application of CsA to the lungs may improve efficacy and reduce systemic exposure to toxic immunosuppressants (Iacono A,et al.Dose related reversal of acute lung rejection by aerosolized ciclosporin.Am J Respir Crit Care Med 1997;155:1690-1698). Cyclosporine A is a cyclic polypeptide consisting of 11 amino acids. It is produced as a metabolic product by the fungal species Beauveria nivea. Cyclosporine is an immunosuppressant belonging to the group of calcineurin inhibitors that has been used in most post-transplant regimens since the early 1980s in Europe to prevent graft rejection after organ transplantation.

[0012] The use of aerosolized cyclosporine to prevent and treat lung disease is described in WO 00 / 45834. More specifically, the delivery of cyclosporine to transplanted lungs by aerosol inhalation is disclosed. Cyclosporine can be administered either in dry powder or wet form, such as cyclosporine powder aerosolized with propylene glycol. However, this document does not mention the use of cyclosporine in the form of liposomal cyclosporine A. Furthermore, none of the treated subjects are reported to have bronchiolitis obliterans.

[0013] A study by Corcoran et al. (Preservation of post-transplant lung function with aerosol cyclosporin. Eur Respir J 2004;23:378-383) concluded that peripheral lung deposition of CsA propylene glycol (CsA-PG) of approximately 5 mg or more improves lung function in transplant patients, whereas lower doses result in decline. From the latter study it was derived that peripherally deposited CsA in the lung should reach an effective threshold of 15 mg or more per week or 2 mg or more per day to obtain a therapeutic effect.

[0014] ATIacono et al., in Eur. Respir. J. 2004;23:384-390, reported on aerosol cyclosporine therapy in lung transplant recipients with bronchiolitis obliterans. In this study, cyclosporine was again used in powder form dissolved in propylene glycol. Most notably, bilateral lung transplant recipients were reported to have an increased risk of mortality following the development of bronchiolitis obliterans compared with single lung transplant recipients.

[0015] A phase II clinical trial in 58 lung transplant patients showed a statistically significant difference in BOS-free survival and overall survival in favor of CsA-PG therapy compared with placebo after up to 2 years of treatment with inhaled CsA-PG (Lacono AT, et al. A randomized trial of inhaled cyclosporine in lung-transplant recipients. N Engl J Med 2006;354:141-150). In contrast, a multicenter phase III clinical trial showed no efficacy over standard treatment when CsA was used as an adjunct targeted therapy to prevent chronic rejection in lung transplant patients. The results of this study are at odds with numerous preclinical and clinical studies that allow for the expectation of therapeutic response. From this result, it was concluded that administration of cyclosporine aerosol to this highly vulnerable patient population is not without challenges, and one or more of these challenges may have influenced the study results. Analysis of these challenges concluded that the use of simpler delivery systems that administer the drug at more frequent intervals within the setting of inhaled therapy or total body replacement may be successful (Niven RW, et al. The challenges of developing an inhaled cyclosporine product for lung transplant patients. Respiratory Drug Delivery 2012;51-60).

[0016] Patient intolerance and lack of adherence due to long inhalation times of up to 30 minutes have been reported with CsA-PG preparations (Corcoran TE. Inhaled delivery of aerosolized cyclosporine. Adv Drug Deliv Rev 2006;58:1119-1127). Propylene glycol is known to be hyperosmolar and may be poorly tolerated by patients, necessitating premedication with bronchodilators and local anesthetics.

[0017] Taking these challenges into consideration, a new liposomal formulation of cyclosporine for inhalation was developed, which is described in WO 2007 / 065588.

[0018] Furthermore, new inhalation systems for inhaling CsA have been proposed, and it is envisioned that these systems will allow for more efficient deposition of CsA in the lungs. An example of such a system is the vibrating membrane nebulizer. Such inhalation systems achieve better targeting of the drug by producing particles of appropriate size for high peripheral deposition. Also, the high drug delivery rate of such devices supports much shorter inhalation times, which are expected to be advantageous in terms of patient adherence.

[0019] In a Phase Ib clinical trial, the lung deposition and pharmacokinetics of 10 mg and 20 mg radiolabeled aerosolized liposomal CsA (L-CsA) were investigated in five bilateral and seven single lung transplant patients. Aerosols were generated with an eFlow® nebulizer. Patients were given single dose applications of 10 mg or 20 mg liposomal CsA, which were well tolerated. 40 ± 6% (for the 10 mg dose) and 33 ± 7% (for the 20 mg dose), respectively, were shown to be deposited in the lungs. This resulted in peripheral lung doses of 2.2 ± 0.5 mg (for the 10 mg dose) and 3.5 ± 0.9 mg (for the 20 mg dose), respectively. Assuming once or twice daily administration of a nominal drug dose of 10 mg L-CsA, peripheral depositions of 14 mg and 28 mg / week, respectively, could be achieved. Overall inhalation times for the 10 mg and 20 mg nominal doses were approximately 9 ± 1 min and 20 ± 5 min, respectively. In single-lung transplant patients, almost all deposition (88–90%) occurred in the transplanted portion of the lung. There were no statistically significant differences between single- and double-lung transplant patients. Although several preclinical and clinical studies have been performed with inhaled CsA, conclusions regarding the actual efficacy of inhaled cyclosporine for double-lung transplant patients are conflicting. Thus, currently available studies cannot draw any conclusions regarding the actual efficacy of inhaled cyclosporine in the treatment of pulmonary chronic graft rejection, and more specifically, of bronchiolitis obliterans syndrome (BOS) after lung transplantation.

[0020] Bronchiolitis obliterans syndrome (BOS) is physiologically defined as a persistent ≥20% decline in FEV1 from maximal post-transplant values. Existing immunosuppressive regimens remain largely ineffective. Increased cyclosporine inhalation is deposited in the lungs, resulting in higher airway concentrations, which may increase efficacy in treating BOS.

[0021] WO 2016 / 146645 discloses a cyclosporine liquid formulation for use as an inhalation aerosol in a method for preventing or treating chronic pulmonary graft rejection in single lung transplant patients. In a specific embodiment, the chronic pulmonary graft rejection is characterized by bronchiolitis obliterans syndrome (BOS). However, while this document highlights the unexpectedly successful treatment of a subpopulation of single lung transplant patients, no conclusions can be drawn about the treatment of bilateral lung transplant patients, particularly those who already have bronchiolitis obliterans syndrome (BOS). In light of this disclosure, successful treatment of bilateral lung transplant patients who already have BOS is not expected.

[0022] A. Iacono et al. reported on the stabilization of lung function and improved survival with aerosolized liposomal cyclosporine A (L-CsA) for bronchiolitis obliterans syndrome in The Journal of Heart and Lung Transplantation, Vol 37, No 4S, 211. However, this document does not mention the results of the study and therefore the efficacy of the treatment for specific patient subpopulations, i.e., single or double lung transplant recipients. Thus, there remains a need for prevention or effective treatment of bronchiolitis obliterans syndrome (BOS) when it develops and is diagnosed in patients who have received a double lung transplant. It is therefore an object of the present invention to provide a means of successful prevention or treatment of double lung transplant patients who have already developed and been diagnosed with BOS, particularly the more severe forms of BOS, such as BOS 1 or BOS 2. Further objects of the present invention will become apparent in view of the present disclosure. [Prior art documents] [Patent documents]

[0023] [Patent Document 1] International Publication No. 00 / 45834 Brochure [Patent Document 2] International Publication No. 2007 / 065588 Brochure [Patent Document 3] International Publication No. 2016 / 146645 Brochure [Non-patent literature]

[0024] [Non-Patent Document 1] Hachem RR, Trulock EP.Bronchiolitis obliterans syndrome: pathogenesis and management.Semin Thorac Cardiovasc Surg 2004;16:350-355 [Non-Patent Document 2] Knoop C,et al.Immunosuppressive therapy after human lung transplantation.Eur Respir J 2004;23:159-171 [Non-Patent Document 3] Moffatt-Bruce S., “Invited commentary”, Ann Thorac Surg.2009 Sep;88(3):964-5.doi:10.1016 / j.athoracsur.2009.06.014 [Non-Patent Document 4] Iacono AT,et al.A randomized trial of inhaled cyclosporine in lung-transplant recipients.N Engl J Med 2006;354:141-150 [Non-Patent Document 5] Hadjiliadis D,et al.Is transplant Operation important in determining posttransplant risk of bronchiolitis obliterans syndrome in lung transplant recipients?Chest 2002;122:1168-1175 [Non-Patent Document 6] Soubani AO, Uberti JP. Bronchiolitis obliterans following haematopoietic stem cell transplantation. Eur Respir J 2007;29:1007-1019

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Non-licensed literature 9

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Non-licensed Document 11

Non-licensed Document 12

[0025] In a first aspect, the present invention provides a composition comprising liposomal cyclosporine A (L-CsA) for use in the prevention of bronchiolitis obliterans syndrome (BOS) in bilateral lung transplant patients or for treating or preventing or delaying the progression of BOS in bilateral lung transplant patients who have been diagnosed with BOS, comprising The composition comprises a therapeutically effective dose of cyclosporine A and is administered to said patient by inhalation of the composition in aerosolized form.

[0026] In a second aspect, the present invention provides a method of preventing bronchiolitis obliterans syndrome (BOS) in a bilateral lung transplant patient, or treating BOS or preventing or delaying the progression of BOS in a bilateral lung transplant patient who has been diagnosed with BOS, comprising: (a) identifying patients who have undergone bilateral lung transplantation and are at risk of developing or have subsequently developed BOS, specifically BOS grade I or higher; (b) administering to said patient by inhalation a therapeutically effective dose of aerosolized liposomal cyclosporine A (L-CsA); The present invention relates to a method comprising the steps of: [Brief description of the drawings]

[0027] [Figure 1] FIG. 1 is a flow chart summarizing details of the enrollment of single and double lung transplant patients in the clinical study, described further below.

[0028] [Diagram 2]FIG. 1 shows a Kaplan-Meier plot of the probability of BOS progression-free survival for single and double lung transplant patients diagnosed with BOS during the 48-week study period.

[0029] [Diagram 3] FIG. 1 shows a Kaplan-Meier plot of event-free survival probability for bilateral lung transplant patients diagnosed with BOS.

[0030] [Figure 4] FIG. 1 shows a Kaplan-Meier plot of event-free survival probability for single lung transplant patients diagnosed with BOS.

[0031] [Diagram 5] FIG. 1 shows a Kaplan-Meier plot of overall survival probability for single and double lung transplant patients diagnosed with BOS 5 years after randomization.

[0032] [Figure 6] FIG. 1 shows a regression trend analysis of the course of absolute FEV1 values ​​over the 48-week study period for single and double lung transplant patients in the L-CsA (upper graph; "L-CsA") and SOC (lower graph; "SOC") treatment groups.

[0033] [Figure 7] FIG. 1 shows a regression trend analysis of the course of absolute FEV1 values ​​over the 48-week study period for bilateral lung transplant patients in the L-CsA (upper graph; "L-CsA") and SOC (lower graph; "SOC") treatment groups.

[0034] [Figure 8] FIG. 1 shows a regression trend analysis of the course of absolute FEV1 values ​​over the 48-week study period for single lung transplant patients in the L-CsA (upper graph; "L-CsA") and SOC (lower graph; "SOC") treatment groups. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] The following terms or expressions used in this specification should generally be interpreted as outlined in this section, unless otherwise defined in the specification or unless the specific context indicates or requires otherwise.

[0036] The terms "consist of", "consists of" and "consisting of" as used herein are so-called closed language, meaning that only the components referenced are present. The terms "comprise", "comprises" and "comprising" as used herein are so-called open language, meaning that one or more additional components may or may not be present.

[0037] The term "active pharmaceutical ingredient" (also referred to throughout this document as "API") refers to any type of pharma- ceutically active compound or derivative that is useful in the prevention, diagnosis, stabilization, treatment, or generally speaking, management of a condition, disorder, or disease.

[0038] The term "therapeutically effective amount" as used herein refers to a dose, concentration or strength that is useful for producing a desired pharmacological effect. In the context of the present invention, the term "therapeutically effective" also includes prophylactic activity. The therapeutic dose should be defined according to the individual application. Depending on the nature and severity of the disease, the route of application, and the height and condition of the patient, the therapeutic dose should be determined by methods known to those skilled in the art.

[0039] In the context of the present invention, a "pharmaceutical composition" is a preparation of at least one API and at least one adjuvant, which in the simplest case may be an aqueous liquid carrier such as, for example, water or saline.

[0040] The term "a" or "an" does not exclude a plurality; i.e., the singular forms "a," "an," and "the" should be understood to include plural referents unless the context clearly indicates or otherwise requires. In other words, all references to singular features or limitations of this disclosure include the corresponding plural features or limitations, and vice versa, unless expressly specified otherwise or clearly implied to the contrary by the referenced context. Thus, the terms "a," "an," and "the" have the same meaning as "at least one" or "one or more," unless otherwise defined. For example, reference to "an ingredient" includes mixtures of ingredients, and the like.

[0041] The phrases "one embodiment," "an embodiment," "a specific embodiment," and the like mean that a particular feature, property, or characteristic, or a particular group or combination of features, properties, or characteristics, when referred to in combination with the respective phrase, is present in at least one embodiment of the invention. The appearance of these phrases in various places throughout this specification does not necessarily refer to the same embodiment. Furthermore, the particular features, properties, or characteristics may be combined in any suitable manner in one or more embodiments.

[0042] As used herein, the term "treatment" includes therapeutic interventions that can result in a cure of a disease, condition or symptom, but also includes enhancement, amelioration, control, control of progression, and the like.

[0043] The term "prophylaxis" is intended to include preventing or slowing the progression of a disease, condition or symptom, or preventing further growth and spread of a disease state or symptom, as well as recurrence or progression following initial improvement or initial elimination of the cause.

[0044] The terms "patient" and "subject" are used interchangeably herein. Typically, these terms refer to humans. However, the present invention is not limited to humans only, and may be used in animals, as appropriate.

[0045] Terms such as "essentially," "about," "approximately," "substantially," and the like in connection with an attribute or value include the exact attribute or exact value, as well as any attribute or value that would typically be considered to fall within a normal range or variability accepted in the relevant art. For example, "substantially free of water" means that water is not intentionally included in the formulation, but does not exclude the presence of residual moisture.

[0046] As used herein, the term "about" or "ca." accounts for variability accepted in the pharmaceutical industry and inherent in pharmaceutical products, such as differences in content due to manufacturing variations and / or product degradation over time. The term allows for any variation in pharmaceutical practice that allows a product to be evaluated to be considered bioequivalent in mammals to the recited strength of the claimed product.

[0047] As used herein, "vehicle" may generally refer to any compound, construct or substance that is part of a formulation that aids, enables, or improves the delivery of a biologically active compound or substance.

[0048] The term "pharmaceutical acceptable" means that a compound or mixture is generally safe, non-toxic, and useful in the preparation of pharmaceutical compositions that are not biologically or otherwise undesirable, including those that are acceptable for human pharmaceutical use.

[0049] Broadly, the present invention provides a composition comprising cyclosporine A (CsA) for use in the prevention of bronchiolitis obliterans syndrome (BOS) in bilateral lung transplant patients, or for treating or preventing or slowing the progression of BOS in bilateral lung transplant patients who have been diagnosed with BOS, comprising: The composition comprises a therapeutically effective dose of cyclosporine A and is administered to said patient by inhalation of the composition in aerosolized form.

[0050] The present invention further provides a composition comprising cyclosporine A (CsA) for use in treating bronchiolitis obliterans syndrome (BOS) in a bilateral lung transplant patient who has been diagnosed with BOS, or for preventing or slowing the progression of BOS, comprising: The composition comprises a therapeutically effective dose of cyclosporine A and is administered to said patient by inhalation of the composition in aerosolized form.

[0051] In a first aspect, more specifically, the present invention relates to a composition comprising liposomal cyclosporine A (L-CsA) for use in the prevention of bronchiolitis obliterans syndrome (BOS) in bilateral lung transplant patients or for treating or preventing or slowing the progression of BOS in bilateral lung transplant patients who have been diagnosed with BOS, comprising The composition is administered to said patient by inhalation of an aerosolized form of the composition comprising a therapeutically effective dose of cyclosporine A (CsA).

[0052] Compositions for use according to the invention comprise a therapeutically effective dose or amount of cyclosporine A (CsA), or more specifically liposomal CsA (L-CsA), as further described below and as described in detail, for example, in WO 2007 / 065588 supra. Pharmaceutical compositions for use according to the invention may, in specific embodiments, be liquid compositions. In these embodiments, compositions for use according to the invention comprise L-CsA and a liquid carrier or vehicle capable of dissolving, dispersing or suspending L-CsA. In specific embodiments, these compositions comprise a therapeutically effective dose of CsA, an aqueous carrier liquid, a first solubility enhancer selected from the group of phospholipids, and a second solubility enhancer selected from the group of non-ionic surfactants, forming liposomally solubilized CsA (L-CsA).

[0053] The phospholipids that may be included in the composition for use according to the invention are in particular mixtures of natural or concentrated phospholipids, for example lecithins such as the commercially available Phospholipon G90, 100 or Lipoid 90, S 100. Thus, in a preferred embodiment, the phospholipids that may be included in the composition for use according to the invention may be selected from the group of phospholipids that are mixtures of natural phospholipids.

[0054] Phospholipids are amphipathic lipids containing phosphorus. They are also known as phosphatides and play an essential role, especially as bilayer-forming components of biological membranes, and phospholipids chemically derived from phosphatidic acid are frequently used for pharmaceutical purposes. The latter is (usually) doubly acylated glycerol-3-phosphate, The fatty acid residue may be of different lengths. The derivatives of phosphatidic acid are, for example, phosphocholine or phosphatidylcholine, in which the phosphate group is further esterified with choline, as well as phosphatidylethanolamine, phosphatidylinositol, etc. Lecithin is a natural mixture of various phospholipids, which usually contains a high proportion of phosphatidylcholine. The preferred phospholipids according to the present invention are lecithin and pure or concentrated phosphatidylcholine, such as dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine and distearoylphosphatidylcholine.

[0055] In a specific embodiment, the first solubility-promoting substance selected from the group of phospholipids contained in the composition for use according to the invention can be selected from the group of phospholipids, and can be lecithin, more specifically lecithin containing unsaturated fatty acid residues.In an even more preferred embodiment, the membrane-forming substance selected from the group of phospholipids is a lecithin selected from the group consisting of soybean lecithin, Lipoid S100, Phospholipon® G90, 10, preferably Lipoid S100 or equivalent lecithin.In a further preferred embodiment, the membrane-forming substance selected from the group of phospholipids is selected from Lipoid S100, Lipoid S75, particularly Lipoid S100.

[0056] In a specific embodiment, the weight ratio of the first membrane-forming substance selected from the above group of phospholipids to CsA is selected in the range of about 8:1 to about 11:1, preferably about 8.5:1 to about 10:1, for example about 13:1.

[0057] The pharmaceutical composition for use according to the present invention may further comprise a second dissolution enhancer or two or more different dissolution enhancers selected from the group of non-ionic surfactants.Non-ionic surfactants, like other surfactants, have at least one molecular region that is somewhat hydrophilic and at least one molecular region that is somewhat lipophilic.There are monomeric low molecular weight non-ionic surfactants and non-ionic surfactants with oligomeric or polymeric structures.Examples of suitable non-ionic surfactants that can be included in the present invention include polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, such as polyoxyethylene sorbitan oleate, sorbitan fatty acid esters, poloxamers, vitamin E-TPGS (D-α-tocopheryl-polyethylene glycol-1000-succinate) and tyloxapol.

[0058] In a specific embodiment, the second solubility enhancer selected from the group of non-ionic surfactants may be selected from the group of polysorbates and vitamin E-TPGS, and is preferably selected from the group of polysorbates. In a particularly preferred embodiment, the solubility enhancer selected from the group of non-ionic surfactants is polysorbate 80.

[0059] In a specific embodiment of the pharmaceutical composition, the amount of the first membrane-forming substance selected from the group of phospholipids, preferably lecithin, is greater than the amount of the second solubility-promoting substance selected from the group of non-ionic surfactants. In an exemplary embodiment, the weight ratio of the first membrane-forming substance selected from the group of phospholipids, preferably lecithin, to the second solubility-promoting substance selected from the group of non-ionic surfactants, preferably polysorbate, is selected in the range of about 15:1 to about 9:1, preferably about 14:1 to about 12:1, for example about 13:1.

[0060] In a further specific embodiment, the weight ratio between the (total of) the first solubility promoter selected from the group of phospholipids and the second solubility promoter selected from the group of nonionic surfactants on the one hand and CsA on the other hand is selected in the range of about 5:1 to about 20:1, preferably about 8:1 to about 12:1, more preferably about 10:1.

[0061] In yet a further specific embodiment, the weight ratio between a first solubility enhancing substance selected from the group of phospholipids, preferably lecithin, a second solubility enhancing substance selected from the group of non-ionic surfactants, preferably polysorbate, and CsA is selected in the range of about 15:1:1.5 to about 5:0.3:0.5, preferably about 9:0.7:1.

[0062] In a specific embodiment, the composition for use according to the invention, or more specifically, the liquid composition, comprises cyclosporine A (CsA) in the form of liposomal cyclosporine A (L-CsA), or in other words, in the form solubilized by liposomes. Thus, in a specific embodiment, the liquid composition for use according to the invention is a liposomal preparation. The liposomes comprising CsA, or in other words, liposomal CsA (L-CsA), are formed mainly by the phospholipids contained in the composition, and are preferably unilamellar liposomes. The liposomes preferably have an average diameter of up to about 100 nm, measured as z-average using, for example, photon correlation spectroscopy with a Malvern ZetaSizer device, and a polydispersity index of up to about 0.5, preferably up to about 0.4, also measured by photon correlation spectroscopy.

[0063] In a specific embodiment, the liquid composition for use according to the present invention comprises an aqueous liquid vehicle.The liquid vehicle may comprise water and optionally one or more physiologically acceptable organic solvents, such as ethanol or propylene glycol.However, in a preferred embodiment, the pharmaceutical composition, particularly in the form of a liquid pharmaceutical composition, is free or substantially free of organic solvents, particularly free of propylene glycol, or comprises only ethanol as organic solvent.

[0064] Liquid compositions for use according to the invention may be prepared by providing an aqueous solution or suspension of CsA in a suitable liquid carrier, preferably an aqueous liquid carrier, and dissolving the CsA after addition of at least one phospholipid and at least one non-ionic surfactant as described above, optionally in the form of a liposome.

[0065] In a specific embodiment, liquid compositions for use according to the invention can be prepared from the corresponding solid formulation for reconstitution, which optionally involves mixing or contacting L-CsA with an aqueous solvent or vehicle immediately prior to inhalation. Thus, in a specific embodiment, liquid compositions comprising liposomal CsA (L-CsA) for use according to the invention are prepared by reconstitution of liposomal cyclosporine A (L-CsA), preferably L-CsA in lyophilized form.

[0066] The solid formulation for reconstitution containing L-CsA can be prepared by any method suitable for removing solvent from liquid formulation.However, the preferred examples of the method for preparing such solid formulation or composition include freeze-drying and spray-drying.Preferably, freeze-drying is used.

[0067] To protect the active ingredient during the drying process, it may be useful to incorporate cryoprotectants and / or bulking agents such as sugars or sugar alcohols, in particular sucrose, fructose, glucose, trehalose, mannitol, sorbitol, isomalt or xylitol. Of these agents, sucrose is particularly preferred.

[0068] The portion of the solid composition containing an effective amount of the active compound, i.e., CsA provided in the form of L-CsA (i.e., unit dose), is preferably soluble or dispersible in the above-mentioned aqueous liquid vehicle. In a specific embodiment, the aqueous liquid vehicle has a volume of about 10 ml or less. Preferably, an effective amount or unit dose of CsA or L-CsA is soluble or dispersible in an aqueous liquid vehicle with a volume of about 5 ml or less, about 4 ml or less, or even about 3 ml or less. The volume of aqueous liquid vehicle required for reconstitution of the solid L-CsA formulation depends on the dose of the active ingredient, as well as the desired concentration. If a smaller dose is required for therapeutic effect, a smaller volume of the aqueous liquid vehicle may be sufficient to dissolve or disperse the solid formulation containing L-CsA.

[0069] In a specific embodiment, an aqueous solution is preferably used as the aqueous liquid vehicle for reconstitution. Thus, in a preferred embodiment of the liquid composition of the present invention, the aqueous liquid vehicle comprises saline.

[0070] In a specific embodiment, saline is used as the aqueous liquid vehicle, and the concentration of sodium chloride is adjusted to produce a liquid formulation with physiologically acceptable osmolarity and tolerability after reconstitution. The osmolarity of the liquid composition for use according to the invention is in a preferred embodiment in the range of about 450 to about 550 mOsmol / kg. However, some degree of hypo- and hyper-osmolarity is generally still tolerated. The presence of an osmotic anion (such as chloride) at a concentration of 31 to 300 mM may improve tolerability (Weber et al. "Effect of nebulizer type and antibiotic concentration on device performance", Paediatric Pulmonology 23 (1997) 249-260). Hyperosmolar formulations may actually be preferred in certain applications. For example, the osmolarity of the reconstituted liquid composition for use according to the invention may be in the range of 150 to 800 mOsmol / kg. Preferably, the aqueous liquid composition has an osmolality of about 250 to about 700 mOsmol / kg, or about 250 to 600 mOsmol / kg, and most preferably, the aqueous liquid composition for use according to the present invention has an osmolality of about 400 to about 550 mOsmol / kg.

[0071] In specific embodiments, the liquid composition for use according to the invention comprises an aqueous liquid vehicle consisting essentially of saline. In these specific embodiments, as well as other embodiments in which the aqueous liquid vehicle comprises additional components or solvents, the concentration of sodium chloride may range from about 0.1 to about 0.9% (w / v). Preferably, a saline solution having a sodium chloride concentration of about 0.25% (w / v) is used, the term "w / v" referring to the weight of dissolved sodium chloride per volume of liquid vehicle contained in the aqueous liquid composition.

[0072] When the liquid composition is prepared by reconstitution of a dry formulation, the concentration of sodium chloride may also range from about 0.1 to about 0.9% (w / v), depending on the osmolality of the formulation before drying. Preferably, the above-mentioned 0.25% (w / v) saline solution is used.

[0073] When used to prepare a liquid composition for use according to the invention, the solid composition containing CsA, preferably in the form of L-CsA, for reconstitution can be part of a pharmaceutical kit. Such a kit preferably contains the solid composition together with a liquid aqueous vehicle for reconstitution. Such a kit for preparing a liquid composition for administration as an aerosol is described in WO 03 / 035030.

[0074] After reconstitution, the CsA, or more specifically the L-CsA formulation, should have the same composition as before drying. If the formulation is a liposomal formulation, the formulation should also contain liposomes after reconstitution. Preferably, the size of the liposomes is also similar before drying and after reconstitution. With regard to the size of the liposomes, it is particularly preferred that the size of the liposomes is between 40 and 100 nm, measured as the z-average by photon correlation spectroscopy, and that they show a homogenous size distribution (polydispersity index <0.4) after reconstitution with 0.25% (w / v) saline.

[0075] Surprisingly, it has been found that liquid compositions comprising, inter alia, liposomal cyclosporine A (L-CsA) as described above are useful in methods for preventing bronchiolitis obliterans syndrome (BOS) in bilateral lung transplant patients or for treating BOS or preventing or slowing the progression of BOS in bilateral lung transplant patients who have been diagnosed with BOS, The composition is administered to the patient by inhalation of the liquid composition in aerosolized form containing a therapeutically effective dose of cyclosporine A (Cs-A).

[0076] In accordance with the present invention, bronchiolitis obliterans syndrome (also referred to herein as "BOS") can be effectively prevented or treated, preferably treated, in bilateral lung transplant patients, or the progression of BOS can be effectively prevented or delayed in patients who have received a bilateral lung transplant (also referred to herein as "bilateral lung transplant patients") and who have been diagnosed with BOS, particularly BOS 1 or BOS 2.

[0077] Surprisingly, treatment, or more specifically, prevention or delay of the progression of manifested BOS, can be achieved more effectively in bilateral lung transplant patients compared to patients who have received a single lung transplant (also referred to herein as "single lung transplant patients"), particularly those diagnosed with BOS. More specifically, in bilateral lung transplant patients who inhale a liposomal cyclosporine A liquid formulation for use according to the present invention in addition to standard immunosuppressive therapy (hereinafter also referred to as "standard of care" or "SOC"), a significant delay or even prevention of the progression of manifested BOS is obtained. When treated with the L-CsA-containing composition for use according to the present invention or when treated only with SOC, no comparable delay or prevention of BOS was seen within the same time frame in a bilateral lung transplant population receiving only standard immunosuppressive therapy or when compared to single lung transplant patients.

[0078] It should be noted that the different effects of the inhaled cyclosporine compositions for use according to the invention taking into account the type of transplant (double lung transplant vs. single lung transplant) were completely surprising and unexpected given the previous results of the clinical study disclosed in WO 2016 / 146645.

[0079] According to the present invention, a liquid composition comprising L-CsA is useful in a method for preventing bronchiolitis obliterans syndrome (BOS) in bilateral lung transplant patients or for treating or preventing or delaying the progression of BOS in bilateral lung transplant patients who have been diagnosed with BOS. However, in a preferred embodiment, a liquid composition comprising L-CsA for use according to the present invention is useful in a method for treating or preventing or delaying the progression of BOS in bilateral lung transplant patients who have been diagnosed with BOS. The presence of BOS can be determined based on spirometry of forced expiratory volume (FEV). Preferably, a decrease in forced expiratory volume in one second (FEV1) is used as an indicator of the presence of BOS and therefore of the risk of chronic lung graft rejection. FEV1 measurements can be performed according to the current American Thoracic Society (ATS) / European Respiratory Society (ERS) spirometry guidelines. Forced expiratory volume in one second (FEV1) is expressed in liters (L).

[0080] BOS is considered to be present when FEV1 is persistently decreased by at least 20% from the patient's maximum in the absence of other causes. BOS may be confirmed by at least two FEV1 measurements, at least 3 weeks apart. The post-transplant maximum is the two best FEV1 values ​​taken at least 3 weeks apart. FEV1 measurements should be sustained and measured at least 3 weeks apart. Bronchodilator administration should be stopped before assessing FEV1. Declines in FEV1 due to causes other than acute rejection or chronic rejection, such as lymphocytic bronchitis or infection, are likely to respond to appropriate medical management, whereas persistent irreversible functional decline is associated with chronic rejection and progression of BOS.

[0081] Based on the rate of decline in FEV1, BOS can be graded (Estenne M, et al. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant 2002;21(3):297-310). The following definitions and criteria can be applied: -BOS 0: FEV1 > 90% of baseline -BOS 0-p: FEV1 81%-90% of baseline -BOS 1: FEV1 66%-80% of baseline -BOS 2: FEV1 51%-65% of baseline -BOS 3: FEV1 50% or less of baseline

[0082] The composition for use according to the invention may be useful in a method for treating BOS or preventing or delaying the progression of BOS in bilateral lung transplant patients who have been diagnosed with BOS, i.e. any grade of BOS, such as BOS 0, BOS 0-p, BOS 1, BOS 2 or BOS 3, preferably BOS 1, BOS 2 or BOS 3. However, in a specific embodiment, the liquid composition for use according to the invention is particularly useful for treating bilateral lung transplant patients who have been diagnosed with BOS 0-p or higher, preferably BOS 1 or BOS 2. In a more specific embodiment, the liquid composition for use according to the invention is particularly useful for treating bilateral lung transplant patients who have been diagnosed with BOS 0-p or BOS 1.

[0083] In fact, the dose administered to single lung transplant patients is preferably about half the dose administered to double lung transplant patients, in order to be able to treat both single and double lung transplant patients as one population within a single study. Since the active compound CsA has a local effect, it was expected that the same effect would be obtained with a halved dose if the target surface was also halved. In other words, it was expected that the same effect would be obtained in single and double lung transplant patients if the dose was adjusted according to the type of transplant. Nevertheless, even when administered at comparable doses, the inventors surprisingly found that the effect of inhaled cyclosporine in preventing or delaying manifested BOS, especially BOS 1 or BOS 2, was much more pronounced in the double lung transplant population.

[0084] Surprisingly, it has been found that the compositions for use according to the present invention are able to prevent or significantly delay or reduce the progression of BOS, in particular BOS 1 or BOS 2, manifested and diagnosed after double lung transplantation when compared to conventional treatment with standard immunosuppressive therapy (SOC) alone or when compared to single lung transplant patients.

[0085] Therefore, the CsA or L-CsA-containing composition for use according to the invention used in the treatment of double lung transplant patients can contribute to significantly prolong and maximize the survival probability and duration of patients at risk of developing or who have developed BOS, more specifically BOS 1 or BOS 2, after double lung transplantation, and thus reduce or minimize the onset or progression of chronic lung graft rejection. The composition for use according to the invention can be administered according to a predetermined administration regimen. More specifically, the composition can be administered to the double lung transplant patient a certain number of times during each week of treatment. For example, the composition can be administered three times a week. In a preferred embodiment, the composition for use according to the invention is administered daily. In a specific embodiment, the composition for use according to the invention is administered twice or even several times a day to said double lung transplant patient at risk of developing or who has been diagnosed with BOS.

[0086] Compositions, preferably liquid compositions, for use according to the invention preferably have a CsA concentration in the range of about 0.5 to about 10 mg / mL, or in other words the liquid composition comprises CsA in the form of L-CsA at a concentration of about 0.5 to about 10 mg / mL, preferably about 1 to about 6 mg / mL, more preferably about 1 up to about 5 mg / mL. Most preferably, compositions for use according to the invention contain CsA (in the form of L-CsA) at a concentration of about 4 mg / mL.

[0087] The volume of a unit dose of the composition for use according to the invention is preferably low to allow short nebulization times. The volume, also called "volume of dose" or "dose unit volume" or "unit dose volume", should be understood as the volume intended to be used for one single administration. A unit dose is defined as the dose of CsA (in the form of L-CsA) in a composition, more specifically in a liquid composition, filled into a nebulizer for one single administration. Specifically, the volume of a unit dose may be less than 10 mL. Preferably, the volume ranges from about 0.3 to about 3.5 mL, more preferably from about 1 to about 3 mL. For example, when a composition is obtained after reconstitution whose volume is about 1.25 mL or about 2.5 mL, the volume of the liquid vehicle, preferably the aqueous liquid vehicle, or even more preferably the saline solution for reconstitution, should be adapted according to the desired volume of the reconstituted composition.

[0088] The therapeutically effective unit dose of CsA contained in the composition for use according to the invention preferably ranges from about 1 mg to about 15 mg per day for a single lung transplant patient. Most preferably, an effective unit dose of about 10 mg per day of CsA may be administered to a single lung transplant patient. Such doses have been found to be well tolerated by double lung transplant patients at risk of developing or diagnosed with BOS.

[0089] The therapeutically effective daily amount of CsA administered to a bilateral lung transplant patient diagnosed with BOS may range from 2 mg to 30 mg. Thus, in a preferred embodiment, CsA is administered in an effective daily amount ranging from 2 to 30 mg, or in an effective daily amount ranging from 5 to 30 mg. In a preferred embodiment, an effective daily amount of about 20 mg of CsA may be administered to a bilateral lung transplant patient at risk of developing or diagnosed with BOS. It should be understood that when CsA is administered in the form of L-CsA, all amounts outlined above refer to the amount of CsA contained in the liposome.

[0090] The compositions for use according to the invention, or more preferably liquid compositions, can be advantageously aerosolized and administered by a nebulizer capable of converting a solution, colloidal preparation or suspension, such as the present composition containing CsA in the form of L-CsA, into a high percentage of droplets capable of reaching the periphery of the lungs. In practice, jet nebulizers, ultrasonic nebulizers, piezoelectric nebulizers, electrohydrodynamic nebulizers, membrane nebulizers, electronic membrane nebulizers or electronic vibrating membrane nebulizers can be used. Examples of suitable nebulizers include SideStream® (Philips), AeroEclipse® (Trudell), LC Plus® (PARI), LC Star® (PARI), LC Sprint® (PARI), I-Neb® (Philips / Respironics), IH50 (Beurer), MicroMesh® (Health & Life, Schill), Micro Air® U22 (Omron), Multisonic® (Schill), Respimat® (Boehringer), eFlow® (PARI), AeroNebGo® (Aerogen), AeroNeb Pro® (Aerogen), and AeroDose® (Aerogen) families of devices.

[0091] However, preferably, especially when nebulizing liquid compositions containing L-CsA, piezoelectric, electrohydrodynamic, membrane, electronic membrane or electronic vibrating membrane nebulizers may be used. In these cases, suitable nebulizers include I-Neb® (Philips / Respironics), IH50 (Beurer), MicroMesh® (Health & Life, Schill), Micro Air® U22 (Omron), Multisonic® (Schill), Respimat® (Boehringer), eFlow® (PARI), AeroNebGo® (Aerogen), AeroNeb Pro® (Aerogen) and AeroDose® (Aerogen) device families. In a preferred embodiment, the composition for use according to the invention is aerosolized with an electronic vibrating membrane nebulizer to target the drug CsA, either neat or in the form of liposomal CsA (L-CsA), to the lower airways. In a particularly preferred embodiment, the liquid composition for use according to the invention is aerosolized with an eFlow® nebulizer (PARI Pharma GmbH).

[0092] The eFlow® nebulizer nebulizes liquid drug formulations, such as the compositions of the present invention, using a perforated vibrating membrane to produce an aerosol with low ballistic momentum and a high percentage of droplets in the respirable size range, typically less than 5 pm. The eFlow® nebulizer is designed to nebulize pharmaceutical agents more quickly and efficiently, with higher nebulization rates, lower drug wastage, and a higher percentage of drug available as delivered dose (DD) and respirable dose (RD) compared to conventional nebulizers, such as jet nebulizers.

[0093] Preferably, suitable nebulizers, particularly vibrating membrane nebulizers, are capable of delivering such unit doses at a rate of at least about 0.1 mL / min, or at a rate of at least about 100 mg / min, assuming that the relative density of the composition is typically around 1. More preferably, the nebulizer is capable of producing an output rate of at least about 0.15 mL / min or 150 mg / min, respectively. In further embodiments, the output rate of the nebulizer is at least about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or 1 mL / min.

[0094] Furthermore, the output speed of the nebulizer should be selected to achieve a short nebulization time of the liquid composition.Obviously, the nebulization time depends on the volume of the composition to be aerosolized and the output speed.Preferably, the nebulizer should be selected or adapted so that it can aerosolize the volume of the liquid composition containing an effective dose of the active compound within about 20 minutes.More preferably, the nebulization time of a unit dose is about 10 minutes or less.Even more preferably, the nebulization time of a unit dose is about 5 minutes or less.

[0095] In addition to providing a high delivered dose and having a short nebulization time, nebulizers for administering CsA in the form of L-CsA are preferably constructed to inhibit contamination of the environment with CsA. To this end, a filter device can be placed in the exhalation valve of the nebulizer.

[0096] In a preferred embodiment, the nebulizer is equipped with features for monitoring, for example, the time, date and duration of inhalation by the patient. An example of such a feature is a chip card on which the time and duration of nebulization is recorded.

[0097] Alternatively, wireless transmission of such data to a cloud and / or server can be applied, allowing medical staff to verify patient adherence. The monitoring system may include the nebulizer, controller, server, data bank, cloud, provider, physician, health insurance company, and / or phone service as described above.

[0098] It has been found that at least 65% or at least 75% adherence is beneficial to obtain relevant prevention or delay of the progression of BOS in double lung transplant patients. To achieve at least 65% adherence, double lung transplant patients who are at risk of developing or have been diagnosed with BOS, particularly BOS 1 or BOS 2, must inhale the formulation as intended in at least 65% of the intended inhalation cycle. For example, based on a twice-daily inhalation regimen, this means that the patient is not allowed to miss more than 39 inhalations during an 8-week period, which corresponds to approximately 5 inhalations per week. Omitted inhalations, inhalations that are not performed until a complete unit dose is inhaled, or inhalations that are insufficient for other reasons are considered to be "missed" inhalations, in other words inhalations that are not "as intended". More preferably, the formulation for use according to the present invention is inhaled with at least 75% adherence, i.e., the patient must inhale the formulation as intended in at least 75% of the intended inhalation cycle, based on a twice-daily inhalation regimen. This is achieved if no more than 28 inhalations are missed in an 8 week period, or approximately 3.5 inhalations are missed per week.

[0099] In another embodiment, the feature for recording the nebulization time, date and duration is connected to a system that generates a signal as soon as the inhalation is not performed correctly in a predetermined number of inhalation cycles in a timely manner. By using such a monitoring system, it can be ensured that the patient uses the nebulizer device correctly, regardless of the presence or absence of a system that generates a signal. The system for generating a signal can include, for example, the detection by a sensor of the presence of fluid in the fluid reservoir, the measurement of the inhalation flow, the inhalation time, the inhalation duration and / or the inhalation volume. Visual, auditory or sensory feedback can be given, for example, on the use factors that affect the relevant patient behavior and treatment, or on the diagnosis of application. This feedback can include information for improving the patient's adherence to a defined medical protocol and / or the deposition and distribution of CsA in the lungs.

[0100] For example, in an embodiment in which the time, date and duration of each inhalation are recorded in the characteristic for monitoring, the patient can be continuously monitored. In an embodiment in which the monitoring system is connected to a system that generates a signal, the patient's inhalation behavior can be modified as soon as the patient's adherence falls below a predetermined adherence limit. The signal can be a signal generated by the nebulizer itself, but also a signal generated by a remote device, for example notifying the patient's physician. When notified of the lack of adherence, the physician can contact the patient and remind him / her that proper inhalation is essential for successful prevention of chronic lung graft rejection.

[0101] The present inventors have found that monitoring is useful in lung transplant patients, particularly bilateral lung transplant patients, since the effects of liquid L-CsA composition inhalation formulations are more pronounced in compliant patients.

[0102] Furthermore, it has been found to be advantageous to administer the composition for use according to the invention to a double lung transplant patient at risk of developing BOS or diagnosed with BOS for an extended period of time, such as at least 2 weeks, or at least 4 weeks, or at least 8 weeks, or at least 12 weeks, or at least 16 weeks, or at least 20 weeks or more. In a particularly preferred embodiment, the liquid composition for use according to the invention is administered for a period of at least 24 weeks, or even 36 weeks, or even 48 weeks, or even longer, such as 12 months, 24 months, 36 months, or even several years, such as 4 years, or 5 years, or even 6 years, which may be shown to prevent BOS or to delay or reduce the progression of BOS, particularly BOS 1 or BOS 2, in double lung transplant patients.

[0103] In a further preferred embodiment, administration of the composition for use according to the invention is carried out continuously every day, preferably one or even multiple times, preferably twice a day, for a period of at least 24 weeks, preferably at least 48 weeks.

[0104] In a further embodiment, the inhaled CsA composition of the invention is used in combination with one or more active ingredients used in standard immunosuppressive therapy following lung transplantation.Thus, in a preferred embodiment, the liquid composition for use according to the invention is characterized in that the bilateral lung transplant patient is treated simultaneously with standard immunosuppressive therapy (also referred to herein as "SOC").

[0105] Standard immunosuppressive therapy after lung transplantation may include the administration of one or more active ingredients from the groups of immunosuppressants and corticosteroids. Examples of immunosuppressants are compounds belonging to the groups of immunoglobulins (antibodies), cell cycle inhibitors (antimetabolites / antiproliferative drugs), such as azathioprine and mycophenolic acid and their salts, and calcineurin inhibitors, such as cyclosporine, tacrolimus, or mTOR inhibitors, such as sirolimus and everolimus. Examples of corticosteroids are compounds belonging to the groups of hydrocortisone, methylprednisolone, prednisone, and any of their salts, esters, and derivatives.

[0106] In a specific embodiment, the composition for use according to the invention is used in combination with one or more active ingredients selected from the group consisting of tacrolimus, mycophenolate mofetil and / or corticosteroids in a standard immunosuppressive therapy, preferably oral.Thus, in a specific embodiment, the composition for use according to the invention is administered in combination with a standard immunosuppressive therapy comprising the administration of one or more active ingredients selected from the group consisting of tacrolimus or cyclosporine; mycophenolate mofetil or sirolimus; and corticosteroids.

[0107] In a further specific embodiment, the composition for use according to the invention is used in combination with a triple drug therapy in which a combination of a calcineurin inhibitor, a cell cycle inhibitor and a corticosteroid is administered. Preferably, the calcineurin inhibitor is tacrolimus, the cell cycle inhibitor is mycophenolate mofetil and the corticosteroid is prednisone. The active ingredient used in combination with the composition according to the invention is preferably administered orally. In these cases of standard immunosuppressive therapy, tacrolimus is usually administered in an amount to achieve a whole blood level (WBTL) of 8 to 12 ng / mL, preferably in an amount of about 0.06 mg / kg (with respect to the body weight of the patient to be treated). Furthermore, mycophenolate mofetil in standard immunosuppressive therapy is typically administered in an amount of about 1 g, sometimes up to 3 g, preferably about 1 g. Prednisone, when used under standard immunosuppressive therapy, is typically administered in an amount of about 20 to about 25 mg / day, preferably about 20 mg / day.

[0108] As a result, the use of the inhaled cyclosporine liquid composition according to the invention in combination with these ingredients allows the usual dose of the active ingredient used in standard immunosuppressive therapy to be reduced. In other words, the dose (defined herein as the usual dose) typically required for successful immunosuppression without the use of inhaled CsA, or more specifically L-CsA, can often be reduced. This is advantageous, since the use of systemically administered immunosuppressants can lead to significant adverse effects that are generally dose-dependent.

[0109] The composition for use according to the present invention allows effective treatment or prevention of BOS in double lung transplant patients, or effective delay of the progression of BOS in double lung transplant patients who have been diagnosed with BOS. As mentioned above, the decrease in forced expiratory volume in 1 second (FEV1) can be used as an indicator of the presence of BOS and therefore as an indicator of the risk of chronic lung graft rejection. Thus, in a specific embodiment, the composition for use according to the present invention is useful for treating BOS in double lung transplant patients, in particular BOS 1 or BOS 2, and the progression of BOS in double lung transplant patients is substantially prevented or reduced to a level of up to 50%, or up to 40%, or up to 30%, or up to 20%, or even up to 15%, or 10%, or even up to 5% decrease in FEV1 of said patient, compared to the FEV1 value of said patient at the start of treatment, or at the start of randomization, or at the start of the study, respectively. In a preferred embodiment, the progression of BOS, in particular BOS 1 or BOS 2, in a bilateral lung transplant patient is substantially prevented or reduced to a level of up to a 20% decrease in forced expiratory volume in 1 second (FEV1) of said patient compared to said patient's FEV1 value at the start of treatment or at the start of randomization or at the start of the study, respectively.

[0110] This effect may be achieved by treatment of a bilateral lung transplant patient at risk of developing or diagnosed with BOS with a composition of the invention or with a method of the invention for an extended period of time such as at least 2 weeks, or at least 4 weeks, or at least 8 weeks, or at least 12 weeks, or at least 16 weeks, or at least 20 weeks, or even longer, such as at least 24 weeks, or even 36 weeks, or even 48 weeks, or even longer, such as 12 months, 24 months, 36 months, or even several years, such as 4 years, or 5 years, or 6 years, in which case it may be shown to prevent, delay or reduce the progression of BOS, particularly BOS 1 or BOS 2, in a bilateral lung transplant patient.

[0111] In a further preferred embodiment, after treatment with a composition for use according to the invention for a period of at least 24 weeks followed by at least 24 weeks of no treatment for said bilateral lung transplant, the progression of BOS in said bilateral lung transplant patient is substantially prevented or reduced to a level of up to a 20%, preferably up to a 10% decrease in said patient's forced expiratory volume in one second (FEV1) compared to said patient's FEV1 value at the start of treatment or at the start of randomization or at the start of the study, respectively.

[0112] Furthermore, it has been found that the compositions for use according to the present invention enable a significant extension of event-free survival in bilateral lung transplant patients at risk of developing BOS or diagnosed with BOS, preferably diagnosed with BOS, where event-free survival is characterized as the period of survival during which the bilateral lung transplant patient does not experience at least a 20% decline in FEV1 and / or the need for retransplantation or death.

[0113] Furthermore, the composition for use according to the invention allows for a significant extension of the event-free survival probability of a bilateral lung transplant patient at risk of developing or diagnosed with BOS, in particular BOS 1 or BOS 2. Thus, in a preferred embodiment, the composition for use according to the invention allows for the treatment of a bilateral lung transplant patient at risk of developing or diagnosed with BOS, where the event-free survival probability is at least 50%, or at least 60%, or at least 70%, or at least 80%, or even at least 90% after a period of at least 12 weeks, or at least 24 weeks, or at least 36 weeks, or even at least 48 weeks, or even longer, such as 12 months, 24 months, 36 months, or even years, such as 4 years, or 5 years, or even 6 years, from the start of treatment, and the events are selected from a decline in FEV1 of at least 10% or 20% and / or the need for retransplantation or death. In a preferred embodiment, the probability of event-free survival of a bilateral lung transplant patient at risk of developing BOS or diagnosed with BOS, preferably diagnosed with BOS, after treatment with a composition for use according to the invention for a period of at least 24 weeks, followed by at least 24 weeks without treatment, is at least 60%, preferably at least 80%.

[0114] In further embodiments, for bilateral lung transplant patients at risk of developing or diagnosed with BOS, the risk of experiencing an event selected from at least a 10% or at least a 20% decline in FEV1, the need for retransplantation, and / or death may be significantly reduced within an extended period of at least 2 weeks, or at least 4 weeks, or at least 8 weeks, or at least 12 weeks, or at least 16 weeks, or at least 20 weeks, or even longer, such as at least 24 weeks, or even 36 weeks, or even 48 weeks, or even longer, such as 12 months, 24 months, 36 months, or even years, such as 4 years, or 5 years, or even 6 years, but preferably within 48 weeks, from the start of treatment.

[0115] Thus, the composition for use according to the present invention allows for the treatment of a bilateral lung transplant patient at risk of developing or diagnosed with BOS, where the risk of experiencing an event selected from at least a 20% decline in FEV1, the need for re-transplantation and / or death (event free survival probability) is reduced by at least 30% (absolute), preferably at least 35% (absolute), within at least 2 weeks, or at least 4 weeks, or at least 8 weeks, or at least 12 weeks, or at least 16 weeks, or at least 20 weeks, or even longer, such as at least 24 weeks, or even 36 weeks, or even 48 weeks, or even longer, such as 12 months, 24 months, 36 months, or even years, such as 4 years, or 5 years, or even 6 years, preferably within at least 48 weeks, from the start of treatment for a bilateral lung transplant patient treated with an aerosolized form of the composition of the present invention comprising CsA or preferably L-CsA, compared to the risk of experiencing the corresponding event under treatment with standard immunosuppressive therapy (SOC) alone.

[0116] In a preferred embodiment, the risk of experiencing an event selected from the abovementioned decline in FEV1 of at least 20%, the need for retransplantation and / or death is reduced by at least 30%, preferably at least 35% (absolute), in particular after treatment with a composition for use according to the invention for a period of at least 24 weeks, followed by at least 24 weeks without treatment.

[0117] A further measure for determining the potential prevention or delay of the progression of BOS in bilateral lung transplant patients is the determination of the mean monthly change in FEV1, or more specifically the monthly loss or decline (ΔFEV1 / month, hereinafter also referred to as "FEV1 slope"), determined for such patients based on FEV1 measurements taken regularly and repeatedly over a period of at least 12 weeks, or at least 24 weeks, or at least 36 weeks, or even at least 48 weeks, or 12 months, or even 24 months, or 36 months, or even longer, such as over a period of time as mentioned above, for example after 4 years, or 5 years, or even 6 years, preferably over a period of 48 weeks. Thus, in a preferred embodiment, the composition for use according to the invention allows for the treatment of a bilateral lung transplant patient at risk of developing BOS or diagnosed with BOS, in which the monthly change in FEV1 (ΔFEV1 / month) remains substantially constant or has a value in the range of about 0 to about 0.055 L / month (corresponding to a loss or decline in FEV1 of up to 0.055 L / month), or about 0 to about 0.05 L / month, or about 0 to about 0.045 L / month, about 0 to about 0.04 L / month. In a preferred embodiment, the composition for use according to the invention allows for the treatment of a bilateral lung transplant patient at risk of developing BOS or diagnosed with BOS, in which the monthly change in FEV1 (ΔFEV1 / month) remains substantially constant or has a value in the range of about 0 to about 0.04 L / month (meaning that the monthly loss in FEV1 is in the range of about 0 to about 0.04 L).

[0118] Yet another measure for determining the potential delay or progression of BOS in bilateral lung transplant patients at risk of developing or who have been diagnosed with BOS is the measurement of the absolute change in FEV1, or more specifically the absolute loss (ΔFEV1 / absolute), determined for such patients based on FEV1 measurements taken at the start of treatment and at the end of treatment, specifically over a period of at least 12 weeks, or at least 24 weeks, or at least 36 weeks, or even after an extended period such as at least 48 weeks, or 12 months, or even 24 months, or 36 months, or even longer, such as after 4 years, or 5 years, or even 6 years, preferably a period of 48 weeks. Thus, in a specific embodiment, the composition for use according to the invention allows the treatment of a bilateral lung transplant patient at risk of developing BOS or diagnosed with BOS, in which the absolute change in FEV1 (ΔFEV1 / absolute) between baseline (start of treatment) and the end of the treatment period, e.g. 48 weeks after the start of treatment, is 350 mL or less, meaning that the total loss of FEV1 in said patient is 350 mL or less, preferably 300 mL or less, or 250 mL or less, or 200 mL or less, or even 150 mL or less. In a further embodiment, the absolute change in FEV1 (ΔFEV1 / absolute) between baseline (start of treatment) and the end of the treatment period, e.g. 48 weeks after the start of treatment, in the bilateral lung transplant patient at risk of developing BOS or diagnosed with BOS, preferably diagnosed with BOS, is in the range of 150-350 ml.

[0119] A still further measure for determining the potential delay or progression of BOS in a bilateral lung transplant patient at risk of developing BOS or who has been diagnosed with BOS and who is being treated with a composition for use according to the present invention is the determination of the relative change in FEV1, or more specifically the relative loss of FEV1 (ΔFEV1 / relative), relative to that of a patient treated with standard immunosuppressive therapy (SOC) alone, particularly after prolonged treatment such as over a period of at least 12 weeks, or at least 24 weeks, or at least 36 weeks, or even 48 weeks, or 12 months, or even 24 months, or 36 months, or even longer than 4 years, or 5 years, or even 6 years, preferably over a period of 48 weeks. Thus, in a specific embodiment, the composition for use according to the invention allows the treatment of a bilateral lung transplant patient who has been diagnosed with BOS, where the relative change or difference (ΔFEV1 / relative) in FEV1 of a bilateral lung transplant patient treated with a composition comprising L-CsA for use according to the invention relative to the loss of FEV1 in a patient treated with standard immunosuppressive therapy (SOC) alone is at least 200 mL, or at least 250 mL, or at least 300 mL, or even such as at least 350 mL, or at least 400 mL, after a period of at least 12 weeks, or at least 24 weeks, or at least 36 weeks, or even at least 48 weeks, or 12 months, or even 24 months, or 36 months, or even longer, 4 years, or 5 years, or even 6 years, preferably over a period of 48 weeks, after the start of treatment.

[0120] In a preferred embodiment, a composition comprising L-CsA for use according to the invention allows for the treatment of bilateral lung transplant patients at risk of developing or diagnosed with BOS, in which the relative loss or difference in FEV1 (ΔFEV1 / relative) relative to the loss in FEV1 of patients treated with standard immunosuppressive therapy (SOC) alone is in the range of about 200 to about 400 mL after 48 weeks of treatment. This means, for example, that according to these preferred embodiments, after a period of 48 weeks, patients treated with a composition according to the invention have an FEV1 value that is about 200 to about 400 mL higher than the FEV1 value of a bilateral lung transplant patient treated with standard immunosuppressive therapy alone.

[0121] The compositions for use according to the present invention may be particularly useful in the successful treatment of bilateral lung transplant patients who have not been diagnosed with airway stenosis prior to the start of treatment, who are at risk of developing BOS or who have been diagnosed with BOS, as confirmed by bronchoscopy with bronchoalveolar lavage (BAL), and especially those who have not yet been diagnosed with airway stenosis 24 weeks after the start of treatment.

[0122] Furthermore, the compositions for use according to the present invention may be particularly useful in the successful treatment of bilateral lung transplant patients at risk of developing or diagnosed with BOS who have not been diagnosed with an untreated infection prior to the initiation of treatment, and especially those patients who have not been diagnosed with an untreated infection 24 weeks after initiation of treatment.

[0123] The composition comprising CsA, particularly L-CsA, for use according to the present invention must be inhaled in aerosolized form. However, this can help to significantly reduce the patient's systemic exposure. Thus, the composition for use according to the present invention further allows the treatment of double lung transplant patients who are at risk of developing BOS or have been diagnosed with BOS, and the average blood concentration of CsA in double lung transplant patients treated with a liquid composition comprising CsA by inhalation is up to 100ng / mL, preferably up to 60ng / mL.

[0124] In a further aspect, the present invention provides the use of a composition comprising cyclosporine A (CsA) in the preparation of a medicament for preventing or treating bronchiolitis obliterans syndrome (BOS) in a double lung transplant patient or for preventing or delaying the progression of BOS in a double lung transplant patient diagnosed with BOS, the composition being administered to the patient by inhalation of an aerosolized form of the composition comprising a therapeutically effective dose of CsA. As outlined above in relation to the composition of the first aspect of the invention, the composition comprising CsA may be used in solid or liquid form to prepare a medicament according to this aspect of the invention. When solid compositions are used, they may be reconstituted with a suitable liquid vehicle or solvent, as described in detail above. In addition, all features disclosed and described above in relation to the composition for use according to the first aspect of the invention may also be applied to the use of such a composition according to this aspect of the invention.

[0125] In yet a further aspect, the invention provides a method of preventing bronchiolitis obliterans syndrome (BOS) in a bilateral lung transplant patient, or treating or preventing or delaying the progression of BOS in a bilateral lung transplant patient who has been diagnosed with BOS, comprising: (a) identifying patients who have undergone bilateral lung transplantation and are at risk of developing or have subsequently developed BOS; (b) administering to said patient by inhalation a therapeutically effective dose of aerosolized cyclosporine A (CsA); The present invention provides a method comprising:

[0126] It should be pointed out that for the method according to this aspect of the invention, all the features disclosed and described above in relation to the composition for use according to the first aspect of the invention may also be applied to the method for preventing bronchiolitis obliterans syndrome (BOS) in a double lung transplant patient or for treating BOS or for preventing or delaying the progression of BOS in a double lung transplant patient who has been diagnosed with BOS according to this aspect of the invention.

[0127] However, for the avoidance of doubt, the following is a list of numbered embodiments of compositions comprising cyclosporine A (CsA), in particular liposomal CsA (L-CsA), for use in preventing bronchiolitis obliterans syndrome (BOS) in a double lung transplant patient, or for preventing or delaying the progression of BOS in a double lung transplant patient who has been diagnosed with BOS according to this aspect of the invention, which are also included in the method of preventing bronchiolitis obliterans syndrome (BOS) in a double lung transplant patient, or for preventing or delaying the progression of BOS in a double lung transplant patient who has been diagnosed with BOS according to this aspect of the invention:

[0128] 1. A composition comprising cyclosporine A (CsA) for use in the prevention of bronchiolitis obliterans syndrome (BOS) in bilateral lung transplant patients or for treating or preventing or slowing the progression of BOS in bilateral lung transplant patients who have been diagnosed with BOS, The composition is administered to said patient by inhalation of an aerosolized form of the composition comprising a therapeutically effective dose of cyclosporine A.

[0129] 2. A composition comprising cyclosporine A (CsA) for use according to item 1 in the treatment of bronchiolitis obliterans syndrome (BOS) in bilateral lung transplant patients diagnosed with BOS or for preventing or delaying the progression of BOS, The composition is administered to said patient by inhalation of an aerosolized form of the composition comprising a therapeutically effective dose of cyclosporine A.

[0130] 3. The composition for use according to items 1 or 2, wherein the bilateral lung transplant patient has been diagnosed with BOS 1 or BOS 2.

[0131] 4. A composition for use according to any of items 1 to 3, comprising cyclosporine A in the form of liposomal cyclosporine A (L-CsA).

[0132] 5. A composition for use according to any of items 1 to 4, which is a liquid composition.

[0133] 6. A composition for use according to item 5, comprising an aqueous liquid vehicle.

[0134] 7. The composition for use according to item 6, wherein the aqueous liquid vehicle comprises saline.

[0135] 8. The composition for use according to item 6 or 7, wherein the aqueous liquid vehicle consists essentially of saline, preferably saline at a concentration of 0.25%.

[0136] 9. The composition for use according to any of items 1 to 8, wherein the liquid composition has a CsA concentration in the range of 0.5 to 10 mg / mL.

[0137] 10. A composition for use according to any of items 1 to 9, wherein the liquid composition is prepared by reconstitution of liposomal cyclosporine A in lyophilized form.

[0138] 11. A composition for use according to any of items 1 to 10, wherein cyclosporine A is administered in an effective daily dose ranging from 5 to 30 mg.

[0139] 12. A composition for use according to any of items 1 to 11, wherein cyclosporine A is administered in an effective daily dose of 20 mg.

[0140] 13. The composition for use according to any of items 1 to 12, which is administered to the patient twice a day.

[0141] 14. The composition for use according to any of items 1 to 13, which is administered for a period of at least 24 weeks.

[0142] 15. The composition for use according to any of items 1 to 14, wherein a bilateral lung transplant patient is treated concomitantly with standard immunosuppressive therapy.

[0143] 16. The composition for use according to item 15, wherein the standard immunosuppressive therapy comprises the administration of one or more active ingredients selected from the group consisting of tacrolimus or cyclosporine; mycophenolate mofetil or sirolimus; and corticosteroids.

[0144] 17. The composition for use according to item 15 or 16, wherein the standard immunosuppressive therapy comprises oral administration of tacrolimus, mycophenolate mofetil and prednisone.

[0145] 18. The composition for use according to any one of items 15 to 17, wherein tacrolimus is administered in an amount of 0.06 mg / kg.

[0146] 19. The composition for use according to any one of items 15 to 18, wherein mycophenolate mofetil is administered in an amount of 1 g.

[0147] 20. The composition for use according to any one of items 15 to 19, wherein prednisone is administered in an amount of about 20 to about 25 mg per day.

[0148] 21. A composition for use according to any of items 1 to 20, wherein the formulation is aerosolized with an electronic vibrating membrane nebulizer.

[0149] 22. A composition for use according to any of items 1 to 21, wherein the formulation is aerosolized with an eFlow® nebulizer.

[0150] 23. A composition for use according to any of items 1 to 22, in which the progression of BOS in a bilateral lung transplant patient diagnosed with BOS is prevented or reduced to a level of up to a 20% decrease in the patient's forced expiratory volume in 1 second (FEV1) compared to the FEV1 value at the start of treatment.

[0151] 24. The composition for use according to any of items 1 to 23, wherein the probability of event-free survival of a bilateral lung transplant patient diagnosed with BOS is at least 60% at least 48 weeks after the start of treatment, the events being selected from a decline in FEV1 of at least 20%, the need for retransplantation and / or death.

[0152] 25. A composition for use according to any of items 1 to 24, wherein the risk of experiencing an event selected from at least a 20% decline in FEV1, the need for retransplantation and / or death within a period of at least 48 weeks from the start of treatment for bilateral lung transplant patients treated with a composition of the invention in aerosolized form comprising CsA is reduced by at least 30% (absolute), preferably by at least 35% (absolute), compared to the risk of experiencing the corresponding event under treatment with standard immunosuppressive therapy (SOC) alone.

[0153] 26. The composition for use according to any of items 1 to 25, wherein the mean monthly change in FEV1 (ΔFEV1 / month) in a bilateral lung transplant patient who has been diagnosed with BOS remains substantially constant or has a value in the range of about 0 to about 0.04 L / month.

[0154] 27. A composition for use according to any of items 1 to 26, in which the absolute change in FEV1 (ΔFEV1 / absolute) between baseline (start of treatment) and the end of the treatment period in a bilateral lung transplant patient diagnosed with BOS is 350 mL or less.

[0155] 28. A composition for use according to any of claims 1 to 27, in which the relative loss in FEV1 (ΔFEV1 / relative) of a bilateral lung transplant patient diagnosed with BOS compared to the loss in FEV1 of a patient treated with standard immunosuppressive therapy (SOC) alone is at least 200 mL.

[0156] 29. The composition for use according to any of items 1 to 28, wherein the double lung transplant patient has not been diagnosed with airway stenosis before the start of treatment and preferably 24 weeks after the start of treatment, as confirmed by bronchoscopy with bronchoalveolar lavage (BAL).

[0157] 30. The composition for use according to any of items 1 to 29, wherein the bilateral lung transplant patient who has been diagnosed with BOS has not been diagnosed with an untreated infection prior to randomization and preferably at 24 weeks after initiation of treatment.

[0158] 31. A composition for use according to any of items 1 to 30, in which a bilateral lung transplant patient who has been diagnosed with BOS and is being treated with a liquid composition comprising CsA has a maximum blood concentration of CsA of up to 100 ng / mL, preferably up to 60 ng / mL.

[0159] 32. The composition for use according to item 21 or 22, wherein the nebulizer is capable of delivering the unit dose at a rate of at least about 0.1 mL / min.

[0160] 33. A method for preventing bronchiolitis obliterans syndrome (BOS) in a bilateral lung transplant patient, or for treating BOS or preventing or delaying the progression of BOS in a bilateral lung transplant patient who has been diagnosed with BOS, comprising: (a) identifying patients who have undergone bilateral lung transplantation and are at risk of developing or have subsequently developed BOS; (b) administering to said patient by inhalation a therapeutically effective dose of aerosolized cyclosporine A (CsA); The method includes:

[0161] 34. The method according to item 33 for treating bronchiolitis obliterans syndrome (BOS) in bilateral lung transplant patients or preventing or delaying the progression of BOS in bilateral lung transplant patients who have been diagnosed with BOS, (a) Identifying patients who underwent bilateral lung transplantation and subsequently developed BOS; (b) administering to said patient by inhalation a therapeutically effective dose of aerosolized cyclosporine A (CsA); The method includes:

[0162] 35. The method according to item 33 or 34, wherein the bilateral lung transplant patient has been diagnosed with BOS 1 or BOS 2 (BOS grade I or II).

[0163] 36. The method of item 33 or 34, wherein CsA is administered in the form of an aerosolized composition comprising liposomal cyclosporine A (L-CsA).

[0164] 37. The method of item 33, wherein the CsA is administered in the form of an aerosolized liquid composition comprising cyclosporine A (CsA).

[0165] 38. The method according to item 33, wherein CsA is administered in the form of liposomal cyclosporine A (L-CsA).

[0166] 39. The method according to item 36, wherein the composition further comprises an aqueous liquid vehicle.

[0167] 40. The method of claim 39, wherein the aqueous liquid vehicle comprises saline.

[0168] 41. The method according to item 39 or 40, wherein the aqueous liquid vehicle consists essentially of saline, preferably saline at a concentration of 0.25% (w / v).

[0169] 42. The method according to item 37, wherein the liquid composition has a CsA concentration in the range of 0.5 to 10 mg / mL.

[0170] 43. The method according to item 38, wherein the liquid composition is prepared by reconstitution of a lyophilized form of liposomal cyclosporine A (L-CsA).

[0171] 44. The method according to item 33, wherein cyclosporine A is administered in an effective daily dose ranging from 5 to 30 mg.

[0172] 45. The method according to item 33, wherein cyclosporine A is administered in an effective daily dose of 20 mg.

[0173] 46. ​​The method of item 33, wherein the composition is administered to the patient twice a day.

[0174] 47. The method according to item 33, wherein CsA is administered for a period of at least 24 weeks.

[0175] 48. The method according to item 33, wherein the bilateral lung transplant patient is treated simultaneously with standard immunosuppressive therapy.

[0176] 49. The method according to item 48, wherein the standard immunosuppressive therapy comprises administration of one or more active ingredients selected from the group consisting of tacrolimus or cyclosporine; mycophenolate mofetil or sirolimus; and corticosteroids.

[0177] 50. The method according to item 48, wherein the standard immunosuppressive therapy comprises oral administration of tacrolimus, mycophenolate mofetil and prednisone.

[0178] 51. The method according to item 49 or 50, wherein tacrolimus is administered in an amount of 0.06 mg / kg.

[0179] 52. The method according to item 49 or 50, wherein mycophenolate mofetil is administered in an amount of 1 g.

[0180] 53. The method according to item 49 or 50, wherein prednisone is administered in an amount of 20 mg / day.

[0181] 54. The method according to item 33, wherein the formulation is aerosolized with an electronic vibrating membrane nebulizer.

[0182] 55. The method of item 33, wherein the formulation is aerosolized with an eFlow® nebulizer.

[0183] 56. The method according to item 36, wherein the formulation is inhaled with at least 75% adherence.

[0184] 57. The method according to item 33, wherein the progression of BOS in a bilateral lung transplant patient at risk of developing BOS or diagnosed with BOS is prevented or reduced to a level of up to a 20% decrease in the forced expiratory volume in 1 second (FEV1) of said patient compared to the FEV1 value at the start of treatment.

[0185] 58. The method according to item 33, wherein the probability of event-free survival in bilateral lung transplant patients at risk of developing or diagnosed with BOS is at least 60% at least 48 weeks after initiation of treatment, the events being selected from a decline in FEV1 of at least 20%, the need for retransplantation and / or death.

[0186] 59. The method according to item 33, wherein the risk of experiencing an event selected from at least a 20% decline in FEV1, the need for retransplantation and / or death within a period of at least 48 weeks from the start of treatment for a bilateral lung transplant patient treated with an aerosolized form of the composition of the present invention comprising CsA is reduced by at least 30% (absolute), preferably at least 35% (absolute), compared to the risk of experiencing the corresponding event under treatment with standard immunosuppressive therapy (SOC) alone.

[0187] 60. The method according to item 33, wherein the mean monthly change in FEV1 (ΔFEV1 / month) in a bilateral lung transplant patient who has been diagnosed with BOS remains substantially constant or has a value in the range of about 0 to about 0.04 L / month.

[0188] 61. The method according to item 33, in which the absolute change in FEV1 (ΔFEV1 / absolute) between baseline (start of treatment) and the end of the treatment period in a bilateral lung transplant patient diagnosed with BOS is 350 mL or less.

[0189] 62. The method according to item 33, wherein the relative loss in FEV1 (ΔFEV1 / relative) of a bilateral lung transplant patient diagnosed with BOS to the loss in FEV1 of a patient treated with standard immunosuppressive therapy (SOC) alone is at least 200 mL.

[0190] 63. The method according to item 33, wherein the bilateral lung transplant patient at risk of developing or diagnosed with BOS has not been diagnosed with airway stenosis prior to initiation of treatment and preferably 24 weeks after initiation of treatment, as confirmed by bronchoscopy with bronchoalveolar lavage (BAL).

[0191] 64. The method according to item 33, wherein the bilateral lung transplant patient at risk of developing or diagnosed with BOS has not been diagnosed with an untreated infection prior to initiation of treatment and preferably 24 weeks after initiation of treatment.

[0192] 65. The method according to item 33, wherein a bilateral lung transplant patient at risk of developing BOS or diagnosed with BOS and treated with a liquid composition comprising CsA has a maximum blood concentration of CsA of up to 100 ng / mL, preferably up to 60 ng / mL.

[0193] 66. The method of item 54 or 55, wherein the nebulizer is capable of delivering the unit dose at a rate of at least about 0.1 mL / min.

[0194] 65. Use of a composition comprising liposomal cyclosporine A (L-CsA) in the preparation of a medicament for preventing bronchiolitis obliterans syndrome (BOS) in a bilateral lung transplant patient, or for treating BOS in a bilateral lung transplant patient who has been diagnosed with BOS, or for preventing or slowing the progression of BOS, wherein the composition is administered to the patient by inhalation of an aerosolized form of the composition comprising a therapeutically effective dose of CsA. Detailed Description of the Drawings

[0195] Figure 1 shows a flow chart summarizing the enrollment details of single and double lung transplant patients in the study described in the following examples. A total of 43 patients were evaluated for eligibility, of which 23 patients met the eligibility criteria. Prior to randomization, one patient died and one patient withdrew from the study. Twenty-one patients were randomized, 11 to the L-CsA treatment group and 10 to the SOC (standard of care, i.e., standard immunosuppressive therapy) treatment group. One patient in the L-CsA group withdrew from the study due to progressive skin cancer during the 24-week follow-up. As this patient's cancer was progressive, traditional systemic immunosuppression was discontinued and this patient was managed with curative intent.

[0196] Figure 2 shows a Kaplan-Meier plot of the probability of BOS progression-free survival for single and double lung transplant patients diagnosed with BOS during the 48-week study period (i.e., no distinction is made between single and double lung transplant patients). Patients in the SOC group tended to have a higher risk of treatment failure (defined as BOS progression, retransplantation, or death) during the study period compared with L-CsA (hazard ratio (HR): 3.19; 95% confidence interval (95%CI): 0.62-16.50; p=0.14).

[0197] Figure 3 shows a Kaplan-Meier plot of event-free survival probability for only bilateral lung transplant patients diagnosed with BOS (i.e., there are no results for single lung transplant patients). The event-free survival probability for bilateral lung transplant patients diagnosed with BOS was 83% in the L-CsA treatment group compared with 50% in the SOC treatment only group. Furthermore, for bilateral lung transplant patients, the hazard ratio (HR) was 3.43, 95% CI 0.31-37.95; p=0.29, implying a 3.43-fold increased risk of experiencing BOS progression, need for retransplantation, or death for the bilateral lung transplant patient group under SOC treatment alone compared with bilateral lung transplant patients under L-CsA treatment.

[0198] Figure 4 shows a Kaplan-Meier plot of event-free survival probability for single lung transplant patients only (i.e., there are no results for double lung transplant patients). The event-free survival probability for single lung transplant patients was 80% in the L-CsA treatment group compared with 50% in the SOC treatment only group. Furthermore, for single lung transplant patients, the hazard ratio (HR) was 2.78, 95% CI 0.29-26.98; p=0.36, implying that the risk of experiencing BOS progression, need for retransplantation, or death was 2.78 times higher for the group of single lung transplant patients under SOC treatment alone compared with single lung transplant patients under L-CsA treatment.

[0199] Figure 5 shows Kaplan-Meier plots of overall survival probability for single- and double-lung transplant patients 5 years after randomization. The data demonstrate a significant improvement in single- or double-lung transplant patients treated with L-CsA: 5 patients (45%) of 11 participants treated with L-CsA were alive at 5 years of follow-up compared with 0 of the first 10 patients treated with SOC alone. Median survival for the group of patients treated with L-CsA was 4.1 years compared with 2.9 years for the group of patients treated with SOC alone (p=0.03). Cause of death was chronic allograft rejection, with the exception of 2 cases, one from disseminated skin cancer (L-CsA) and one from renal failure (SOC).

[0200] Figure 6 shows the analysis of the overall FEV1 evolution in single and double lung transplant patients (i.e. no distinction is made between single and double lung transplant patients) after adjustment for pre-randomization and post-randomization measurement data in a random slope mixed model. In the group of patients treated with L-CsA (11 patients), a small decrease in the mean absolute FEV1 value was observed starting from approximately 1.75 L at randomization to 1.70 L at the end of the 48-week period, whereas for the group of patients treated with SOC (10 patients; one patient required mechanical ventilation and therefore had no PFT measurements after randomization; this patient was included in the calculation of the FEV1 slope: an FEV1 value of 0 was imposed at the time the patient progressed to mechanical ventilation; this patient had no PFT measurements after randomization), a stable and significant decrease in the FEV1 value was observed from approximately 1.75 L to approximately 1.15 L. In this overall analysis of single and double lung transplant patients, the monthly change in FEV1 (ΔFEV1 / month) was −0.054 with a 95% CI of −0.100 to −0.006 versus −0.007 with a 95% CI of −0.033 to 0.018 for the L-CsA-treated group (p=0.10).

[0201] Figure 7 shows the evolution of the mean absolute FEV1 values ​​for the bilateral lung transplant patients in the L-CsA treatment group (upper graph; "L-CsA") and SOC treatment group (lower graph; "SOC") over the 48-week study period (i.e., there are no results for the single lung transplant patients). In the group of patients treated with L-CsA (6 patients), the mean absolute FEV1 values ​​remained almost constant at 1.8 L throughout the 48 weeks. In contrast, in the group of bilateral lung transplant patients in the SOC group (4 patients), the mean absolute FEV1 values ​​decreased significantly from approximately 1.8 L to approximately 1.1 L over the same period. Thus, the monthly change in FEV1 (ΔFEV1 / month) for the bilateral lung transplant patients was 0.000 with a 95% CI of -0.049 to 0.049 for the L-CsA treatment group and -0.061 with a 95% CI of -0.096 to -0.026 for the SOC treatment group (p=0.07).

[0202] FIG. 8 shows the evolution of the mean absolute FEV1 values ​​for single lung transplant patients (i.e., there are no results for double lung transplant patients) in the L-CsA (upper graph; "L-CsA") and SOC (lower graph; "SOC") treatment groups over the 48-week study period. In the L-CsA treated group (5 patients), a decrease in the mean absolute FEV1 values ​​was observed from approximately 1.75 L immediately after randomization to approximately 1.4 L at 48 weeks after randomization. For the single lung transplant group in the SOC group (6 patients; one patient required mechanical ventilation and therefore had no PFT measurements after randomization; the patient was included in the calculation of the FEV1 slope: an FEV1 value of 0 was imposed at the time the patient progressed to mechanical ventilation; this patient had no PFT measurements after randomization), the mean FEV1 values ​​decreased significantly over the same period (graphs for the SOC treatment group ended at month 1 due to the calculation method) from approximately 1.75 L to approximately 1.05 L. Thus, the monthly change in FEV1 (ΔFEV1 / month) in bilateral lung transplant patients was −0.029 with 95% CI −0.019 to 0.001 for the L-CsA treatment group and −0.600 with 95% Cl −2.074 to 0.872 for the SOC treatment group (p=0.37).

[0203] The following examples serve to illustrate the present invention but should not be understood as limiting the scope of the invention. Working Example

[0204] Example 1: In vitro aerosol characterization of liquid CsA formulations A liposomal cyclosporine liquid formulation for inhalation was prepared consisting of the active substance CsA (Ph.Eur.) and the excipients lipoid S100, polysorbate 80, edetate disodium, disodium hydrogen phosphate dodecahydrate, and sodium dihydrogen phosphate monohydrate. The formulation was adjusted to physiologically tolerable values ​​of pH (6.5 ± 0.2) and osmolarity (350-450 mOsmol / kg).

[0205] Aerosols were generated using an eFlow® nebulizer using a mixing chamber with a volume of approximately 95 ml. The aerosols generated with this nebulizer were characterized using breath simulation, laser diffraction and impactor measurements. The results of these measurements are summarized in Table 1.

[0206] Table 1: Aerosol characteristics of liposomal cyclosporine (L-CsA) formulations nebulized with the eFlow® nebulizer JPEG2024069355000002.jpg32131Values ​​are expressed as mean ± standard deviation; MMD = mass median diameter; DD = delivered dose (from the mouthpiece); RD = respirable dose

[0207] A delivered dose (DD) (amount from the mouthpiece) of 76% and a respirable dose (RD) of droplets smaller than 3.3 μm of approximately 47% were achieved. Particles smaller than 3.3 pm are more likely to deposit in the distal parts of the lungs, which are considered the optimal drug deposition site for effective lung graft protection. In general, aerosol droplets smaller than 5 μm are more likely to deposit throughout the lungs and should be considered for some degree of lung graft protection as well. The respirable dose of droplets smaller than 5 μm was approximately 68%.

[0208] Based on these results, it can be concluded that for a nominal drug amount of 10 mg, the corresponding delivered dose (mg) is approximately 7.6 mg CsA. The respirable doses (mg) for droplets below 5 pm and 3.3 pm are approximately 6.8 mg and 4.7 mg CsA, respectively.

[0209] Example 2: In vitro aerosol characterization of reconstituted CsA formulations Sucrose was added as a lyoprotectant to the formulation described in Example 1. The formulation was then lyophilized. Just before nebulization, the formulation was reconstituted with 2.3 ml of 0.25% saline. The liposome size was in the range of 40-100 nm (0.040-0.10 μm) and the polydispersity index after reconstitution was less than 0.40.

[0210] The reconstituted formulations were nebulized with an eFlow® nebulizer having the same inhalation chamber as the nebulizer in Example 1, i.e., a mixing chamber with a volume of approximately 95 ml. The results of the aerosol characterization data obtained with the reconstituted formulations are shown in Table 2.

[0211] The results showed no substantial difference compared to those obtained in Example 1.

[0212] Table 2: Aerosol characteristics of reconstituted liposomal cyclosporine formulations nebulized with the eFlow® nebulizer JPEG2024069355000003.jpg87161Values ​​are expressed as mean ± standard deviation; MMAD = mass median aerodynamic diameter; GSD = geometric standard deviation; DD = delivered dose (from mouthpiece); RD = respirable dose

[0213] Example 3: Clinical Trial with Inhaled Cyclosporine in the Treatment of BOS Clinical Study Registration: Forty-three patients were assessed for eligibility, of which 23 met the eligibility criteria. One patient died and one patient withdrew before randomization. Twenty-one patients were randomized, 11 to the L-CsA group and 10 to the SOC group (Figure 1). One patient in the L-CsA group withdrew from the study during the 24-week follow-up period due to progressive skin cancer. In this case, standard systemic immunosuppression was discontinued.

[0214] Patients with BOS 1 or BOS 2 were eligible if they were free of untreated infection and airway stenosis as determined by bronchoscopy with bronchoalveolar lavage (BAL) performed before randomization, at week 24, and when clinically indicated.

[0215] Grading of bronchiolitis obliterans syndrome (BOS) was applied as follows: BOS assessment was performed continuously based on bimonthly FEV1 measurements. The definition of BO was based on the modified BOS criteria from the publication by Estenne et al. (Estenne M, et al. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Haert Lung Transplant. 2002;21(3):297-310).

[0216] The following definitions and criteria were applied: -BOS 0: FEV1 > 90% of baseline -BOS 0-p: FEV1 81%-90% of baseline -BOS 1: FEV1 66%-80% of baseline -BOS 2: FEV1 51%-65% of baseline -BOS 3: FEV1 50% or less of baseline

[0217] Clinical study design: Twenty-one single- or double-lung transplant patients diagnosed with BOS grade 1 or 2 were enrolled in this single-center, randomized, open-label clinical trial evaluating the addition of aerosolized L-CsA to standard immunosuppression for BOS 1 and BOS 2 (grades 1–2) compared with standard immunosuppression alone (SOC).

[0218] Patients were planned to be followed for 48 weeks (24 weeks with L-CsA as described below, and 24 weeks without in the study group). Patients in the SOC group could be crossed over to the L-CsA group after meeting the primary endpoint, or to the L-CsA group if the primary endpoint occurred during the 24 weeks of follow-up.

[0219] Patients were assigned to receive twice-daily standard-of-care systemic immunosuppression plus 5 mg / 1.25 ml or 10 mg / 2.5 ml L-CsA therapy for single lung transplant (SLT) or double lung transplant (DLT) patients, respectively (L-CsA group), or standard-of-care systemic immunosuppression alone (SOC group) for 24 weeks, followed by 24 weeks of no study drug (L-CsA).

[0220] The L-CsA formulation was used in the form of a lyophilisate reconstituted with 0.25% saline and nebulised using an eFlow® nebuliser (PARI, Germany). A filter was placed on the exhaust valve of the inhalation chamber. Furthermore, the nebuliser was designed so that it could be operated only when a key card (eFlow® chip card) was introduced into the nebuliser, on which the inhalation time and duration were monitored.

[0221] Treatment protocol: Patients were randomly assigned to either the L-CsA group (treatment) or the SOC group (no treatment with CsA). L-CsA was administered at 5 or 10 mg twice daily (for single or double lung transplant patients, respectively) in addition to standard immunosuppression consisting of tacrolimus (0.06 mg / kg; trough levels 8–12 ng / ml) and mycophenolate mofetil (1 gm PO bid) or sirolimus (2 mg PO day; levels 7–12 ng / ml) and prednisone (20 mg / day), while the SOC group received standard immunosuppression alone. When utilized, combined sirolimus and tacrolimus blood levels were maintained at 4–5 ng / ml. Adjustments were made according to clinician-based assessment of clinical parameters and protocols at the study site. Infectious prophylaxis included Valcyte, voriconazole, and sulfamethoxazole / trimethoprim. Intensive immunosuppression consisted of pulsed corticosteroids (intravenous methylprednisolone at a dose of 1 gm per day for 3 days or oral prednisone (100 mg tapered to 10 mg over 14 days)) or antithymocyte globulin (1.5 mg / kg / day for 3-5 days). Progression of BOS by FEV1 was verified before and after treatment for concurrent disease measured at least 3 weeks apart and confirmed by two collaborators.

[0222] Endpoints: The primary endpoint of BOS progression was: 1) ≥20% decrease in FEV1 from randomization; 2) Death, or 3) Re-implantation.

[0223] Secondary endpoints included changes in lung function, aerosol tolerability, pharmacokinetics, cytokine changes and drug toxicity. Routine laboratory data were collected at 30-day intervals. Cytokines (IL-1β, IL-2, IL-6, IL-8, IL-10, IL-17, IFN-γ and TNF-α) were measured from BAL fluid before randomization and at the end of the treatment period by multiplex assay (BioRad®) using a Luminex 100 reader and analyzed using BioRad software.

[0224] Statistical analysis: The combined primary endpoints of BOS progression and overall patient survival were compared by Kaplan-Meier and log-rank tests. Transplant type as a factor influencing survival was evaluated by Cox proportional hazards model. Data are presented as hazard ratios (HR) and 95% confidence intervals (95%CI). For pulmonary function analysis, multivariate linear mixed-effects statistical models (PROC MIXED, SAS version 9.1.3; SAS Institute, Cary, NC) were utilized (Laird NM, Ware JH. Random-effects models for longitudinal data; Biometric 1982;38:963-974). The mixed models analyzed within- and between-group values ​​pre- and postrandomization, adjusting for changes that may affect function after randomization. Cytokine values ​​were compared by two-way analysis of variance. Laboratory values ​​and drug levels were analyzed using mixed-model statistics. All outcomes, including crossover cases, were analyzed as intent to treat. A total of 242 pulmonary function tests, 42 bronchoalveolar lavage (BAL) specimens for cytokines and 603 blood samples were analyzed.

[0225] result Patient Characterization: Eleven patients were randomized to the L-CsA group and 10 to the SOC group (see Figure 1). The baseline characteristics and clinical management of the two groups were similar. The distribution of baseline demographic characteristics did not differ appreciably between the groups. The mean duration of treatment with L-CsA was 167.5 ± 12.5 days. There were no adverse events attributable to L-CsA requiring withdrawal from the clinical study, and no patients were lost to follow-up.

[0226] Two cases who met the primary endpoint in the SOC group received crossover therapy with L-CsA, one patient randomized to L-CsA restarted L-CsA after the first 24-week drug interval (FEV1 decline >20%), and one patient withdrew from the study after the first 24-week L-CsA interval because recurrent skin cancer required discontinuation of systemic immunosuppression.

[0227] Stabilization of bronchiolitis obliterans: Event-free survival probabilities were analyzed by Kaplan-Meier survival analysis overall, i.e., without stratification by single and double lung transplant patients, and with stratification by single or double lung transplant (also referred to herein as "SLT" or "DLT", respectively). Patients who, at any time, for any reason, terminated participation in the study without experiencing an endpoint event were censored.

[0228] To perform the analysis, we defined a Full Analysis Set (FAS) and a Per-Protocol Analysis Set (PPS). The FAS included all patients who received at least one dose of study treatment. The PPS included all patients from the FAS without major protocol violations (e.g., incorrect enrollment, <75% adherence, prohibited concomitant medications) that were considered to compromise the scientific aspects and interpretation of the study results.

[0229] Stabilization of BOS was observed in both bilateral and single-lung recipients analyzed explicitly according to the primary study endpoint in the L-CsA-treated group compared with the SOC group: 9 of 11 patients treated with L-CsA and SOC had an event-free survival probability of 82%, compared with 50% in 5 of 10 patients treated with SOC alone (HR: 3.19; 95% CI: 0.62 to 16.50; p=0.14; see Figure 2).

[0230] For bilateral lung transplant patients, the probability of event-free survival was 83% in the L-CsA treatment group compared with 50% in the SOC treatment alone group. Furthermore, for bilateral lung transplant patients, the hazard ratio (HR) was 3.43, 95% CI 0.31-37.95; p=0.29, implying a 3.43-fold increased risk of experiencing BOS progression, need for retransplantation, or death for the bilateral lung transplant patient group under SOC treatment alone compared with bilateral lung transplant patients under L-CsA treatment (see Figure 3).

[0231] For single lung transplant patients, the probability of event-free survival was 80% in the L-CsA treatment group versus 50% in the SOC treatment alone group. Furthermore, for single lung transplant patients, the hazard ratio (HR) was 2.78, 95% CI 0.29-26.98; p=0.36, implying that the risk of experiencing BOS progression, need for retransplantation, or death was 2.78 times higher for the group of single lung transplant patients under SOC treatment alone compared with those under L-CsA treatment (see Figure 4).

[0232] Of the two cases who experienced a major event in the L-CsA group, one responded to L-CsA reinitiation (based on the primary endpoint criteria) and the other was retransplanted; of the five major events in the SOC group, two were retransplanted, two required mechanical ventilation, and one of the two cases who crossed over from SOC responded to L-CsA.

[0233] As can be seen from the Kaplan-Meier in Figures 2-4, the effect of L-CsA administered to double lung transplant patients is significantly higher than that of single lung transplant patients when analyzed over the entire 48-week treatment and observation period. The hazard ratio (HR) 1:2.78 (L-CsA:SOC) as a measure of survival probability for single lung transplant patients is significantly less favorable than that for double lung transplant patients with a ratio of 1:3.43 (L-CsA:SOC).

[0234] Overall survival probability at 5 years after randomization demonstrated a significant improvement in single or double lung transplant patients treated with L-CsA: 5 patients (45%) of 11 participants treated with L-CsA were alive at 5 years of follow-up compared with 0 of the first 10 patients treated with SOC alone. The median survival time for the group of patients treated with L-CsA was 4.1 years compared with 2.9 years for the group of patients treated with SOC alone (p=0.03; see Figure 5). Cause of death was chronic allograft rejection, with the exception of 2 cases, one from disseminated skin cancer (L-CsA) and one from renal failure (SOC).

[0235] Changes in lung function Changes in FEV1 (forced expiratory volume after the first second of forced expiration) were observed during the 48-week study period as a measure of stabilization or progression of BOS in single- and double-lung transplant patients diagnosed with BOS in the L-CsA and SOC groups.

[0236] As shown in Figure 6, the analysis of the overall FEV1 evolution of single and double lung transplant patients after adjusting for pre- and post-randomization measurement data in a random slope mixed model gives clear results: in the group of patients treated with L-CsA (11 patients), a small decrease in the mean absolute FEV1 value was observed starting from approximately 1.75 L at randomization to 1.70 L at the end of the 48-week period, while for the group of patients treated with SOC (10 patients; one patient had no PFT measurements after randomization because he required mechanical ventilation; this patient was included in the calculation of the FEV1 slope: an FEV1 value of 0 was imposed at the time the patient progressed to mechanical ventilation; this patient had no PFT measurements after randomization), a stable and significant decrease in the FEV1 value was observed from approximately 1.75 L to approximately 1.15 L. It should be noted that in this overall analysis of single and double lung transplant patients, the monthly change in FEV1 (ΔFEV1 / month) was −0.054 with a 95% CI of −0.100 to −0.006 versus −0.007 with a 95% CI of −0.033 to 0.018 for the L-CsA-treated group (p=0.10).

[0237] As shown in Figure 7, the evolution of absolute FEV1 values ​​during the 48-week study period for only bilateral lung transplant patients in the L-CsA (upper graph; "L-CsA") and SOC (lower graph; "SOC") treatment groups gives even more significant results: in the group of patients treated with L-CsA (6 patients), the mean absolute FEV1 value remained almost constant at 1.8 L throughout the 48 weeks. In contrast, in the group of bilateral lung transplant patients in the SOC group (4 patients), the mean absolute FEV1 value decreased significantly from approximately 1.8 L to approximately 1.1 L over the same period. It should therefore be noted that the monthly change in FEV1 (ΔFEV1 / month) for bilateral lung transplant patients was 0.000 with a 95% CI of -0.049 to 0.049 for the L-CsA treatment group and -0.061 with a 95% CI of -0.096 to 0.026 for the SOC treatment group (p=0.07).

[0238] As shown in FIG. 8, the evolution of absolute FEV1 values ​​during the 48-week study period for only single-lung transplant patients in the L-CsA (upper graph; "L-CsA") and SOC (lower graph; "SOC") treatment groups shows a similar trend: in the group of patients treated with L-CsA (5 patients), a decrease in the mean absolute FEV1 value was observed from approximately 1.75 L immediately after randomization to approximately 1.4 L at 48 weeks after randomization. For the single-lung transplant group in the SOC group (6 patients; one patient required mechanical ventilation and therefore had no PFT measurements after randomization; the patient was included in the calculation of the slope of FEV1: an FEV1 value of 0 was imposed at the time the patient progressed to mechanical ventilation; this patient had no PFT measurements after randomization), the mean FEV1 value decreased significantly over the same period (graph for the SOC treatment group ends at month 1 due to the calculation method) from approximately 1.75 L to approximately 1.05 L. Thus, the monthly change in FEV1 (ΔFEV1 / month) in bilateral lung transplant patients was −0.029 with 95% CI −0.019 to 0.001 for the L-CsA treatment group and −0.600 with 95% Cl −2.074 to 0.872 for the SOC treatment group (p=0.37).

Claims

1. A composition comprising liposomal cyclosporine A (L-CsA) for use in the prevention of obstructive bronchiolitis syndrome (BOS) in patients who have undergone bilateral lung transplantation, A composition administered to the patient by inhalation of an aerosolized composition containing a therapeutically effective dose of cyclosporine A.

2. The composition for use according to claim 1, wherein the two lung transplant patients have been diagnosed with BOS 1 or BOS 2.

3. A composition for use according to claim 1 or 2, which is a liquid composition comprising an aqueous liquid vehicle.

4. The composition for use according to claim 3, wherein the aqueous liquid vehicle essentially consists of physiological saline, preferably physiological saline with a concentration of 0.25%.

5. The composition for use according to any one of claims 1 to 4, wherein the liquid composition has a CsA concentration in the range of 0.5 to 10 mg / mL.

6. The composition for use according to any one of claims 1 to 5, wherein the liquid composition is prepared by reconstitution of liposome cyclosporine A in a freeze-dried form.

7. A composition for use according to any one of claims 1 to 6, wherein cyclosporine A is administered in an effective daily dose in the range of 5 to 30 mg.

8. A composition for use according to any one of claims 1 to 7, wherein cyclosporine A is administered in an effective daily dose of 20 mg.

9. A composition for use according to any one of claims 1 to 8, which is administered to the patient twice a day.

10. A composition for use according to any one of claims 1 to 9, administered over a period of at least 24 weeks.

11. The composition for use according to any one of claims 1 to 10, wherein the bilateral lung transplant patients are simultaneously treated with standard immunosuppressive therapy.

12. The composition for use according to any one of claims 1 to 11, wherein the formulation is aerosolized by an electronic vibrating membrane nebulizer.

13. The composition for use according to any one of claims 1 to 12, wherein the formulation is inhaled with at least 75% adherence.

14. The progression of BOS in the aforementioned bilateral lung transplant patient diagnosed with BOS is prevented, or the forced expiratory volume in one second (FEV1) at the start of treatment is prevented. １ Compared with the value, the patient's FEV １ A composition for use according to any one of claims 1 to 13, which reduces the amount to a level of up to 20% reduction.

15. The event-free survival rate for the bilateral lung transplant patients diagnosed with BOS is at least 60% at least 48 weeks after the start of treatment, and the event rate is at least 20% FEV. １ A composition for use according to any one of claims 1 to 14, selected from a decrease in, need for re-transplantation, and / or death.

16. FEV of the aforementioned bilateral lung transplant patients diagnosed with BOS １ Average monthly change (ΔFEV) １ A composition for use according to any one of claims 1 to 15, wherein the amount (per month) remains substantially constant or has a value in the range of about 0 to about 0.04 L / month.

17. At least 20% of FEV in the bilateral lung transplant patients treated with the aerosolized composition of the present invention containing CsA within at least 48 weeks from the start of treatment. １ A composition for use according to any one of claims 1 to 16, wherein the risk of experiencing an event selected from a decrease in saturation, the need for re-transplantation, and / or death is reduced by at least 30% (absolutely), preferably at least 35% (absolutely), compared to the risk of experiencing the corresponding event under treatment with standard immunosuppressive therapy (SOC) alone.

18. FEV of the aforementioned bilateral lung transplant patients diagnosed with BOS １ Average monthly change (ΔFEV) １ A composition for use according to any one of claims 1 to 17, wherein the amount (per month) remains substantially constant or has a value in the range of about 0 to about 0.04 L / month.

19. The absolute change in FEV １ (ΔFEV １ / absolute) between baseline (before the start of said treatment) and the end of the treatment period in said double lung transplant patient diagnosed with BOS is 350 mL or less, the composition for use according to any one of claims 1 to 18.

20. FEV in patients treated with standard immunosuppressive therapy (SOC) alone １ FEV in the aforementioned bilateral lung transplant patients diagnosed with BOS, for the loss of １ Relative loss (ΔFEV) １ A composition for use according to any one of claims 1 to 19, wherein the (relative) is at least 200 mL.

21. The composition for use according to any one of claims 1 to 20, wherein the two lung transplant patients are not diagnosed with airway stenosis before the start of the treatment and preferably at 24 weeks after the start of the treatment, as confirmed by bronchoscopy using bronchoalveolar lavage (BAL).

22. The composition for use according to any one of claims 1 to 21, wherein the bilateral lung transplant patient diagnosed with BOS is not diagnosed with an untreated infection before randomization and preferably at 24 weeks after the start of treatment.

23. The composition for use according to any one of claims 1 to 22, wherein the maximum blood concentration of CsA in the bilateral lung transplant patient diagnosed with BOS and treated with a liquid composition containing CsA is up to 100 ng / mL, preferably up to 60 ng / mL.

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