Cyclosporine preparations for use in the treatment of bronchiolitis obliterans (BOS)

Abstract

The present invention relates to a composition comprising cyclosporine A (CsA) for use in the prevention of bronchiolitis obliterans syndrome (BOS) in double lung transplant patients, or for treating BOS in double lung transplant patients who have 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 cyclosporine A. [Selected Figure] Figure 1

Description

Technical Field

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

Background Art

[0002] Lung transplantation has become an effective treatment option for various chronic and end-stage lung diseases. Lung preservation techniques have been developed over time, resulting in satisfactory short-term outcomes (Hachem RR, Trulock EP. Bronchiolitis obliterans syndrome: pathogenesis and management. Semin Thorac Cardiovasc Surg 2004;16:350 - 355). Immunosuppression is usually an important post-transplant intervention 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-lobe and double-lobe lung transplants are possible. Double-lung transplantation is indicated in cases of cystic fibrosis, primary pulmonary hypertension, α1-antitrypsin deficiency, emphysema with overall dysfunction, frequent severe infections, and idiopathic pulmonary fibrosis with complications due to repeated infections.

[0004] Despite systemic immunosuppressive therapy with cyclosporine or tacrolimus, azathioprine or mycophenolate mofetil, and corticosteroids, chronic rejection after lung transplantation is a serious lung complication that accounts for 30% of deaths in lung transplantation, and thus the evaluation of new treatment options is desired.

[0005] The development of bronchiolitis obliterans (BOS), the leading cause of chronic lung graft failure, is a major factor in morbidity and mortality among long-term lung transplant survivors and remains a significant limiting factor for long-term survival after lung transplantation. It occurs in 60–70% of transplant recipients who survive for five years. The median time to the onset of BOS is approximately 18 months. The etiology of BOS is multifactorial and not fully understood, but chronic rejection resulting from an immune-dependent response (acute rejection episode) is considered the main cause of BOS after lung transplantation, despite the use of systemic calcineurin inhibitors for immunosuppression (Moffatt-Bruce S., “Invited commentary”, Ann Thorac Surg. 2009 Sep;88(3):964-5.doi:10.1016 / j.athoracsur.2009.06.014) (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 occurs, airway damage is progressive and irreversible, and patients ultimately die from transplant failure or pneumonia.

[0006] Currently, there are no satisfactory treatment options for BOS after bilateral lung transplantation. Enhanced immunosuppression using drugs commonly used for high-dose basic immunosuppression has proven ineffective, and increased drug load is temporarily accompanied by a high incidence of adverse events over time. While immunosuppressive antibodies may be useful in preventing acute lung graft rejection, therapeutic attempts to treat chronic rejection have yielded disappointing results. From a pathological mechanism standpoint, this is comprehensive, as acute lung graft rejection is essentially vasculitis stemming from an adverse reaction to the vascular epithelium. In contrast, although all the details are not yet fully understood, there is agreement that chronic lung rejection is bronchiolitis rather than vasculitis, as the cause lies in the pulmonary lumen, i.e., the bronchioles. Therefore, systemically administered drugs are required to cross the capillary-alveolar barrier. Photopheresis is frequently chosen as a last resort for advanced BOS patients and is performed for psychological rather than medical reasons. Therefore, new therapies for the prevention and treatment of chronic lung graft rejection, especially after bilateral lung transplantation, are highly desirable.

[0007] Currently, the median survival time is 4.6 years for unilateral lung transplant patients and 6.6 years for bilateral lung transplant patients. This difference in survival has been shown to be associated with a significant delay in the development of BOS after bilateral lung transplantation compared to unilateral 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, if BOS has already been diagnosed, delaying its progression, has been identified as a key 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 hematopoietic 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 administration, it is well known that CsA blocks T lymphocyte proliferation by inhibiting the phosphatase activity of calcineurin enzymes 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 cannot be treated with local immunotherapy, lung transplants are an exception due to their inherent communication with the external environment, making inhalation a treatment option.

[0011] Topical application of CsA to the lungs has been suggested to improve efficacy and potentially reduce systemic exposure to toxic immunosuppressants (Iacono A, et al. Dose related reversal of acute lung rejection by aerosolized cyclosporine. 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 metabolite by the fungal species Beauveria nivea. Cyclosporine is an immunosuppressant belonging to the group of calcineurin inhibitors that have been used in Europe since the early 1980s in most post-transplant regimens to prevent graft rejection after organ transplantation.

[0012] The use of aerosolized cyclosporine for the prevention and treatment of lung disease is described in International Publication No. 00 / 45834. More specifically, the delivery of cyclosporine to transplanted lungs by aerosol inhalation is disclosed. Cyclosporine can be administered in either a dry powder or a moist 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 have been reported to develop 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 approximately 5 mg or more of CsA propylene glycol (CsA-PG) improves lung function in transplant patients, while lower doses lead to a decrease. The latter study suggested that for therapeutic effects to be achieved, the amount of CsA deposited in the periphery of the lungs should reach an effective threshold of 15 mg / week or 2 mg / day or more.

[0014] ATIacono et al. reported on aerosol cyclosporine therapy in lung transplant recipients with bronchiolitis obliterans in Eur.Resspir.J.2004;23:384-390. In this study as well, cyclosporine was used in powder form dissolved in propylene glycol. Most notably, bilateral lung transplant recipients were reported to have an increased risk of death after the onset of bronchiolitis obliterans compared with unilateral 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 compared to placebo after up to two 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 using CsA as an adjunctive targeted therapy to prevent chronic rejection in lung transplant patients did not demonstrate efficacy beyond standard treatment. The results of this study contradict numerous preclinical and clinical studies that would have allowed for expectations of a treatment response. From these results, it was concluded that the administration of cyclosporine aerosol to this highly fragile patient population is not without its challenges, and one or more of these challenges may have influenced the study's outcomes. Analysis of these challenges led to the conclusion that the use of a simpler delivery system that administers the drug at more frequent intervals within an inhalation therapy or systemic replacement setting 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] Regarding CsA-PG preparations, patient intolerance and lack of adherence have been reported due to long inhalation times of up to 30 minutes (Corcoran TE. Inhaled delivery of aerosolized cyclosporine. Adv Drug Deliv Rev 2006;58:1119-1127). Propylene glycol is known to be highly osmotic and may be intolerable to patients, so premedication with bronchodilators and local anesthetics is necessary.

[0017] In consideration of these challenges, a new liposomal formulation of cyclosporine for inhalation has been developed. The formulation is described in International Publication No. 2007 / 065588.

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

[0019] In a Phase Ib clinical trial, the pulmonary deposition and pharmacokinetics of 10 mg and 20 mg of radiolabeled aerosolized liposomal CsA (L-CsA) were investigated in five bilateral lung transplant patients and seven unilateral lung transplant patients. Aerosols were generated using an eFlow® nebulizer. Patients were given a single dose of 10 mg or 20 mg of liposomal CsA, which were well tolerated. Lung deposition was shown to be 40 ± 6% (for the 10 mg dose) and 33 ± 7% (for the 20 mg dose), respectively. 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 of L-CsA, peripheral depositions of 14 mg and 28 mg / week, respectively, could be achieved. The overall inhalation times for nominal doses of 10 mg and 20 mg were approximately 9 ± 1 minute and 20 ± 5 minutes, respectively. In unilateral lung transplant patients, almost all deposition (88–90%) occurred in the transplanted portion of the lung. There was no statistically significant difference between unilateral and bilateral lung transplant patients. Although several preclinical and clinical studies have been conducted on inhaled CsA, the conclusions regarding the actual efficacy of inhaled cyclosporine in bilateral lung transplant patients are inconsistent. Therefore, currently available studies cannot draw conclusions regarding the actual efficacy of inhaled cyclosporine in the treatment of chronic lung graft rejection, more specifically, post-lung transplant bronchiolitis syndrome (BOS).

[0020] Obstructive bronchiolitis syndrome (BOS) is physiologically defined as a sustained decrease of 20% or more in FEV1 from the highest post-transplant value. Existing immunosuppressive regimens remain largely ineffective. Increased cyclosporine, due to its deposition in the lungs upon inhalation and resulting higher airway concentrations, may enhance the effectiveness of treating BOS.

[0021] International Publication No. 2016 / 146645 discloses a cyclosporine liquid formulation for use as an inhalation aerosol in a method for preventing or treating chronic lung graft rejection in unilateral lung transplant patients. In specific embodiments, chronic lung graft rejection is characterized by bronchiolitis obliterans (BOS). However, while this document highlights the unexpectedly successful treatment of a subpopulation of unilateral lung transplant patients, it cannot draw conclusions regarding the treatment of bilateral lung transplant patients, particularly those who have already developed bronchiolitis obliterans (BOS). Given this disclosure, success in treating bilateral lung transplant patients who have already developed BOS is not predictable.

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

[0023] [Patent Document 1] International Publication No. 00 / 45834 Pamphlet [Patent Document 2] International Publication No. 2007 / 065588 Brochure [Patent Document 3] International Publication No. WO 2016 / 146645 Pamphlet

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[0025] In a first aspect, the present invention relates to a composition comprising liposomal cyclosporine A (L-CsA) for use in preventing bronchiolitis obstructive (BOS) in bilateral lung transplant patients, or for treating BOS in bilateral lung transplant patients diagnosed with BOS, or for preventing or delaying the progression of BOS, The present invention relates to a composition administered to a patient by inhalation of an aerosolized form of the composition containing a therapeutically effective dose of cyclosporine A.

[0026] In a second aspect, the present invention relates to a method for preventing bronchiolitis obliterans (BOS) in bilateral lung transplant patients, or for treating BOS in bilateral lung transplant patients diagnosed with BOS, or for preventing or delaying the progression of BOS, (a) A step to identify patients who have undergone bilateral lung transplantation and are at risk of developing BOS, specifically BOS grade I or higher, or who have subsequently developed it; (b) The step of administering a therapeutically effective dose of aerosolized liposomal cyclosporine A (L-CsA) to the patient by inhalation. Regarding methods including [Brief explanation of the drawing]

[0027] [Figure 1] The following flowchart summarizes the details of enrolling single-lung and double-lung transplant patients in clinical studies, which are further described below.

[0028] [Figure 2]This figure shows Kaplan-Meier plots of the progression-free survival probability for BOS in single-lung transplant patients and double-lung transplant patients diagnosed with BOS during a 48-week study period.

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

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

[0031] [Figure 5] This figure shows Kaplan-Meier plots of overall survival probabilities for single-lung transplant patients and double-lung transplant patients diagnosed with BOS 5 years after randomization.

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

[0033] [Figure 7] This figure shows a regression trend analysis of the course of absolute FEV1 values ​​over a 48-week study period for both lung transplant patients treated with L-CsA (upper graph; "L-CsA") and SOC (lower graph; "SOC").

[0034] [Figure 8] This figure shows the regression trend analysis of absolute FEV1 values ​​over a 48-week study period for single-lung transplant patients treated with L-CsA (upper graph; "L-CsA") and SOC (lower graph; "SOC"). [Modes for carrying out the invention]

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

[0036] As used herein, the terms “consist of,” “consists of,” and “consisting of” are so-called closed language, meaning that only the component being referred to exists. As used herein, the terms “comprise,” “comprises,” and “comprising” are so-called open language, meaning that one or more further components may or may not exist.

[0037] The term “Pharmaceutical Active Ingredient” (also referred to as “API” throughout this document) refers to any type of pharmaceutically active compound or derivative that is useful for the prevention, diagnosis, stabilization, treatment, or, more generally, management of a condition, disorder, or disease.

[0038] As used herein, the term “therapeutically effective dose” refers to a dose, concentration, or strength useful for producing the desired pharmacological effect. In the context of this invention, the term “therapeutically effective” also includes prophylactic activity. The therapeutic dose should be defined according to the individual administration example. Depending on the nature and severity of the disease, the route of administration, and the patient’s height and condition, the therapeutic dose should be determined in a manner known to those skilled in the art.

[0039] In the context of the present invention, “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 water or physiological saline.

[0040] The expressions "a" or "an" do not exclude the plural; that is, the singular forms "a," "an," and "the" should be understood to include multiple referents unless explicitly indicated in the context or otherwise required. In other words, all references to a singular feature or limitation in this disclosure include the corresponding plural feature or limitation unless explicitly specified otherwise or clearly implied in the context in which they are referred, and vice versa. Thus, unless specifically defined, the terms "a," "an," and "the" are synonymous with "at least one" or "one or more." For example, a reference to "an ingredient" includes mixtures of ingredients, etc.

[0041] Expressions such as "one embodiment," "an embodiment," and "a specific embodiment" mean that a particular feature, property, or characteristic, or a particular group or combination of features, properties, or characteristics, is present in at least one embodiment of the present invention when referred to in combination with each expression. The appearance of these expressions in various places throughout this specification does not necessarily refer to the same embodiment. Furthermore, particular features, properties, or characteristics can 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 the cure of a disease, condition, or symptom, but also includes improvement, enhancement, control, and control of progression.

[0043] The term “prevention” is intended to include preventing or delaying the progression of a disease, condition, or symptom, or preventing further growth and expansion of the disease condition or symptom, as well as preventing recurrence or progression after initial improvement or initial removal of the cause.

[0044] The terms “patient” and “subject” are used synonymously herein. Typically, these terms refer to human beings. However, the present invention is not limited to humans and may be used for animals as appropriate.

[0045] Terms such as “essentially,” “about,” “approximately,” and “substantially” in relation to attributes or values ​​include the exact attribute or exact value, as well as any attribute or value that is typically considered to fall within the normal range or variability accepted in the relevant technical field. For example, “substantially water-free” means that the formulation does not intentionally contain water, but does not exclude the presence of residual moisture.

[0046] Where used herein, the terms “about” or “ca.” are acceptable in the pharmaceutical industry and complement inherent variability in pharmaceuticals, such as differences in content due to manufacturing variations and / or product degradation over time. These terms allow for any variation in the practice of pharmaceuticals that enables a product to be assessed as having the enumerated strength of the claimed product and being considered biologically equivalent in mammals.

[0047] As used herein, “vehicle” may generally mean any compound, construct, or substance that is part of a formulation that assists, enables, or improves the delivery of a bioactive compound or substance.

[0048] The term "pharmaceutically acceptable" means that a compound or mixture is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and not biologically or otherwise undesirable, and includes those that are acceptable for human pharmaceutical use.

[0049] In a broad sense, the present invention relates to a composition comprising cyclosporine A (CsA) for use in preventing bronchiolitis obstructive (BOS) in bilateral lung transplant patients, or for treating BOS in bilateral lung transplant patients diagnosed with BOS, or for preventing or delaying the progression of BOS, The present invention relates to a composition administered to a patient by inhalation of an aerosolized form of the composition containing a therapeutically effective dose of cyclosporine A.

[0050] Furthermore, the present invention relates to a composition comprising cyclosporine A (CsA) for use in the treatment of bronchiolitis obliterans (BOS) in bilateral lung transplant patients diagnosed with BOS, or for preventing or delaying the progression of BOS, The present invention relates to a composition administered to a patient by inhalation of an aerosolized form of the composition containing a therapeutically effective dose of cyclosporine A.

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

[0052] Compositions for use according to the present invention are further described below and include, for example, a therapeutically effective dose or amount of cyclosporine A (CsA), or more specifically liposome CsA (L-CsA), as described in detail in the aforementioned International Publication No. 2007 / 065588. In specific embodiments, the pharmaceutical compositions for use according to the present invention may be liquid compositions. In these embodiments, the compositions for use according to the present invention include L-CsA and a liquid carrier or vehicle capable of dissolving, dispersing or suspending the L-CsA. In specific embodiments, these compositions include a therapeutically effective dose of CsA, an aqueous carrier liquid, a first dissolution enhancer selected from the group of phospholipids, and a second dissolution enhancer selected from the group of nonionic surfactants, to form liposome-soluble CsA (L-CsA).

[0053] The phospholipids that may be included in the compositions for use according to the present invention are, in particular, natural or concentrated phospholipids, such as mixtures of lecithin, including commercially available Phospholipon G90, 100, or Lipoid 90, S 100. Therefore, in preferred embodiments, the phospholipids that may be included in the compositions for use according to the present invention can be selected from the group of phospholipids that are mixtures of natural phospholipids.

[0054] Phospholipids are amphiphilic lipids containing phosphorus. Also known as phosphatides, they play an essential role, particularly as components of the bilayer of biological membranes, and phospholipids chemically derived from phosphatidic acid are frequently used for pharmaceutical purposes. The latter is (usually bi) acylated glycerol-3-phosphate. Fatty acid residues may vary in length. Derivatives of phosphatidic acid include, 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, usually containing a high proportion of phosphatidylcholine. Preferred phospholipids according to the present invention are lecithin, as well as pure or concentrated phosphatidylcholine such as dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, and distearoylphosphatidylcholine.

[0055] In specific embodiments, the first dissolution-promoting agent selected from the group of phospholipids contained in the composition for use according to the present invention may be selected from the group of phospholipids and may be lecithin, more specifically, lecithin containing unsaturated fatty acid residues. In even more preferred embodiments, the membrane-forming agent selected from the group of phospholipids may be lecithin selected from the group consisting of soy lecithin, Lipoid S100, Phospholipon® G90, 10, preferably Lipoid S100 or equivalent lecithin. In even more preferred embodiments, the membrane-forming agent selected from the group of phospholipids may be selected from Lipoid S100, Lipoid S75, and especially Lipoid S100.

[0056] In specific embodiments, the weight ratio of a first membrane-forming substance selected from the above-mentioned 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] A pharmaceutical composition for use according to the present invention may further comprise two or more different dissolution-promoting substances selected from the group of second dissolution-promoting substances or nonionic surfactants. Nonionic surfactants, like other surfactants, have at least one partially hydrophilic molecular region and at least one partially lipophilic molecular region. These include monomeric low molecular weight nonionic surfactants and nonionic surfactants having oligomeric or polymeric structures. Examples of suitable nonionic surfactants that may be included in the present invention include polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, e.g., polyoxyethylene sorbitan oleate, sorbitan fatty acid esters, poloxamers, vitamin E-TPGS (D-α-tocopheryl-polyethylene glycol-1000-succinate), and tyloxapole.

[0058] In specific embodiments, the second dissolution-promoting agent selected from the group of nonionic surfactants may be selected from the group of polysorbate and vitamin E-TPGS, and is preferably selected from the group of polysorbate. In particularly preferred embodiments, the dissolution-promoting agent selected from the group of nonionic surfactants is polysorbate 80.

[0059] In specific embodiments of the present pharmaceutical composition, the amount of a first film-forming substance selected from the group of phospholipids, preferably lecithin, is greater than the amount of a second dissolution-promoting substance selected from the group of nonionic surfactants. In exemplary embodiments, the weight ratio of the first film-forming substance selected from the group of phospholipids, preferably lecithin, to the second dissolution-promoting substance selected from the group of nonionic 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 a first dissolution-promoting substance (total) selected from the group of phospholipids and a second dissolution-promoting substance selected from the group of nonionic surfactants and CsA is selected in the range of about 5:1 to about 20:1, preferably about 8:1 to about 12:1, and more preferably about 10:1.

[0061] In further specific embodiments, the weight ratio between a first dissolution-promoting substance selected from the group of phospholipids, preferably lecithin, a second dissolution-promoting substance selected from the group of nonionic 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 specific embodiments, the composition for use according to the present invention, or more specifically, the liquid composition, comprises cyclosporine A (CsA) in the form of liposomes, or in other words, cyclosporine A (CsA) in a form solubilized by liposomes. Thus, in specific embodiments, the liquid composition for use according to the present invention is a liposome formulation. The CsA-containing liposomes, or in other words, liposomes, CsA (L-CsA), are mainly formed by phospholipids contained in the composition and are preferably monolayer liposomes. The liposomes preferably have an average diameter of up to about 100 nm, measured as a z-mean 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, as measured by photon correlation spectroscopy.

[0063] In specific embodiments, the liquid composition for use according to the present invention comprises an aqueous liquid vehicle. The liquid vehicle may contain water and optionally one or more physiologically acceptable organic solvents such as ethanol or propylene glycol. However, in preferred embodiments, 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 contains only ethanol as the organic solvent.

[0064] Liquid compositions for use according to the present invention can optionally be prepared by preparing a suitable liquid carrier of CsA, preferably an aqueous solution or suspension in a suitable aqueous liquid carrier, and dissolving the CsA after adding at least one phospholipid and at least one nonionic surfactant in the form of liposomes.

[0065] In specific embodiments, a liquid composition for use according to the present invention may be prepared from a corresponding solid formulation for reconstitution, which may include mixing or contacting L-CsA with an aqueous solvent or vehicle immediately before inhalation. Thus, in specific embodiments, a liquid composition containing liposome CsA (L-CsA) for use according to the present invention is prepared by reconstitution of liposome cyclosporine A (L-CsA), preferably in lyophilized form.

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

[0067] To protect the active ingredients during the drying process, it may be useful to incorporate cryoprotective agents and / or fillers such as sugars or sugar alcohols, particularly 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., a unit dose), is preferably soluble or dispersible in the aqueous liquid vehicle. In specific embodiments, the aqueous liquid vehicle has a volume of about 10 ml or less. Preferably, the 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 and the desired concentration. If a smaller dose is required for the therapeutic effect, a smaller volume of aqueous liquid vehicle may be sufficient to dissolve or disperse the solid formulation containing L-CsA.

[0069] In specific embodiments, an aqueous solution is preferably used as the aqueous liquid vehicle for reconstitution. Therefore, in preferred embodiments of the liquid composition of the present invention, the aqueous liquid vehicle contains physiological saline.

[0070] In specific embodiments, physiological saline is used as the aqueous liquid vehicle, and the concentration of sodium chloride is adjusted to produce a liquid formulation with physiologically acceptable osmotic pressure and tolerability after reconstitution. The osmotic pressure of the liquid composition for use according to the present invention is in the range of about 450 to about 550 mOsmol / kg in preferred embodiments. However, some degree of low and high osmotic pressure is generally still tolerable. Tolerability may be improved in the presence of permeable anions (such as chloride) at concentrations of 31 to 300 mM (Weber et al. “Effect of nebulizer type and antibiotic concentration on device performance”, Paediatric Pulmonology 23 (1997) 249-260). High osmotic formulations may actually be preferred in certain applications. For example, the osmotic pressure of the reconstituted liquid composition for use according to the present invention may be in the range of 150 to 800 mOsmol / kg. Preferably, the aqueous liquid composition has an osmotic pressure of about 250 to about 700 mOsmol / kg, or about 250 to about 600 mOsmol / kg. Most preferably, the aqueous liquid composition for use according to the present invention has an osmotic pressure of about 400 to about 550 mOsmol / kg.

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

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

[0073] When used to prepare a liquid composition for use according to the present invention, a solid composition containing CsA, preferably in the form of L-CsA, for reconstitution may be part of a pharmaceutical kit. Such a kit preferably includes 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 International Publication No. 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, it should also contain liposomes after reconstitution. Preferably, the size of the liposomes is the same before drying and after reconstitution. With respect to liposome size, it is particularly preferable that the size of the liposomes, measured as a z-mean by photon correlation spectroscopy, is 40-100 nm and that after reconstitution with 0.25% (w / v) saline, it exhibits a uniform size distribution (polydispersity index < 0.4).

[0075] Surprisingly, liquid compositions containing liposomal cyclosporine A (L-CsA) in particular have been found to be useful in preventing bronchiolitis obliterans (BOS) in bilateral lung transplant patients, or in treating BOS in bilateral lung transplant patients diagnosed with BOS, or in preventing or delaying the progression of BOS. The composition is administered to the patient by inhalation of the liquid composition in an aerosolized form containing a therapeutically effective dose of cyclosporine A (Cs-A).

[0076] According to the present invention, it is possible to effectively prevent or treat, preferably treat, bronchiolitis obliterans (also referred to herein as "BOS") in bilateral lung transplant patients, or to effectively prevent or delay the progression of BOS in patients who have undergone bilateral lung transplants (also referred to herein as "bilateral lung transplant patients") and patients 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 more effectively achieved in bilateral lung transplant patients compared to patients who have received a single lung transplant (hereinafter also referred to as “single lung transplant patients”), particularly those diagnosed with BOS. More specifically, in bilateral lung transplant patients who inhale the liposomal cyclosporine A liquid formulation for use according to the present invention, in addition to standard immunosuppressive therapy (hereinafter also referred to as “standard therapy” or “SOC”), a considerable delay or even prevention of the progression of manifested BOS can be obtained. When treated with the L-CsA-containing composition for use according to the present invention, or with SOC alone, no equivalent delay or prevention of BOS was observed within the same timeframe compared to the bilateral lung transplant population receiving standard immunosuppressive therapy alone, or to patients with a single lung transplant.

[0078] It should be noted that the different effects of the inhaled cyclosporine composition for use according to the present invention, considering the type of transplant (bilateral lung transplant vs. unilateral lung transplant), were entirely surprising and unexpected, given the previous results of the clinical studies disclosed in International Publication No. 2016 / 146645.

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

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

[0081] BOS can be classified based on the rate of decrease in FEV1 (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 baseline 81%~90% -BOS 1: FEV1 66%~80% of baseline -BOS 2: FEV1 51%~65% of baseline -BOS 3: FEV1 less than 50% of baseline

[0082] The compositions for use according to the present invention may be useful in treating BOS in bilateral lung transplant patients diagnosed with BOS, i.e., BOS 0, BOS 0-p, BOS 1, BOS 2, or BOS 3, preferably BOS 1, BOS 2, or BOS 3, or in preventing or delaying the progression of BOS. However, in specific embodiments, the liquid compositions for use according to the present invention are particularly useful in treating bilateral lung transplant patients diagnosed with BOS 0-p or higher, preferably BOS 1 or BOS 2. In even more specific embodiments, the liquid compositions for use according to the present invention are particularly useful in treating bilateral lung transplant patients diagnosed with BOS 0-p or BOS 1.

[0083] In fact, to treat both single-lung and double-lung transplant patients as a single population within a single study, the dose administered to single-lung transplant patients was preferably about half the dose administered to double-lung transplant patients. 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-lung and double-lung transplant patients if the dose was adjusted according to the type of transplant. Nevertheless, even when equivalent doses were administered, the inventors surprisingly found that the effect of inhaled cyclosporine in the prevention or delay of manifested BOS, particularly BOS 1 or BOS 2, was far more pronounced in the double-lung transplant population.

[0084] Surprisingly, it was found that the compositions for use according to the present invention can prevent, significantly delay, or reduce the progression of BOS, particularly BOS 1 or BOS 2, that manifests and is diagnosed after bilateral lung transplantation, compared to conventional treatment with standard immunosuppressive therapy (SOC) alone, or compared to patients with single lung transplantation.

[0085] Therefore, the CsA or L-CsA-containing compositions for use according to the present invention, used in the treatment of bilateral lung transplant patients, can significantly extend and maximize the survival rate and survival duration of patients who are at risk of developing or have developed BOS, more specifically BOS 1 or BOS 2, after bilateral lung transplantation, and thus contribute to reducing or minimizing the onset or progression of chronic lung graft rejection. The compositions for use according to the present invention can be administered according to a predetermined dosing regimen. More specifically, the compositions can be administered to bilateral lung transplant patients a specific number of times during each week of treatment. For example, the compositions can be administered three times a week. In a preferred embodiment, the compositions for use according to the present invention are administered daily. In a specific embodiment, the compositions for use according to the present invention are administered twice or even several times a day to the bilateral lung transplant patients who are at risk of developing or have been diagnosed with BOS.

[0086] The compositions for use according to the present invention, preferably liquid compositions, have a CsA concentration preferably in the range of about 0.5 to about 10 mg / mL, or in other words, the liquid composition contains 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, and more preferably about 1 to a maximum of about 5 mg / mL. Most preferably, the compositions for use according to the present 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 present invention is preferably low to allow for a short spray time. The volume, also called “volume of dose,” “unit volume of dose,” or “unit dose volume,” should be understood as the volume intended for use in a single dose. A unit dose is defined as the amount of the composition, more specifically CsA (in the form of L-CsA) in the liquid composition, filled into a nebulizer for a single dose. Specifically, the volume of a unit dose may be less than 10 mL. Preferably, the volume is in the range of about 0.3 to about 3.5 mL, more preferably about 1 to about 3 mL. For example, if the composition after reconstitution is obtained with a volume of about 1.25 mL or about 2.5 mL, the volume of the liquid vehicle, preferably an aqueous liquid vehicle, or even more preferably saline 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 present invention is preferably in the range of 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 can be administered to a single-lung transplant patient. Such doses have been found to be well tolerable by bilateral-lung transplant patients who are at risk of developing or have been diagnosed with BOS.

[0089] The therapeutically effective daily dose of CsA administered to bilateral lung transplant patients diagnosed with BOS may range from 2 mg to 30 mg. Therefore, in preferred embodiments, CsA is administered in an effective daily dose ranging from 2 to 30 mg, or from 5 to 30 mg. In preferred embodiments, an effective daily dose of approximately 20 mg of CsA may be administered to bilateral lung transplant patients at risk of developing BOS or who have been diagnosed with BOS. When CsA is administered in the form of L-CsA, it should be understood that all amounts outlined above refer to the amount of CsA contained in the liposomes.

[0090] The compositions for use according to the present invention, or more preferably liquid compositions, can be advantageously aerosolized and administered by a nebulizer capable of converting solutions, colloidal formulations, or suspensions such as the present composition containing CsA in the form of L-CsA into droplets of a high proportion that can reach the periphery of the lungs. In practice, jet nebulizers, ultrasonic nebulizers, piezoelectric nebulizers, electrohydrodynamic nebulizers, membrane nebulizers, electron membrane nebulizers, or electron vibrating membrane nebulizers may 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 the AeroDose® (Aerogen) device family.

[0091] However, preferably, especially when spraying liquid compositions containing L-CsA, piezoelectric nebulizers, electrohydrodynamic nebulizers, membrane nebulizers, electron membrane nebulizers, or electron vibrating membrane nebulizers may be used. In these cases, suitable nebulizers include the 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 preferred embodiments, the composition for use according to the present invention is aerosolized in an electron-vibrating membrane nebulizer to target drug CsA in the lower respiratory tract, either as is or in the form of liposomal CsA (L-CsA). In particularly preferred embodiments, the liquid composition for use according to the present invention is aerosolized in an eFlow® nebulizer (PARI Pharma GmbH).

[0092] The eFlow® nebulizer sprays liquid drug formulations, such as the compositions of the present invention, and uses a perforated vibrating membrane to produce an aerosol with low ballistic momentum and a high proportion of droplets within the breathable size range, typically less than 5 pm. Compared to conventional nebulizers such as jet nebulizers, the eFlow® nebulizer is designed to spray pharmaceuticals more quickly and efficiently because it has a higher spraying speed, lower drug consumption, and a higher proportion of drug available as the delivery dose (DD) and breathable dose (RD).

[0093] Preferably, a suitable nebulizer, particularly a vibrating membrane nebulizer, can deliver such a unit dose at a rate of at least about 0.1 mL / min, or at a rate of at least about 100 mg / min, assuming the relative density of the composition is typically about 1. More preferably, the nebulizer can produce output rates 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 nebulizer's output speed should be selected to achieve a short spray time for the liquid composition. Clearly, the spray time depends on the volume of the composition being aerosolized and the output speed. Preferably, the nebulizer should be selected or adapted so that a volume of the liquid composition containing an effective dose of the active compound can be aerosolized within about 20 minutes. More preferably, the spray time per unit dose is about 10 minutes or less. Even more preferably, the spray time per unit dose is about 5 minutes or less.

[0095] In addition to providing a high delivery dose and having a short spray time, nebulizers for administering CsA in the form of L-CsA are preferably constructed to inhibit environmental contamination by CsA. For this purpose, a filter device can be placed in the exhalation valve of the nebulizer.

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

[0097] Alternatively, wireless transmission of such data to the cloud and / or servers can be applied, allowing medical staff to monitor patient adherence. The monitoring system may include nebulizers, controllers, servers, data banks, clouds, providers, physicians, health insurance companies, and / or telephone services, as described above.

[0098] To obtain relevant prevention or delay of BOS progression in bilateral lung transplant patients, adherence of at least 65%, or at least 75%, has been found to be beneficial. To achieve at least 65% adherence, bilateral lung transplant patients at risk of or diagnosed with BOS, particularly BOS 1 or BOS 2, must inhale the formulation as intended in at least 65% of the intended inhalation cycles. For example, based on a twice-daily inhalation regimen, this means that the patient cannot miss more than 39 inhalations over an 8-week period, which corresponds to approximately 5 inhalations per week. Omitted inhalations, inhalations not performed until a complete unit dose is inhaled, or insufficient inhalations for other reasons are considered “missed” inhalations, in other words, inhalations that are not “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 cycles, based on a twice-daily inhalation regimen. This is achieved when the number of missed inhalations over an 8-week period is 28 or less, or approximately 3.5 missed inhalations per week.

[0099] In another embodiment, features for recording nebulizer duration, date, and duration are connected to a system that generates a signal as soon as inhalation is not performed in a timely and correct manner for a predetermined number of inhalation cycles. By using such a monitoring system, it may be possible to ensure that the patient uses the nebulizer device correctly, with or without the signal-generating system. The signal-generating system may include, for example, the detection of the presence of fluid in the fluid reservoir by a sensor, and the measurement of inhalation flow, inhalation time, inhalation duration, and / or inhalation volume. Visual, auditory, or sensory feedback may be provided, for example, regarding relevant patient behavior and use factors influencing treatment, or the diagnosis of administration. This feedback may include information to improve patient adherence to defined medical protocols and / or CsA deposition and distribution in the lungs.

[0100] For example, in embodiments where the time, date, and duration of each inhalation are recorded in the features for monitoring, it is possible to continuously monitor the patient. In embodiments where the monitoring system is connected to a system that generates signals, the patient's inhalation behavior can be corrected as soon as the patient's adherence falls below a predetermined adherence limit. The signals may be generated by the nebulizer itself, or they may be generated by a remote device, for example, to notify the patient's physician. When a lack of adherence is notified, the physician can contact the patient to remind them that proper inhalation is essential for the successful prevention of chronic lung graft rejection.

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

[0102] Furthermore, it has been found to be advantageous to administer the composition for use according to the present invention to bilateral lung transplant patients at risk of developing BOS or diagnosed with BOS for a longer period, such as at least two weeks, or at least four weeks, or at least eight weeks, or at least twelve weeks, or at least sixteen weeks, or at least twenty weeks or longer. In a particularly preferred embodiment, the liquid composition for use according to the present invention may be administered for a period of at least 24 weeks, or even more than 36 weeks, or even more than 48 weeks, or even longer, such as 12 months, 24 months, 36 months, or even several years, such as four years, five years, or even six years, in which case it may be shown to prevent BOS in bilateral lung transplant patients or to delay or reduce the progression of BOS, particularly BOS 1 or BOS 2.

[0103] In a more preferred embodiment, the administration of the composition for use according to the present invention is carried out continuously daily, preferably once or more times, preferably twice a day, for a period of at least 24 weeks, preferably at least 48 weeks.

[0104] In further embodiments, the inhaled CsA composition of the present invention is used in combination with one or more active ingredients used in standard immunosuppressive therapy after lung transplantation. Thus, in preferred embodiments, the liquid composition for use according to the present invention is characterized in that bilateral lung transplant patients are concurrently treated with standard immunosuppressive therapy (also referred to herein as “SOC”).

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

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

[0107] In further specific embodiments, the compositions for use according to the present invention are used in combination with tripartite 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 ingredients used in combination with the compositions according to the present invention are preferably administered orally. In these cases of standard immunosuppressive therapy, tacrolimus is usually administered in an amount that achieves a whole blood level (WBTL) of 8-12 ng / mL, preferably about 0.06 mg / kg (with respect to the body weight of the patient being 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 20-25 mg / day, preferably about 20 mg / day.

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

[0109] The compositions for use according to the present invention enable the effective treatment or prevention of BOS in bilateral lung transplant patients, or the effective delay of BOS progression in bilateral lung transplant patients diagnosed with BOS. As described above, a decrease in forced expiratory volume in one 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. Accordingly, in specific embodiments, the compositions for use according to the present invention are useful for the treatment of BOS in bilateral lung transplant patients, particularly BOS 1 or BOS 2, and the progression of BOS in bilateral lung transplant patients is substantially prevented or reduced to a level of up to 50%, up to 40%, up to 30%, up to 20%, up to 15%, up to 10%, or even up to 5% of the patient's FEV1 value compared to the patient's FEV1 value at the start of treatment, or at the start of randomization, or at the start of the trial, respectively. In a preferred embodiment, the progression of BOS, particularly BOS 1 or BOS 2, in bilateral lung transplant patients is substantially prevented or reduced to a level of up to 20% reduction in the patient's forced expiratory volume in one second (FEV1) compared to the patient's FEV1 value at the start of treatment, randomization, or trial, respectively.

[0110] This effect may be achieved by treating a bilateral lung transplant patient at risk of developing BOS or diagnosed with BOS with the composition of the present invention or by the method of the present invention for at least two weeks, or at least four weeks, or at least eight weeks, or at least twelve weeks, or at least sixteen weeks, or at least twenty weeks, or even longer, for example, at least 24 weeks, or even 36 weeks, or even 48 weeks, or even longer, for example, 12 months, 24 months, 36 months, or even several years, for example, four years, five years, or six years, in which case it may be shown to prevent, delay or reduce the progression of, BOS, particularly BOS 1 or BOS 2, in bilateral lung transplant patients.

[0111] In a more preferred embodiment, after treatment with the composition for use according to the present invention for a period of at least 24 weeks, followed by at least 24 weeks of treatment-free treatment of the bilateral lung transplant, the progression of BOS in the bilateral lung transplant patient is substantially prevented or reduced to a level of up to 20%, preferably up to 10%, of the patient's forced expiratory volume in one second (FEV1) value compared to the 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, the compositions for use according to the present invention have been found to enable a significant extension of event-free survival in bilateral lung transplant patients who are at risk of developing BOS or have been diagnosed with BOS, preferably those diagnosed with BOS, where event-free survival is characterized as the period of survival in which bilateral lung transplant patients do not experience at least a 20% decrease in FEV1 and / or the need for re-transplantation or death.

[0113] Furthermore, the compositions for use according to the present invention enable a significant increase in the event-free survival rate for bilateral lung transplant patients who are at risk of developing or have been diagnosed with BOS, particularly BOS 1 or BOS 2. Thus, in a preferred embodiment, the compositions for use according to the present invention enable the treatment of bilateral lung transplant patients who are at risk of developing or have been diagnosed with BOS, wherein the event-free survival rate is at least 50%, at least 60%, at least 70%, 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, for example, 12 months, 24 months, 36 months, or even several years, for example, 4 years, or 5 years, or even 6 years, and the event is selected from at least 10% or 20% decrease in FEV1 and / or need for re-transplantation or death. In a preferred embodiment, the event-free survival rate for a bilateral lung transplant patient at risk of developing BOS or diagnosed with BOS, preferably diagnosed with BOS, is at least 60%, preferably at least 80%, after treatment with the composition for use according to the present invention for a period of at least 24 weeks, followed by at least 24 weeks without treatment.

[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 a decrease in FEV1 of at least 10% or at least 20% within at least two weeks, or at least four weeks, or at least eight weeks, or at least twelve weeks, or at least sixteen weeks, or at least twenty weeks, or even longer, for example, at least 24 weeks, or even 36 weeks, or even 48 weeks, or even longer, for example, 12 months, 24 months, 36 months, or even several years, for example, four years, five years, or even six years, but preferably within 48 weeks, may be significantly reduced.

[0115] Accordingly, the compositions for use according to the present invention enable the treatment of bilateral lung transplant patients who are at risk of developing or have been diagnosed with BOS, such that the risk of experiencing an event selected from a decrease in FEV1 of at least 20%, the need for re-transplantation, and / or death (event-free survival probability) within a long period of time, preferably within at least 48 weeks, from the start of treatment for 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, for example, at least 24 weeks, or even 36 weeks, or even 48 weeks, or even longer, for example, 12 months, 24 months, 36 months, or even several years, for example, 4 years, or 5 years, or even 6 years, 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.

[0116] In a preferred embodiment, the risk of experiencing an event selected from the above-mentioned at least 20% decrease in FEV1, the need for re-transplantation, and / or death is reduced by at least 30%, preferably at least 35% (absolutely), particularly after treatment with the composition for use according to the present 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 BOS progression 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, hereafter also referred to as the "slope of FEV1"), determined for such patients based on FEV1 measurements taken regularly and repeatedly over the above-mentioned longer periods, such as 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 4 years, or 5 years, or even 6 years, preferably 48 weeks. Therefore, in a preferred embodiment, the composition for use according to the present invention enables the treatment of bilateral lung transplant patients at risk of developing or diagnosed with BOS, in which the monthly variation of FEV1 (ΔFEV1 / month) remains substantially constant, or has values ​​in the range of about 0 to about 0.055 L / month (corresponding to a maximum loss or decrease of FEV1 of 0.055 L / month), or about 0 to about 0.05 L / month, or about 0 to about 0.045 L / month, or about 0 to about 0.04 L / month. In a preferred embodiment, the composition for use according to the present invention enables the treatment of bilateral lung transplant patients at risk of developing or diagnosed with BOS, in which the monthly variation of FEV1 (ΔFEV1 / month) remains substantially constant, or has values ​​in the range of about 0 to about 0.04 L / month (meaning the monthly loss of FEV1 is in the range of about 0 to about 0.04 L).

[0118] Another measure for determining the potential delay or progression of BOS in bilateral lung transplant patients at risk of developing BOS or diagnosed with BOS is a 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 and end of treatment, specifically over periods of at least 12 weeks, or at least 24 weeks, or at least 36 weeks, or even longer, such as 48 weeks, or 12 months, or even longer, such as 24 months, or 36 months, or even longer, such as 4 years, or 5 years, or even 6 years, preferably 48 weeks. Therefore, in specific embodiments, the composition for use according to the present invention enables the treatment of bilateral lung transplant patients at risk of developing BOS or diagnosed with BOS, where the absolute change in FEV1 (ΔFEV1 / absolute) between baseline (start of treatment) and the end of the treatment period, for example 48 weeks after the start of treatment, is 350 mL or less, meaning that the total loss of FEV1 in the 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 further embodiments, the absolute change in FEV1 (ΔFEV1 / absolute) between baseline (start of treatment) and the end of the treatment period, for example 48 weeks after the start of treatment, is in the range of 150 to 350 mL in bilateral lung transplant patients at risk of developing BOS or diagnosed with BOS, preferably diagnosed with BOS.

[0119] Further measures for determining the potential delay or progression of BOS in bilateral lung transplant patients at risk of developing BOS or diagnosed with BOS and being treated with compositions for use according to the present invention are, specifically, the relative change to the loss of FEV1 in patients treated with standard immunosuppressive therapy (SOC) alone, or more specifically, the determination of the relative loss of FEV1 (ΔFEV1 / relative), after long-term treatment, such as 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, such as 4 years, or 5 years, or even 6 years, preferably over a period of 48 weeks. Accordingly, in specific embodiments, the composition for use according to the present invention enables the treatment of bilateral lung transplant patients diagnosed with BOS, wherein the relative change or difference (ΔFEV1 / relative) of FEV1 in bilateral lung transplant patients treated with the composition for use according to the present invention compared to the loss of FEV1 in patients treated with standard immunosuppressive therapy (SOC) alone is at least 200 mL, at least 250 mL, at least 300 mL, or even, for example, at least 350 mL, or at least 400 mL, over a period of at least 12 weeks, or at least 24 weeks, or at least 36 weeks, or even further at least 48 weeks, or 12 months, or even further at least 24 months, or 36 months, or even longer at least 4 years, or 5 years, or even further at least 6 years, preferably over a period of at least 48 weeks after the start of treatment, in amounts of at least 200 mL, or at least 250 mL, or at least 300 mL, or even further at, for example, at least 350 mL, or at least 400 mL.

[0120] In preferred embodiments, a composition comprising L-CsA for use according to the present invention enables the treatment of bilateral lung transplant patients at risk of developing or diagnosed with BOS, wherein the relative loss or difference (ΔFEV1 / relative) of FEV1 compared to the FEV1 loss of patients treated with standard immunosuppressive therapy (SOC) alone is in the range of about 200 to about 400 mL 48 weeks after the start of treatment. This means, for example, according to these preferred embodiments, after a period of 48 weeks, patients treated with the composition according to the present invention have an FEV1 value about 200 to about 400 mL higher than the FEV1 value of bilateral lung transplant patients 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 are at risk of developing or have been diagnosed with BOS, but who have not been diagnosed with airway stenosis before the start of treatment, as confirmed by bronchoscopy with bronchoalveolar lavage (BAL), and especially in patients who have not been diagnosed with airway stenosis at 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 who are at risk of developing BOS or have been diagnosed with BOS, who have not been diagnosed with an untreated infection before the initiation of treatment, and especially in patients who have not been diagnosed with an untreated infection even 24 weeks after the initiation of treatment.

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

[0124] In a further aspect, the present invention provides the use of a composition comprising cyclosporine A (CsA) in the preparation of a pharmacopoeia for the prevention or treatment of bronchiolitis obliterans (BOS) in bilateral lung transplant patients, or for the prevention or delaying of the progression of BOS in bilateral lung transplant patients diagnosed with BOS, wherein the composition is administered to the patient by inhalation of the composition in an aerosolized form containing a therapeutically effective dose of CsA. As outlined above in relation to the composition of the first aspect of the present invention, the composition comprising CsA may be used in solid or liquid form to prepare a pharmacopoeia according to this aspect of the present invention. When a solid composition is used, it 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 present invention may also be applied to the use of such a composition according to this aspect of the present invention.

[0125] In a further embodiment, the present invention relates to a method for preventing bronchiolitis obliterans (BOS) in bilateral lung transplant patients, or for treating BOS in bilateral lung transplant patients diagnosed with BOS, or for preventing or delaying the progression of BOS, (a) A step to identify patients who have undergone bilateral lung transplantation and are at risk of developing or have subsequently developed BOS; (b) The step of administering a therapeutically effective dose of aerosolized cyclosporine A (CsA) to the patient by inhalation. This provides a method that includes this.

[0126] It should be noted that, with respect to this aspect of the present invention, all features disclosed and described above in connection with compositions for use according to the first aspect of the present invention can also be applied to methods for preventing or treating bronchiolitis obliterans (BOS) in bilateral lung transplant patients, or for preventing or delaying the progression of BOS in bilateral lung transplant patients diagnosed with BOS according to this aspect of the present invention.

[0127] However, to avoid misunderstanding, the following is a list of numbered embodiments of compositions comprising cyclosporine A (CsA), particularly liposomal CsA (L-CsA), for use in preventing bronchiolitis obliterans (BOS) in bilateral lung transplant patients, or for preventing or delaying the progression of BOS in bilateral lung transplant patients diagnosed with BOS according to this embodiment of the Invention, which also include methods for preventing or treating BOS in bilateral lung transplant patients, or for preventing or delaying the progression of BOS in bilateral lung transplant patients diagnosed with BOS according to the Invention:

[0128] 1. A composition comprising cyclosporine A (CsA) for use in the prevention of bronchiolitis obstructive (BOS) in bilateral lung transplant patients, or for treating BOS in bilateral lung transplant patients diagnosed with BOS, or for preventing or delaying the progression of BOS, A composition administered to the patient by inhalation of an aerosolized form of the composition containing a therapeutically effective dose of cyclosporine A.

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

[0130] 3. A composition for use as described in item 1 or 2, in a bilateral lung transplant patient diagnosed with BOS 1 or BOS 2.

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

[0132] 5. A liquid composition for use as described in any of items 1 to 4.

[0133] 6. A composition for use as described in item 5, comprising an aqueous liquid vehicle.

[0134] 7. A composition for use as described in item 6, wherein the aqueous liquid vehicle contains physiological saline.

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

[0136] 9. A composition for use according to any one 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 one of items 1 to 9, wherein the liquid composition is prepared by reconstitution of liposome cyclosporine A in a 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 one of items 1 to 11, wherein cyclosporine A is administered in an effective daily dose of 20 mg.

[0140] 13. A composition for use according to any one of items 1 to 12, to be administered to the patient twice daily.

[0141] 14. A composition for use according to any one of items 1 to 13, administered over a period of at least 24 weeks.

[0142] 15. A composition for use according to any of items 1 to 14, in which a bilateral lung transplant patient is concurrently treated with standard immunosuppressive therapy.

[0143] 16. A composition for use according to item 15, wherein 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. A composition for use as described in item 15 or 16, wherein standard immunosuppressive therapy includes oral administration of tacrolimus, mycophenolate mofetil, and prednisone.

[0145] 18. A 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. A 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. A composition for use according to any one of items 15 to 19, wherein prednisone is administered in a dose of approximately 20 to approximately 25 mg / day.

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

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

[0150] 23. A composition for use according to any one of items 1 to 22, which prevents the progression of BOS in a bilateral lung transplant patient diagnosed with BOS, or reduces the patient's FEV1 to a level of up to 20% lower than the FEV1 value at the start of treatment.

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

[0152] 25. A composition for use according to any one of items 1 to 24, wherein the risk of experiencing an event selected from a decrease in FEV1 of at least 20%, need for re-transplantation, and / or death within a period of at least 48 weeks from the start of treatment in a bilateral lung transplant patient treated with the composition of the present invention in an aerosolized form containing 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.

[0153] 26. A composition for use according to any of items 1 to 25, wherein the mean monthly change in FEV1 (ΔFEV1 / month) in bilateral lung transplant patients 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 one of items 1 to 26, wherein the absolute change in FEV1 (ΔFEV1 / absolute) between baseline (start of treatment) and end of treatment in a bilateral lung transplant patient diagnosed with BOS is 350 mL or less.

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

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

[0157] 30. A composition for use according to any one of items 1 to 29, in a bilateral lung transplant patient diagnosed with BOS who has not been diagnosed with an untreated infection before randomization and preferably at 24 weeks after the start of treatment.

[0158] 31. A composition for use according to any one of items 1 to 30, wherein the maximum blood concentration of CsA in a 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.

[0159] 32. A composition for use as described in item 21 or 22, wherein the nebulizer can deliver a unit dose at a rate of at least about 0.1 mL / min.

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

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

[0162] 35. The method described in item 33 or 34 for bilateral lung transplant patients diagnosed with BOS 1 or BOS 2 (BOS grade I or II).

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

[0164] 37. The method according to item 33, wherein CsA is administered in the form of an aerosolized liquid composition containing 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 according to item 39, wherein the aqueous liquid vehicle contains physiological saline.

[0168] 41. The method according to item 39 or 40, wherein the aqueous liquid vehicle essentially consists of physiological saline, preferably physiological 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 liposome cyclosporine A (L-CsA) in a lyophilized form.

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

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

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

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

[0175] 48. The method described in item 33, in which bilateral lung transplant patients are treated concurrently with standard immunosuppressive therapy.

[0176] 49. The method of item 48, wherein 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.

[0177] 50. The method described in item 48, in which standard immunosuppressive therapy includes oral administration of tacrolimus, mycophenolate mofetil, and prednisone.

[0178] 51. The method described in item 49 or 50, wherein tacrolimus is administered at a dose of 0.06 mg / kg.

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

[0180] 53. The method described in item 49 or 50, in which prednisone is administered at a dose of 20 mg / day.

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

[0182] 55. The method according to item 33, wherein the formulation is aerosolized using an eFlow® nebulizer.

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

[0184] 57. The method according to item 33, which prevents the progression of BOS in bilateral lung transplant patients who are at risk of developing BOS or who have been diagnosed with BOS, or reduces the FEV1 of the patient to a level of up to 20% lower than the FEV1 value at the start of treatment.

[0185] 58. The event-free survival rate for bilateral lung transplant patients at risk of developing BOS or diagnosed with BOS is at least 60% at least 48 weeks after the start of treatment, and events are selected from at least a 20% decrease in FEV1, need for retransplantation and / or death, as described in item 33.

[0186] 59. The method according to item 33, wherein the risk of experiencing an event selected from a decrease in FEV1 of at least 20%, need for re-transplantation, and / or death within at least 48 weeks from the start of treatment in a bilateral lung transplant patient treated with the composition of the present invention in an aerosolized form containing 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 bilateral lung transplant patients diagnosed with BOS remains substantially constant or has a value in the range of approximately 0 to approximately 0.04 L / month.

[0188] 61. The method described in item 33, wherein the absolute change in FEV1 (ΔFEV1 / absolute) between baseline (start of treatment) and end of treatment 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 of FEV1 (ΔFEV1 / relative) in a bilateral lung transplant patient diagnosed with BOS is at least 200 mL compared to the FEV1 loss in a patient treated with standard immunosuppressive therapy (SOC) alone.

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

[0191] 64. The method according to item 33, in which bilateral lung transplant patients at risk of developing BOS or who have been diagnosed with BOS are not diagnosed with an untreated infection before the initiation of treatment and preferably at 24 weeks after the initiation of treatment.

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

[0193] 66. The method according to item 54 or 55, wherein the nebulizer can deliver a 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 pharmacopoeia for the prevention of obstructive bronchiolitis (BOS) in a bilateral lung transplant patient, or for the treatment of BOS in a bilateral lung transplant patient diagnosed with BOS, or for the prevention or delay of the progression of BOS, wherein the composition is administered to the patient by inhalation of the composition in an aerosolized form containing a therapeutically effective dose of CsA. Detailed description of the drawing

[0195] Figure 1 shows a flowchart summarizing the details of enrollment of single-lung 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 met the eligibility criteria. Prior to randomization, one patient died and one patient withdrew from the study. Twenty-one patients were randomized, with 11 in the L-CsA treatment group and 10 in the SOC (Standard of Care, i.e., standard immunosuppressive therapy) treatment group. One patient with L-CsA withdrew from the study during 24 weeks of follow-up due to advanced skin cancer. Because this patient's cancer was advanced, traditional systemic immunosuppression was discontinued, and the patient was managed for therapeutic purposes.

[0196] Figure 2 shows Kaplan-Meier plots of BOS progression-free survival probabilities for single-lung transplant patients and double-lung transplant patients diagnosed with BOS during the 48-week study period (i.e., no distinction is made between single-lung and double-lung transplant patients). Patients in the SOC group tended to have a higher risk of treatment failure (defined as BOS progression, re-transplantation, 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 rates for bilateral lung transplant patients diagnosed with BOS (i.e., results for unilateral lung transplant patients are not available). The event-free survival rate for bilateral lung transplant patients diagnosed with BOS was 83% in the L-CsA treatment group compared to 50% in the SOC treatment group. Furthermore, in bilateral lung transplant patients, the hazard ratio (HR) was 3.43 with a 95% CI of 0.31–37.95; p=0.29, meaning that the risk of experiencing BOS progression, need for retransplantation, or death was 3.43 times higher in bilateral lung transplant patients receiving SOC treatment alone compared to bilateral lung transplant patients receiving L-CsA treatment.

[0198] Figure 4 shows a Kaplan-Meier plot of event-free survival probability for single-lung transplant patients only (i.e., results for double-lung transplant patients are not available). The event-free survival probability for single-lung transplant patients was 80% in the L-CsA treatment group, compared to 50% in the SOC treatment group. Furthermore, in single-lung transplant patients, the hazard ratio (HR) was 2.78, with a 95% CI of 0.29–26.98; p=0.36, meaning that compared to single-lung transplant patients with L-CsA treatment, single-lung transplant patients with SOC treatment alone had a 2.78 times higher risk of experiencing BOS progression, need for retransplantation, or death.

[0199] Figure 5 shows Kaplan-Meier plots of overall survival for single-lung and double-lung transplant patients at 5 years after randomization. The data demonstrate a significant improvement in single-lung or double-lung transplant patients treated with L-CsA: 5 out of 11 participants treated with L-CsA (45%) survived to 5-year follow-up compared to 0 out of the first 10 patients treated with SOC alone. The median survival time for the L-CsA-treated group was 4.1 years compared to 2.9 years for the SOC-treated group (p=0.03). The cause of death was chronic allograft rejection, with two exceptions: one due to disseminated skin cancer (L-CsA) and the other to renal failure (SOC).

[0200] Figure 6 shows an analysis of overall FEV1 development in single-lung and double-lung transplant patients (i.e., no distinction is made between single-lung and double-lung transplant patients) after adjusting for pre- and post-randomization measurement data in a randomized slope mixed model. In the group of patients treated with L-CsA (11 patients), a slight decrease in mean absolute FEV1 value was observed, starting from approximately 1.75 L at randomization and ending at 1.70 L over the 48-week period. In the group of patients treated with SOC (10 patients; one patient required mechanical ventilation and therefore no post-randomization PFT measurement was taken; this patient was included in the calculation of the FEV1 slope: the patient was assigned a FEV1 value of 0 when he progressed to mechanical ventilation; this patient had no post-randomization PFT (pulmonary function test) measurement), a stable, significant decrease in FEV1 value from approximately 1.75 L to approximately 1.15 L was observed. In this overall analysis of single-lung transplant patients 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, compared to -0.007 with a 95% CI of -0.033 to 0.018 for patients treated with L-CsA (p=0.10).

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

[0202] Figure 8 shows the development of mean absolute FEV1 values ​​over a 48-week study period for single-lung transplant patients in the L-CsA treatment group (upper graph; "L-CsA") and the SOC treatment group (lower graph; "SOC") (i.e., there are no results for double-lung transplant patients). In the group of patients treated with L-CsA (5 patients), a decrease in mean absolute FEV1 value was observed from approximately 1.75 L immediately after randomization to approximately 1.4 L at 48 weeks after randomization. In the single-lung transplant group in the SOC group (6 patients; one patient required mechanical ventilation and therefore no PFT measurement was available after randomization; the patient was included in the calculation of the slope of FEV1: the patient was assigned a FEV1 value of 0 when he progressed to mechanical ventilation; this patient did not have a PFT (pulmonary function test) measurement after randomization), the mean FEV1 value decreased significantly from approximately 1.75 L to approximately 1.05 L over the same period (due to the calculation method, the graph for the SOC treatment group ends at month 1). Therefore, the monthly change in FEV1 (ΔFEV1 / month) in bilateral lung transplant patients was -0.029 (95% CI) for the L-CsA treatment group, ranging from -0.019 to 0.001, and -0.600 (95% CI) for the SOC treatment group, ranging from -2.074 to 0.872 (p=0.37).

[0203] The following examples are useful in illustrating the present invention, but should not be understood as limiting the scope of the invention. Examples

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

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

[0206] Table 1: Characteristics of aerosols of liposomal cyclosporine (L-CsA) formulations sprayed with the eFlow® nebulizer. JPEG0007879668000001.jpg32131 Values ​​are expressed as mean ± standard deviation; MMD = median mass; DD = delivery dose (from mouthpiece); RD = breathable dose

[0207] 76% of the delivery dose (DD) (amount from the mouthpiece) and approximately 47% of the breathable dose (RD) of droplets smaller than 3.3 μm were achieved. Particles smaller than 3.3 μm are more likely to deposit in the distal part of the lung, which is considered the optimal drug deposition site for effective lung graft protection. Generally, aerosol droplets smaller than 5 μm are more likely to deposit throughout the lung and should be considered similarly for some degree of lung graft protection. The breathable dose of droplets smaller than 5 μm was approximately 68%.

[0208] Based on these results, we can conclude that for a nominal drug dose of 10 mg, the corresponding delivery dose (mg) is approximately 7.6 mg CsA. The breathable doses (mg) for droplets less than 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 formulation Sucrose was added to the formulation described in Example 1 as a lyoprotectant. The formulation was then lyophilized. Immediately before spraying, the formulation was reconstituted with 2.3 ml of 0.25% physiological 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 formulation was atomized using an eFlow® nebulizer with 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 formulation are shown in Table 2.

[0211] The results did not show any substantial difference compared to the results obtained in Example 1.

[0212] Table 2: Aerosol characteristics of reconstituted liposomal cyclosporine formulations sprayed with an eFlow® nebulizer JPEG0007879668000002.jpg87161 Values ​​are expressed as mean ± standard deviation; MMAD = Mass Median Aerodynamic Diameter; GSD = Geometric Standard Deviation; DD = Delivery Dose (from mouthpiece); RD = Breathable Dose

[0213] Example 3: Clinical trial using inhaled cyclosporine in the treatment of BOS Clinical research registration: Forty-three patients were evaluated for eligibility, of which 23 met the eligibility criteria. Prior to randomization, one patient died and one patient dropped out. Twenty-one patients were randomized, with 11 in the L-CsA treatment group and 10 in the SOC treatment group. (Figure 1) One patient with L-CsA dropped out of the study during the 24-week follow-up period due to advanced 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 infections and airway stenosis as determined by bronchoscopy with bronchoalveolar lavage (BAL) performed before randomization, at 24 weeks, and when clinically required.

[0215] The classification of bronchiolitis obliterans syndrome (BOS) was applied as follows: BOS assessment was continuously performed based on bimonthly FEV1 measurements. The definition of BO was based on the modified BOS criteria from the publication of 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 baseline 81%~90% -BOS 1: FEV1 66%~80% of baseline -BOS 2: FEV1 51%~65% of baseline -BOS 3: FEV1 less than 50% of baseline

[0217] Clinical study design: This single-center, randomized, open-label clinical trial enrolled 21 single-lung or double-lung transplant patients diagnosed with BOS grade 1 or 2 to evaluate the addition of aerosolized L-CsA to standard immunosuppression for BOS 1 and BOS 2 (grades 1-2) compared to standard immunosuppression alone (SOC).

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

[0219] Patients were assigned to receive either 5 mg / 1.25 ml or 10 mg / 2.5 ml L-CsA therapy (L-CsA group) twice daily for 24 weeks, in addition to standard immunosuppression, for single-lung transplant (SLT) or double-lung transplant (DLT) patients, or standard immunosuppression alone (SOC group), followed by 24 weeks without the study drug (L-CsA).

[0220] The L-CsA formulation was used in the form of a lyophilized reconstituted product with 0.25% physiological saline and nebulized using an eFlow® nebulizer (PARI, Germany). A filter was placed in the exhaust valve of the inhalation chamber. Furthermore, the nebulizer was designed to operate only when a key card (eFlow® chip card) that monitors inhalation time and duration was inserted into the nebulizer.

[0221] Treatment protocol: Patients were randomly assigned to either the L-CsA group (treated) or the SOC group (no CsA treatment). L-CsA was administered twice daily at a dose of 5 mg or 10 mg (for single-lung or double-lung transplant patients, respectively) in addition to standard immunosuppression consisting of tacrolimus (0.06 mg / kg; trough levels 8–12 ng / ml), mycophenolate mofetil (1 gm PO₄ bid) or sirolimus (2 mg PO₄ daily; levels 7–12 ng / ml), and prednisone (20 mg / day). The SOC group received standard immunosuppression only. When used, the combined blood concentrations of sirolimus and tacrolimus were maintained at 4–5 ng / ml. Adjustments were made based on clinician-based evaluations of clinical parameters and protocols at the research site. Infection prevention included valcite, voriconazole, and sulfamethoxazole / trimethoprim. Enhanced 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). FEV1-mediated progression of BOS was examined before and after treatment for comorbid conditions measured at least 3 weeks apart, and confirmed by two co-investigators.

[0222] Endpoint: The primary endpoints of BOS progression were as follows: 1) A decrease of 20% or more in FEV1 from randomization; 2) Death, or 3) Re-implantation.

[0223] Secondary endpoints included changes in lung function, aerosol tolerance, 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 pre-randomization and at the end of the treatment period using a Luminex 100 reader with multiple assays (BioRad®) and analyzed using BioRad software.

[0224] Statistical analysis: The primary endpoint, a combination of BOS progression and overall patient survival, was compared using the Kaplan-Meier method and the log-rank test. Transplant type as a factor influencing survival was evaluated using the Cox proportional hazards model. Data are presented as hazard ratios (HR) and 95% confidence intervals (95% CI). For pulmonary function analysis, a multivariate linear mixed-effects statistical model (PROC MIXED, SAS version 9.1.3; SAS Institute, Cary, NC) was used (Laird NM, Ware JH. Random-effects models for longitudinal data; Biometric 1982;38:963-974). The mixed model adjusted for changes that may affect function after randomization, analyzing intra-group and inter-group values ​​before and after randomization. Cytokine levels were compared using two-way ANOVA. Clinical laboratory values ​​and drug levels were analyzed using mixed model statistics. All outcomes, including crossover cases, were analyzed as treatment objectives. A total of 242 pulmonary function tests, 42 bronchoalveolar lavage (BAL) samples for cytokine analysis, and 603 blood samples were analyzed.

[0225] result Patient characteristics assessment: Eleven patients were randomized to the L-CsA group and ten to the SOC group (see Figure 1). Baseline characteristics and clinical management were similar in the two groups. The distribution of baseline demographic characteristics did not differ significantly 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 patients in the SOC group who met the primary endpoint received crossover therapy with L-CsA. One patient randomized to L-CsA resumed L-CsA after the initial 24-week interval (FEV1 decrease >20%). One patient withdrew from the study after the initial 24-week interval due to the need to discontinue systemic immunosuppression for recurrent skin cancer.

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

[0228] To conduct the analysis, we defined the Full Analysis Set (FAS) and the Per-Protocol Analysis Set (PPS). The FAS included all patients who received at least one dose of the investigational treatment. The PPS included all patients from the FAS without any major protocol violations that were deemed to impair the scientific aspects and interpretation of the study results (e.g., misenrollment, adherence less than 75%, prohibited concomitant medications).

[0229] Stabilization of BOS was clearly observed in bilateral and unilateral lung recipients compared to the SOC group in the L-CsA treatment group, according to the primary study endpoint: 9 out of 11 patients treated with L-CsA and SOC had an event-free survival rate of 82%, compared to 50% in 5 out of 10 patients treated with SOC alone. (HR (hazard ratio): 3.19; 95% CI (confidence interval): 0.62–16.50; p=0.14; see Figure 2)

[0230] In bilateral lung transplant patients, the event-free survival rate was 83% in the L-CsA treatment group compared to 50% in the SOC treatment group. Furthermore, in bilateral lung transplant patients, the hazard ratio (HR) was 3.43, with a 95% CI of 0.31–37.95; p=0.29, meaning that compared to bilateral lung transplant patients receiving L-CsA treatment, bilateral lung transplant patients receiving SOC treatment alone had a 3.43 times higher risk of experiencing BOS progression, need for retransplantation, or death (see Figure 3).

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

[0232] Of the two cases in the L-CsA group that experienced a major event, one responded to L-CsA resumption (based on the primary endpoint criteria) and the other underwent re-implantation; of the five major events in the SOC group, two resulted in re-implantation, two required mechanical ventilation, and one of the two patients who crossed over from SOC responded to L-CsA.

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

[0234] Overall survival at 5 years after randomization demonstrated a significant improvement in unilateral or bilateral lung transplant patients treated with L-CsA: 5 out of 11 participants treated with L-CsA (45%) survived to 5-year follow-up compared to 0 out of the first 10 patients treated with SOC alone. The median survival time for patients treated with L-CsA was 4.1 years compared to 2.9 years for patients treated with SOC alone (p=0.03; see Figure 5). The cause of death was chronic allograft rejection, with two exceptions: one due to disseminated skin cancer (L-CsA) and the other to renal failure (SOC).

[0235] Changes in lung function In unilateral and bilateral lung transplant patients diagnosed with BOS in the L-CsA and SOC groups, changes in FEV1 values ​​(forced expiratory volume in the first second of forced exhalation) were observed over a 48-week study period as a measure of stabilization or progression of BOS.

[0236] As shown in Figure 6, the analysis of overall FEV1 development in single-lung and double-lung transplant patients after adjusting for pre- and post-randomization measurement data in a randomized slope mixed model yields clear results: In the group of patients treated with L-CsA (11 patients), a slight decrease in mean absolute FEV1 value was observed, starting from approximately 1.75 L at randomization and ending at 1.70 L over a 48-week period. In the group of patients treated with SOC (10 patients; one patient required mechanical ventilation and therefore no post-randomization PFT measurement was taken; this patient was included in the calculation of the FEV1 slope: the patient was assigned a FEV1 value of 0 when he progressed to mechanical ventilation; this patient had no post-randomization PFT (pulmonary function test) measurement), a stable, significant decrease in FEV1 value from approximately 1.75 L to approximately 1.15 L was observed. In this overall analysis of single-lung and double-lung transplant patients, it should be noted that the monthly change in FEV1 (ΔFEV1 / month) was -0.054 with a 95% CI of -0.100 to -0.006, compared to -0.007 with a 95% CI of -0.033 to 0.018 for patients treated with L-CsA (p=0.10).

[0237] As shown in Figure 7, the development of absolute FEV1 values ​​during the 48-week study period for bilateral lung transplant patients only in the L-CsA treatment group (upper graph; "L-CsA") and the SOC treatment group (lower graph; "SOC") yields 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. Therefore, it should 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 Figure 8, the development of absolute FEV1 values ​​during the 48-week study period was similar for single-lung transplant patients in the L-CsA treatment group (upper graph; "L-CsA") and the SOC treatment group (lower graph; "SOC"): In the group of patients treated with L-CsA (5 patients), a decrease in mean absolute FEV1 value was observed from approximately 1.75 L immediately after randomization to approximately 1.4 L at 48 weeks after randomization. In the single-lung transplant group in the SOC group (6 patients; one patient required mechanical ventilation and therefore no PFT measurement was available after randomization; the patient was included in the calculation of the slope of FEV1: the patient was assigned a FEV1 value of 0 when he progressed to mechanical ventilation; this patient did not have a PFT (pulmonary function test) measurement after randomization), the mean FEV1 value decreased significantly from approximately 1.75 L to approximately 1.05 L over the same period (due to the calculation method, the graph for the SOC treatment group ends at month 1). Therefore, the monthly change in FEV1 (ΔFEV1 / month) in bilateral lung transplant patients was -0.029 (95% CI) for the L-CsA treatment group, ranging from -0.019 to 0.001, and -0.600 (95% CI) for the SOC treatment group, ranging from -2.074 to 0.872 (p=0.37).

Claims

1. A therapeutic agent for obstructive bronchiolitis syndrome (BOS) in patients with bilateral lung transplants, comprising a composition containing liposomal cyclosporine A (L-CsA), The composition is administered to the patient by inhalation of an aerosolized form of the composition containing a therapeutically effective dose of cyclosporine A, the composition is a liquid composition comprising an aqueous liquid vehicle, and the bilateral lung transplant patients are simultaneously treated with standard immunosuppressive therapy. The aforementioned two lung transplant patients have been diagnosed with BOS 1 or BOS 2. A therapeutic agent.

2. A therapeutic agent according to claim 1 for treating BOS in bilateral lung transplant patients diagnosed with BOS, or for preventing or delaying the progression of BOS, A therapeutic agent wherein the composition is administered to the patient by inhalation of an aerosolized form of the composition containing a therapeutically effective dose of cyclosporine A.

3. The therapeutic agent according to claim 1 or 2, wherein the aqueous liquid vehicle contains physiological saline.

4. The therapeutic agent according to any one of claims 1 to 3, wherein the aqueous liquid vehicle essentially consists of physiological saline.

5. The therapeutic agent according to claim 4, wherein the aqueous liquid vehicle essentially consists of a 0.25% concentration physiological saline solution.

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

7. The therapeutic agent according to any one of claims 1 to 6, wherein the liquid composition is prepared by reconstitution of liposome cyclosporine A in a lyophilized form.

8. A therapeutic agent according to any one of claims 1 to 7, wherein cyclosporine A is administered in an effective daily dose in the range of 5 to 30 mg.

9. A therapeutic agent according to any one of claims 1 to 8, wherein cyclosporine A is administered in an effective daily dose of 20 mg.

10. The therapeutic agent according to any one of claims 1 to 9, which is administered to the patient twice a day.

11. A therapeutic agent according to any one of claims 1 to 10, administered over a period of at least 24 weeks.

12. The therapeutic agent according to claim 11, wherein the two lung transplant patients are simultaneously treated with a combination of a calcineurin inhibitor, a cell cycle inhibitor, and a corticosteroid.

13. The therapeutic agent according to claim 11 or 12, 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.

14. The therapeutic agent according to any one of claims 11 to 13, wherein the standard immunosuppressive therapy comprises oral administration of tacrolimus, mycophenolate mofetil, and prednisone.

15. The therapeutic agent according to any one of claims 11 to 14, wherein tacrolimus is administered in an amount of 0.06 mg / kg.

16. A therapeutic agent according to any one of claims 11 to 15, wherein mycophenolate mofetil is administered in an amount of 1 g.

17. The therapeutic agent according to any one of claims 11 to 16, wherein prednisone is administered in an amount of approximately 20 to approximately 25 mg / day.

18. The therapeutic agent according to any one of claims 11 to 17, wherein prednisone is administered at a dose of 20 mg / day.

19. The therapeutic agent according to any one of claims 1 to 18, wherein the composition is aerosolized using an electron vibrating membrane nebulizer.

20. The therapeutic agent according to any one of claims 1 to 19, wherein the composition is aerosolized with an eFlow® nebulizer.

21. The therapeutic agent according to claim 19 or 20, wherein the nebulizer can deliver a unit dose at a rate of at least about 0.1 mL / min.

22. The therapeutic agent according to any one of claims 1 to 21, wherein the composition is inhaled with at least 75% adherence.

23. 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 to the value, the patient's FEV １ The therapeutic agent according to any one of claims 1 to 22, which reduces the level to a maximum of 20%.

24. 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 therapeutic agent according to any one of claims 1 to 23, selected from a decrease in blood, the need for re-transplantation, and / or death.

25. FEV of the aforementioned bilateral lung transplant patients diagnosed with BOS １ Average monthly change (ΔFEV) １ The therapeutic agent according to any one of claims 1 to 24, wherein the amount per month remains substantially constant or has a value in the range of about 0 to about 0.04 L / month.

26. 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 The therapeutic agent according to any one of claims 1 to 25, wherein the risk of experiencing an event selected from a decrease in blood glucose, the need for re-transplantation, and / or death is reduced by at least 30% (absolutely) compared to the risk of experiencing the corresponding event under treatment with standard immunosuppressive therapy (SOC) alone.

27. 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 The therapeutic agent according to any one of claims 1 to 26, wherein the risk of experiencing an event selected from a decrease in blood glucose, the need for re-transplantation, and / or death is reduced by at least 35% (absolutely) compared to the risk of experiencing the corresponding event under treatment with standard immunosuppressive therapy (SOC) alone.

28. The absolute change (ΔFEV １ / absolute) of the baseline (before the start of the treatment) and the end of the treatment period of the bilateral lung transplant patient diagnosed with BOS is 350 mL or less, and the therapeutic agent according to any one of claims 1 to 27. １ ​

29. 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 The therapeutic agent according to any one of claims 1 to 28, wherein the (relative) is at least 200 mL.

30. The therapeutic agent according to any one of claims 1 to 29, wherein the aforementioned two-lung transplant patient was not diagnosed with airway stenosis before the start of the treatment, as confirmed by bronchoscopy using bronchoalveolar lavage (BAL).

31. The therapeutic agent according to any one of claims 1 to 30, wherein the aforementioned two lung transplant patients are not diagnosed with airway stenosis before the start of the treatment and at 24 weeks after the start of the treatment, as confirmed by bronchoscopy using bronchoalveolar lavage (BAL).

32. The therapeutic agent according to any one of claims 1 to 31, wherein the bilateral lung transplant patient diagnosed with BOS has not been diagnosed with an untreated infection before randomization.

33. The therapeutic agent according to any one of claims 1 to 32, wherein the bilateral lung transplant patient diagnosed with BOS is not diagnosed with an untreated infection before randomization and at 24 weeks after the start of treatment.

34. The therapeutic agent according to any one of claims 1 to 33, 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.

35. The therapeutic agent according to any one of claims 1 to 34, 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 60 ng / mL.

36. Use of a composition comprising liposomal cyclosporine A (L-CsA) in the preparation of a pharmacopoeci for treating or preventing or delaying the progression of BOS in a bilateral lung transplant patient diagnosed with BOS, wherein the composition is administered to the patient by inhalation of the composition in an aerosolized form containing a therapeutically effective dose of CsA, and the bilateral lung transplant patient is diagnosed with BOS 1 or BOS 2.

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