# US 12,178,843 B2 · Cyclosporine formulations for use in the treatment of bronchiolitis obliterans syndrome (BOS)

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- Number: US 12,178,843 B2
- Document ID: US12178843B2
- Status: Granted
- Kind: B2
- Application number: 18/321,788
- Filed: 2023-05-23
- Published: 2023-11-16
- Granted: 2024-12-31
- Earliest claimed: 2018-04-11
- Assignees: Breath Therapeutics GmbH
- Applicants: Breath Therapeutics GmbH
- Inventors: Aldo Iacono; Oliver Denk; Gerhard Boerner
- Web page: https://patentgrep.com/patent/US12178843B2

## CPC

- A61K 38/13: Cyclosporins
- A61K 9/0078: {for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions}
- A61K 9/127: Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- A61K 47/02: Inorganic compounds
- A61K 47/183: {Amino acids, e.g. glycine, EDTA or aspartame}
- A61K 47/24: containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61P 11/00: Drugs for disorders of the respiratory system
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to a composition comprising cyclosporine A (CsA) for use in the prevention of bronchiolitis obliterans syndrome (BOS) in a double lung transplanted patient, or for the treatment of BOS or for the prevention or delay of the progression of BOS in a double lung transplanted patient being diagnosed with BOS, wherein the composition is administered to said patient by inhalation of said composition in aerosolized form comprising a therapeutically effective dose of cyclo-sporine A.

## Claims

### Claim 1

A method for treating bronchiolitis obliterans syndrome (BOS) in a double lung transplanted patient, or for delaying the onset or progression of BOS in a double lung transplanted patient being diagnosed with BOS, the method comprising administering to said patient by inhalation a composition comprising liposomal cyclosporine A (L-CsA) in aerosolized form comprising a therapeutically effective dose of cyclosporine A.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the double lung transplanted patient is diagnosed with BOS 1 or BOS 2.

### Claim 3 (depends on 1)

The method according to claim 1, wherein the composition is a liquid composition comprising an aqueous liquid vehicle.

### Claim 4 (depends on 3)

The method according to claim 3, wherein the aqueous liquid vehicle essentially consists of saline.

### Claim 5 (depends on 4)

The method according to claim 4, wherein the saline has a concentration of 0.25%.

### Claim 6 (depends on 3)

The method according to claim 3, wherein the liquid composition has a CsA concentration in the range of from 0.5 to 10 mg/mL.

### Claim 7 (depends on 3)

The method according to claim 3, wherein the liquid composition is prepared by reconstitution of liposomal cyclosporine A in lyophilized form.

### Claim 8 (depends on 1)

The method according to claim 1, wherein cyclosporine A is administered at an effective daily dose in the range of 5 to 30 mg.

### Claim 9 (depends on 1)

The method according to claim 1, wherein cyclosporine A is administered at an effective daily dose of 20 mg.

### Claim 10 (depends on 1)

The method according to claim 1, wherein the composition is administered to said patient twice daily.

### Claim 11 (depends on 1)

The method according to claim 1, wherein the composition is administered over a period of at least 24 weeks.

### Claim 12 (depends on 1)

The method according to claim 1, wherein the double lung transplanted patient is co-treated with standard immunosuppressive therapy.

### Claim 13 (depends on 1)

The method according to claim 1, wherein the composition is aerosolized with an electronic vibrating membrane nebulizer.

### Claim 14 (depends on 1)

The method according to claim 1, wherein the composition is inhaled with an adherence of at least 75%.

### Claim 15 (depends on 1)

The method according to claim 1, wherein the onset or progression of BOS of the double lung transplanted patient being diagnosed with BOS is reduced to a level of up to 20% decline of the forced expiratory volume in one second (FEV1) of said patient compared to FEV1-value at the beginning of the treatment.

### Claim 16 (depends on 1)

The method according to claim 1, wherein an event-free survival probability of the double lung transplanted patient being diagnosed with BOS is at least 60% after at least 48 weeks from the beginning of the treatment, wherein an event is selected from a decline in FEV1 of at least 20%, need for re-transplantation, and/or death.

### Claim 17 (depends on 1)

The method according to claim 1, wherein a mean monthly change in FEV1 (ΔFEV1/month) of the double lung transplanted patient being diagnosed with BOS remains substantially constant or has a value in the range of from about 0 to about 0.04 L/month.

### Claim 18 (depends on 1)

The method according to claim 1, wherein a risk to experience an event selected from a decline in FEV1 of at least 20%, need for re-transplantation, and/or death within a period of at least 48 weeks from the beginning of the treatment for the double lung transplanted patient treated with the composition in aerosolized form comprising CsA is reduced by at least 30% (abs.) compared to the risk to experience a corresponding event under treatment with standard immunosuppressive therapy (SOC) alone.

### Claim 19 (depends on 18)

The method according to claim 18, wherein the risk is reduced by at least 35% (abs.).

### Claim 20 (depends on 1)

The method according to claim 1, wherein an absolute change in FEV1 (ΔFEV1/abs.) between baseline (beginning of the treatment) and an end of a treatment period of the double lung transplanted patient being diagnosed with BOS is not more than 350 mL.

### Claim 21 (depends on 1)

The method according to claim 1, wherein a relative loss in FEV1 (ΔFEV1/rel.) of the double lung transplanted patient being diagnosed with BOS relative to a loss of FEV1 in a patient treated with standard immunosuppressive therapy (SOC) alone is at least 200 mL.

### Claim 22 (depends on 1)

The method according to claim 1, wherein the double lung transplanted patient has not been diagnosed with airway stenosis prior to the beginning of the treatment as ascertained by bronchoscopy with bronchoalveolar lavage (BAL).

### Claim 23 (depends on 22)

The method according to claim 22, wherein the double lung transplanted patient has not been diagnosed with airway stenosis prior to week 24 after beginning of the treatment.

### Claim 24 (depends on 1)

The method according to claim 1, wherein the double lung transplanted patient being diagnosed with BOS has not been diagnosed with an untreated infection prior to randomization.

### Claim 25 (depends on 24)

The method according to claim 24, wherein the double lung transplanted patient being diagnosed with BOS has not been diagnosed with an untreated infection prior to week 24 after the beginning of the treatment.

### Claim 26 (depends on 1)

The method according to claim 1, wherein a maximum blood concentration of CsA in the double lung transplanted patient being diagnosed with BOS and being treated with the liquid composition comprising CsA is up to 100 ng/ml.

### Claim 27 (depends on 26)

The method according to claim 26, wherein the maximum blood concentration of CsA is up to 60 ng/mL.