VASOACTIVE INTESTINAL PEPTIDE (VIP) FOR USE IN THE TREATMENT OF DRUG-INDUCED PNEUMONITIS

Abstract

Checkpoint inhibitor-induced pneumonitis (CIP) is characterized clinically by dyspnea, cough and tachypnea. Hypoxia results from a lymphocyte-dominated alveolitis leading to ground glass opacities and consolidations observed by CT scan. Histological findings include lymphocytic infiltrates, granuloma formation and eosinophilic accumulation. In the management of CIP, systemic administration of steroids such as methylprednisolone is the standard therapy. Moreover, CIP in most cases leads to discontinuation of checkpoint inhibitory therapy and steroids limit the therapeutic effect of checkpoint inhibitors resulting in progression of the underlying malignant disease. Therefore, there is a need of other therapeutic options in CIP that ideally could abrogate the alveolar inflammation induced by checkpoint inhibitors without affecting the systemic effect on the immune system. The focus of the present invention is to deliver a solution to that problem by the topic application of VIP (vasoactive intestinal peptide, a peptide of 28 amino acids). A drug for inhalative VIP therapy is commercially available under the name Aviptadil.

Claims

1. Vasoactive Intestinal Peptide (VIP) for use in the treatment of drug-induced pneumonitis.

2. Vasoactive Intestinal Peptide for use according to claim 1, wherein the drug-induced pneumonitis is a checkpoint inhibitor-induced pneumonitis.

3. Vasoactive Intestinal Peptide for use according to claim 1, wherein the drug-induced pneumonitis is a methotrexate-induced pneumonitis.

4. Vasoactive Intestinal Peptide for use according to any of claims 1 to 3, wherein it is provided in a pharmaceutical composition applicable for inhalation.

5. Vasoactive Intestinal Peptide for use according to claim 4, wherein the pharmaceutical composition is provided in a liquid form.

6. Vasoactive Intestinal Peptide for use according to claim 5, wherein the concentration of Vasoactive Intestinal Peptide in the pharmaceutical composition is from 20 μg/ml to 200 μg/ml, preferably from 35 μg/ml to 140 μg/ml, particularly preferred from 60 μg/ml to 80 μg/ml.

7. Vasoactive Intestinal Peptide for use according to claim 4, wherein the pharmaceutical composition is provided in a solid form.

8. Vasoactive Intestinal Peptide for use according to claim 7, wherein the concentration of Vasoactive Intestinal Peptide in the pharmaceutical composition is from 20 μg/mg to 200 μg/mg, preferably from 35 μg/mg to 140 μg/mg, particularly preferred from 60 μg/mg to 80 μg/mg.

9. Vasoactive Intestinal Peptide for use according to any of claims 1 to 8, wherein a daily dose ranges from 140 μg to 560 μg Vasoactive Intestinal Peptide.

10. A method for the treatment of patients with drug-induced pneumonitis, comprising administering to the patient Vasoactive Intestinal Peptide (VIP).

11. The method according to claim 10, wherein the drug-induced pneumonitis is a checkpoint inhibitor-induced pneumonitis.

12. The method according to claim 10, wherein the drug-induced pneumonitis is a methotrexate-induced pneumonitis.

13. The method according to any of claims 10 to 12, wherein Vasoactive Intestinal Peptide is administered to the patient as an aerosolized pharmaceutical composition by inhalation.

14. The method according to claim 13, wherein a liquid pharmaceutical composition is aerosolized for administration.

15. The method according to claim 14, wherein the concentration of Vasoactive Intestinal Peptide in the liquid pharmaceutical composition is from 20 μg/ml to 200 μg/ml, preferably from 35 μg/ml to 140 μg/ml, particularly preferred from 60 μg/ml to 80 μg/ml.

16. The method according to claim 13, wherein a solid pharmaceutical composition is aerosolized for administration.

17. The method according to claim 16, wherein the concentration of Vasoactive Intestinal Peptide in the solid pharmaceutical composition is from 20 μg/mg to 200 μg/mg, preferably from 35 μg/mg to 140 μg/mg, particularly preferred from 60 μg/mg to 80 μg/mg.

18. The method according to any of claims 10 to 17, wherein a daily dose from 140 μg to 560 μg Vasoactive Intestinal Peptide is administered.

Description

EXAMPLE 1

[0038] Using the M-Neb® dose+ mesh nebulizer MN-300/8 and the respective mouthpiece, VIP has been tested with the COPLEY next generation impactor (NGI). The mass median aerodynamic diameter (MMD) of VIP dissolved in 0.9% NaCl was 3.3-3.5 μm per emitted particle. 85.7% of particles had a diameter <5 μg and the dose delivered at the mouthpiece was 90.2% of the tested dosages.

EXAMPLE 2

[0039] VIP has been tested in 0.9% NaCl solution at different drug concentrations (20 μg/ml, 35 μg/ml, 50 μg/ml, 70 μg/ml, 140 μg/ml, 200 μg/ml, 250 μg/ml, 400 μg/ml). Results show that the respective biological activity is best between 35 μg/ml-140 μg/ml.

EXAMPLE 3

[0040] VIP has been tested in 0.9% NaCl solution at different time points over increasing numbers of breathing cycles. Diseases of the lung parenchyma result in geometric changes in the lung periphery that can minimize the deposition of inhaled particles. The specific breathing by using slow and deep inspiration allows aerosol particles to bypass the upper airways thus making them available for deposition in the lower respiratory tract. The prolonged inspiration allows for suitable settling of aerosols in desired location of the lung. The prolongation of inspiration time and the advanced settling promotes inspiratory deposition before its particles in aerosol can be exhaled. Under these conditions it is possible to have almost 100% of the delivered particles depositing before exhalation begins. Inhalation times between 10 min to 15 min are preferable over short times of inhalation between 2-4 min per treatment because patients can take longer breath cycles.

EXAMPLE 4

[0041] A patient, who was treated with checkpoint inhibitors, developed CIP and steroid treatment led to insufficient control. Because of missing other approved therapeutic options the patient was treated off-label with inhaled VIP therapy initiated at a dose of 4×70 μg/ml per day dosage (280 μg per day with overnight break). With this treatment, the patient's general health ameliorated, his lung function normalized within six months of treatment and the radiological alterations (e.g. consolidations) diminished. Alveolar inflammation as measured by bronchoalveolar lavage was dampened by an increase of regulatory T-cell.

EXAMPLE 5

[0042] A 72 year old female was diagnosed with rheumatoid arthritis according to current guidelines and an immunosuppressive therapy with corticosteroid (15 mg prednisolone/day) and methotrexate (15 mg/week) was started.

[0043] Joint involvement improved within one month and steroid dose was tapered. Shortly after finishing steroid dose the patient complained shortness of breath and cough. Lung function demonstrated a restrictive ventilation defect. A CT scan performed demonstrated wide-spread ground glass opacities with an apical predominance.

[0044] Bronchoscopy was performed that ruled out an underlying infection (including bacterial culture, PCR for influenza, parainfluenza, human metapneumonia virua, respiratory syncytial virus, pneumocystis jirovecii, tuberculosis). Bronchoalveolar lavage demonstrated a lymphocyte predominance and ex-vivo alveolar lymphocytes demonstrated increased proliferation when cultured with methotrexate.

[0045] These findings allow the diagnosis of a methotrexate-induced pneumonitis. Because the patient experienced side effects of previous steroid treatment the patient was treated with inhaled VIP (as depicted in more detail in example 4 above). The inhalation of VIP lead to a clinical amelioration most likely by interfering with the proinflammatory cascade triggered by methotrexate.