US-12616741-B2 - Therapeutic combination comprising a pulmonary surfactant and a steroid for the prophylaxis of BPD

Abstract

Administering a pulmonary surfactant and a corticosteroid in a low dose is effective for the prophylaxis of bronchopulmonary dysplasia (BPD) in preterm neonates.

Inventors

• Alan JOBE
• Augusto SCHMIDT
• Noah HILLMAN
• Matthew KEMP

Assignees

• CHIESI FARMACEUTICI S.P.A.
• CHILDREN'S HOSPITAL MEDICAL CENTER

Dates

Publication Date

20260505

Application Date

20210317

Claims (17)

1. 1 . A method for the prophylaxis of bronchopulmonary dysplasia (BPD) in a preterm neonate, comprising administering to a preterm neonate poractant alfa in a dose of 200 mg/kg of body weight of said neonate and budesonide in a dose of 0.1 mg/kg of body weight of said neonate, wherein said poractant alfa and budesonide are administered from the 1 st to the 4 th day of life of the preterm neonate.
2. 2 . A method according to claim 1 , wherein said preterm neonate is kept under a non-invasive ventilation procedure.
3. 3 . A method according to claim 2 , wherein said non-invasive ventilation procedure is nasal CPAP.
4. 4 . A method according to claim 1 , wherein said poractant alfa and budesonide are administered simultaneously.
5. 5 . A method according to claim 1 , wherein said poractant alfa and budesonide are administered sequentially.
6. 6 . A method according to claim 1 , wherein said poractant alfa and budesonide are administered separately.
7. 7 . A method according to claim 1 , wherein said poractant alfa and budesonide are administered separately.
8. 8 . A method according to claim 1 , wherein said poractant alfa and budesonide are administered in the form of an aqueous suspension comprising a pharmaceutically acceptable carrier.
9. 9 . A method according to claim 1 , wherein said preterm neonate is of a gestational age of 26 to 35 weeks.
10. 10 . A method according to claim 1 , wherein said preterm neonate is of a gestational age of 28 to 32 weeks.
11. 11 . A method according to claim 1 , wherein: said preterm neonate is kept under a non-invasive ventilation procedure; said non-invasive ventilation procedure is nasal CPAP; said preterm neonate is of a gestational age of 26 to 35 weeks; and said budesonide and said poractant alfa exhibit a synergistic effect.
12. 12 . A method according to claim 11 , wherein said preterm neonate is of a gestational age of 28 to 32 weeks.
13. 13 . A method according to claim 11 , wherein said poractant alfa and budesonide are administered simultaneously.
14. 14 . A method according to claim 11 , wherein said poractant alfa and budesonide are administered sequentially.
15. 15 . A method according to claim 11 , wherein said preterm neonate is of a gestational age of 28 to 32 weeks and said poractant alfa and budesonide are administered simultaneously.
16. 16 . A method according to claim 11 , wherein said preterm neonate is of a gestational age of 28 to 32 weeks and said poractant alfa and budesonide are administered sequentially.
17. 17 . A method of reducing lung inflammation in a pre-term neonate treated with mechanical ventilation, comprising the step of administering a composition to said pre-term neonate, wherein said administration occurs during, before, or after said mechanical ventilation, and wherein the composition comprises: (a) poractant alfa in a dose of 200 mg/kg of body weight of said neonate; in combination with (b) budesonide in a dose of 0.1 mg/kg of body weight of said neonate.

Description

CROSS REFERENCES TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62/661,245, filed on Apr. 23, 2018, and U.S. Provisional Patent Application No. 62/751,830, filed on Oct. 29, 2018, both of which are incorporated herein by reference in their entireties. BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to compositions for the prophylaxis of diseases of prematurity. The present invention also relates to methods for the prophylaxis of diseases of prematurity. Discussion of the Background The human lung is composed of a large number of small air sacs, called alveoli, in which gases are exchanged between the blood and the air spaces of the lungs. In healthy individuals, this exchange is mediated by the presence of a protein-containing surfactant complex that prevents the lungs from collapsing at the end of expiration. The lung surfactant complex is composed primarily of lipid and contains minor amounts of various proteins. An absence of adequate levels of this complex results in malfunction of the lungs. This syndrome is called Respiratory Distress Syndrome (RDS) and it commonly affects preterm neonates. The mainstay of the treatment of RDS is the replacement therapy with exogenous pulmonary surfactant preparations extracted from animal lungs, known as modified natural surfactants. For instance, modified natural surfactants used in the clinical practice are poractant alfa derived from porcine lung, and sold under the trademark of Curosurf®, beractant (Surfacten® or Survanta®) bovactant (Alveofact®), both derived from bovine lung, and calfactant derived from calf lung (Infasurf®). Exogenous pulmonary surfactants are currently administered by endotracheal instillation as a suspension in a saline aqueous solution to intubated pre-term infants kept under mechanical ventilation with oxygen. Although said therapy has greatly increased postnatal survival, children that survive RDS have a high risk of developing broncho-pulmonary dysplasia (BPD), a common and serious complication of prematurity, associated with significant mortality, morbidity and healthcare resource utilization. Despite advances in both prenatal and neonatal care the incidence of the condition continues to rise. The management of BPD and its related problems remains a major challenge for neonatologists and pediatricians. Multiple interventions have been proposed to prevent and treat BPD but many are still not evidence based. Current treatments appear to have reduced the severity of BPD but have had little effect on its incidence. BPD is an evolving process of lung injury and its pathophysiology varies at different stages of the disease. Its management therefore is unlikely to be in the form of a single intervention but rather a combined approach with different strategies used to target different factors and/or stages of the disease. For this reason, it is useful to categorize intervention for BPD at three subsequent stages when designing an overall management plan. These are: i) prevention of BDP; ii) treatment of evolving BPD; and iii) treatment of established BPD (see Bowen P et al Pediatrics and Child Health 2013, 24:1, 27-31, which is incorporated herein by reference in its entirety). The prevention of BPD in neonates affected by RDS has been managed by systemic administration of a corticosteroid, antenatal or within few hours postnatal. However, the effectiveness of postnatal corticosteroid administration is offset by possible adverse systemic effects, e.g., hypertension, hyperglycemia, gastrointestinal complications, and neurodevelopmental disability. As an alternative to systemic administration, delivery of corticosteroid by inhalation or intracheal instillation has been proposed for the prophylaxis of BDP. For example, US 2010/0317636, which is incorporated herein by reference in its entirety, discloses a method for the prophylaxis of BPD in an infant suffering from respiratory distress syndrome by administering to the infant a combination of a corticosteroid having a high local to systemic anti-inflammatory activity and a lung surfactant. Yeh et al (Pediatrics 2008, 121 (5), e1310-e1318, which is incorporated herein by reference in its entirety) proposed the intratracheal instillation of budesonide using the pulmonary surfactant Survanta® as a carrier, while Dani et al (Pediatr Pulmonol 2009, 44, 1159-1167, which is incorporated herein by reference in its entirety) have proposed the intratracheal instillation of beclometasone dipropionate in combination with Cursourf®. However, through these approaches as well, a large population of preterm neonates would be exposed to corticosteroids, many without benefit if otherwise they would not develop BPD (see Bancalari E Am J Respir Crit Care Med 2016, 193:1, 12, which is incorporated herein by reference in its entirety). Postnatal corticosteroids could find their place in therapy in the prevention of BPD as in this way