A method for treating premature neonates by administering recombinant human surfactant protein D (rhSP-D).

Abstract

A method for shortening the duration of mechanical ventilation in premature infants at risk of developing bronchopulmonary dysplasia (BPD) includes administering an effective amount of recombinant human surfactant protein D (rhSP-D) to the infant. In a further embodiment, a method for shortening the length of hospital stay in premature infants at risk of developing BPD includes administering an effective amount of rhSP-D to the infant. In a specific embodiment, a method for reducing the probability that premature infants at risk of developing BPD will develop one or more secondary complications due to preterm birth includes administering an effective amount of recombinant human surfactant protein D (rhSP-D) to the infant. Pharmaceutical compositions for use in the described methods and uses of the pharmaceutical compositions are also described.

Description

Technical Field

[0001] The present disclosure relates to the field of medical treatment, and particularly to advanced treatments aimed at improving respiratory function, reducing inflammation, curing infections, and reducing the dependence on mechanical ventilation for patients suffering from respiratory diseases. In a specific aspect, the present disclosure relates to a method and composition for shortening the length of hospital stay of premature infants by administering rhSP-D in neonatal care therapy.

Background Art

[0002] Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity, resulting in significant morbidity and mortality. BPD is a multifactorial chronic lung disease that affects extremely premature infants (gestational age (GA) less than 29 weeks). BPD is thought to occur as a result of incomplete or abnormal lung development due to prematurity, injury, infection, and inflammation, resulting in simplified large alveoli, thereby causing abnormal and inefficient gas exchange and impaired lung mechanics. Multiple risk factors before and after birth, including mechanical ventilation, oxygen toxicity, intrauterine fetal growth retardation, lung immaturity, respiratory microbiota dysbiosis, vascular events such as patent ductus arteriosus (PDA), and infection, affect the onset of BPD. Demographic risk factors for BPD include male sex, low birth weight, growth impairment of GA, and family history of asthma. BPD is associated with long-term hospital stays in the neonatal period, growth retardation, as well as long-term outcomes such as lung function impairment, neurodevelopmental disorders, reduced quality of health-related life, and increased medical costs. In the United States, the median annual hospitalization cost for infants with BPD is 2.4 times that of infants without BPD.

[0003] BPD remains a significant unresolved issue in premature infants. Globally, the morbidity of BPD is reported to be 17-75% in very premature infants (GA less than 29 weeks), and the incidence of BPD is inversely proportional to GA. In recent years, advances in the clinical management of premature infants have improved survival rates and increased BPD morbidity. Current clinical management of very premature newborns may involve prenatal steroid administration to the pregnant mother, postnatal surfactant therapy, postnatal steroid administration, combination therapy with surfactant and steroids, caffeine therapy, vitamin A administration, and avoidance of unnecessary mechanical ventilation. However, none of these are labeled as treatments or preventive measures for BPD.

[0004] Premature infants born at 29 weeks of gestation or earlier often require prolonged hospitalization (e.g., in a neonatal intensive care unit or NICU) due to underdeveloped organs and complications associated with premature birth. These complications may include respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis, and sepsis. Prolonged hospitalization in the NICU not only increases the risk of hospital-acquired infections and stress for the infant and their family, but also leads to a significant increase in healthcare costs. Therefore, interventional treatments are needed that can safely shorten the duration of NICU stay by addressing the underlying physiological challenges faced by premature infants.

[0005] Mechanical ventilation is the primary intervention for neonates experiencing respiratory distress or respiratory failure, a common condition in premature babies. While mechanical ventilation plays a life-saving role, prolonged use can lead to numerous negative outcomes, including ventilator-associated lung injury, bronchopulmonary dysplasia, chronic lung disease, pneumonia, weakened diaphragmatic function, and other complications with increased morbidity. Therefore, innovative interventions are needed that can shorten the duration of mechanical ventilation, thereby reducing associated risks and improving outcomes for neonatal patients.

[0006] Commercially available surfactant preparations are essential for lung function by regulating the immune response and breaking the vicious cycle of injury and inflammation while reducing inflammation and infection in the body. Commercial surfactant preparations containing phospholipids such as surfactant protein B (SP-B) and surfactant protein C (SP-C) contribute to a decrease in surface tension, thereby preventing alveolar collapse necessary for effective respiratory function. Conventional commercially available surfactant preparations do not contain surfactant protein D (SP-D). While the therapeutic potential of surfactant protein administration has been recognized in certain patient populations, methods for improving lung health in premature infants and reducing the need for long-term mechanical support have not yet been demonstrated.

[0007] These and other shortcomings are addressed in accordance with the nature of this disclosure. [Overview of the project]

[0008] This disclosure introduces novel therapeutic methods and pharmaceutical compositions for the administration of rhSP-D to premature infants requiring mechanical ventilation, with the aim of shortening the duration of hospital stay (e.g., NICU) for these infants. Specifically, this disclosure provides a method for shortening the duration (in days) of mechanical ventilation required for premature infants by administering an effective dose of rhSP-D. Furthermore, it also aims to mitigate bronchopulmonary dysplasia (BPD). This method involves the delivery of rhSP-D to patients receiving mechanical ventilation due to respiratory failure of any cause. This disclosure further encompasses pharmaceutical compositions containing rhSP-D. In some embodiments, rhSP-D is formulated for delivery by intratracheal, endotracheal, inhalation, or spray methods. Compositions containing rhSP-D (known as zerplutide alfa) have been shown to promote lung maturation by compensating for deficiencies in native SP-D levels in the lungs of premature infants, enhance lung function by compensating for deficiencies in native SP-D levels in premature infants, reduce inflammation, improve overall health markers in premature infants, thereby shortening the duration of mechanical ventilation by facilitating early extubation from mechanical ventilation and facilitating early discharge from the hospital / NICU. In certain embodiments, the infants are premature infants born at 29 weeks of gestation or less.

[0009] In specific cases, methods for shortening the duration of mechanical ventilation in premature infants at risk of developing bronchopulmonary dysplasia (BPD) include administering an effective amount of recombinant human surfactant protein D (rhSP-D) to the infant.

[0010] In a further embodiment, a method for shortening the length of hospital stay for premature infants at risk of developing BPD includes administering an effective dose of rhSP-D to the infant.

[0011] In certain embodiments, a method for reducing the probability that a premature infant at risk of developing BPD will develop one or more secondary complications due to premature birth includes administering an effective amount of recombinant human surfactant protein D (rhSP-D) to the infant.

[0012] In specific embodiments, the Disclosure relates to the use of a pharmaceutical composition in (1) shortening the duration of mechanical ventilation in premature infants at risk of developing bronchopulmonary dysplasia (BPD), (2) shortening the length of hospital stay in premature infants at risk of developing BPD, or (3) reducing the probability that premature infants at risk of developing BPD will develop one or more secondary complications due to premature birth, wherein the pharmaceutical composition comprises recombinant human surfactant protein D (rhSP-D). [Brief explanation of the drawing]

[0013] In drawings that are not necessarily drawn to scale, similar symbols may describe similar components from different viewpoints. Similar symbols with different letter suffixes may represent different examples of similar components. In drawings, the various embodiments discussed herein are shown generally as examples, and are not limiting.

[0014] [Figure 1A] Figure 1A is a study diagram illustrating the study stages used in embodiments of this disclosure. Initially, eight subjects (GA weeks 25–28, 6 / 7 days) were randomized in a 3:1 ratio, so that six subjects received standard care (SOC) and up to two doses of zelpultide alfa intratracheally administered at each dose level starting at 2 mg / kg (2 mg / kg, 4 mg / kg, or 6 mg / kg, Figure 1A), and two subjects received SOC and up to two doses of air-sham (1 mL of air aspirated into an intratracheal infusion syringe). The dosing interval was 24 hours. Twelve additional subjects (GA weeks 23–28, 6 / 7 days) were randomized in a 3:1 ratio to receive either the maximum tolerable dose of zelpultide alfa or air-sham once daily for up to seven days. Dose-restriction toxicity (DLT) was a determinant of whether new subjects could receive relatively high doses of zelpultide alfa and whether additional subjects would be enrolled in the study thereafter. If a DLT event occurred, continued administration to the individual was temporarily suspended and the individual was transferred to a dose-response care monitor (DSMC).

[0015] [Figure 1B] Figure 1B is a flowchart of 38 randomized premature neonatal patients included in the treatment intention analysis.

[0016] [Figure 2A] Figure 2A is a graph showing the duration (in days) of mechanical ventilation in subjects treated with zelpultide alfa and subjects treated with airsham at 36 weeks postmenstrual (PMA). A total of 30 patients (21 treated with zelpultide alfa and 9 treated with airsham) reached 36 weeks PMA. At 36 weeks PMA, the duration of mechanical ventilation was reduced in subjects treated with zelpultide alfa and subjects treated with airsham (17.7 days and 25.8 days, respectively).

[0017] [Figure 2B] Figure 2B is a graph showing the percentage of survivors receiving mechanical ventilation at each study time point. For zerplutide alfa, there were 28, 26, 23, and 22 survivors on days 1, 7, 28, and 36 weeks post-majority (PMA), respectively. For aersham, there were 9 survivors among all patients who visited the hospital. Subjects who died were excluded. Subjects treated with zerplutide alfa had a lower percentage of mechanical ventilation at 36 weeks post-majority (PMA) compared with those treated with aersham.

[0018] [Figure 3] Figure 3 is Table I, which shows the baseline demographics and characteristics of the subjects included in the study.

[0019] [Figure 4] Figure 4 is Table II, which summarizes adverse events (AEs) and serious adverse events (SAEs). For each treatment, the number of patients who experienced AEs and SAEs from the initial treatment to week 36 of the post-treatment period (PMA) is shown as a percentage in parentheses.

[0020] [Figure 5A]Figure 5A shows a table (III.A follows Table III.B) of AEs reported in more than 10% of subjects in any treatment group from the first treatment to 36 weeks PMA. The number of patients experiencing an AE in each treatment group is represented as the percentage in parentheses. [Figure 5B] Figure 5B shows a table (III.A follows Table III.B) of AEs reported in more than 10% of subjects in any treatment group from the first treatment to 36 weeks PMA. The number of patients experiencing an AE in each treatment group is represented as the percentage in parentheses.

[0021] [Figure 6] Figure 6 is Table IV showing SAE reported from the first treatment to 36 weeks PMA in any treatment group. The number of patients experiencing an SAE in each treatment group is represented as the percentage in parentheses.

[0022] [Figure 7] Figure 7 is Table V showing the primary efficacy outcomes including the incidence or mortality of BPD at 36 weeks PMA in all zelplotide alpha and air sham treatment groups. The definition and classification of BPD are based on Jensen et al. (2019).

[0023] [Figure 8] Figure 8 is Table VI showing additional outcomes and co - morbidities that occurred in any treatment group from the first treatment to 36 weeks PMA. The number of patients experiencing an outcome and co - morbidity in each treatment group is represented as the percentage in parentheses, except for the number of hospital days expressed as mean (SD). For the mean number of hospital days, the number of hospital days was recalculated excluding the subjects who died. Data from 6 subjects who died by 36 weeks PMA were excluded from the analysis. As a result, it was 87.2 days (±24.1, n = 21) in the total zelplotide alpha group and 90.2 days (±21.1, n = 9) in the air sham group.

[0024] [Figure 9]Figure 9 is Table VII, showing the pharmacokinetics of zelpultide alfa (ng / mL) and aersham, and illustrating the change from baseline in SP-D blood concentration on day 1 in each treatment group.

[0025] [Figure 10A] Figure 10A shows Tables VIII.A and VIII.B, which represent the dosages of treatment received by premature neonates in the first (Table VIII.A) and second (Table VIII.B) phases of the Phase 1b trial. [Figure 10B] Figure 10B shows Tables VIII.A and VIII.B, which represent the dosages of treatment received by premature neonates in the first (Table VIII.A) and second (Table VIII.B) phases of the Phase 1b trial.

[0026] [Figure 11] Figure 11 is Table IX, showing the morbidity or mortality rate of bilateral pulmonary disease (BPD) and the number of days of mechanical ventilation from initial treatment to week 36 of post-treatment malabsorption (PMA) for each treatment group and the overall zelpultide alfa group. The number of patients who experienced BPD or death in each treatment group is shown as a percentage in parentheses.

[0027] [Figure 12] Figure 12 is Table X, showing the grade of BPD or mortality for each treatment group and the overall zelpultide alfa group from initial treatment to week 36 of PMA. The number of patients with BPD of each grade or who died in each treatment group is shown as a percentage in parentheses.

[0028] [Figure 13] Figure 13 is Table XI, showing the average number of days of mechanical ventilation for each treatment group and the entire zelpultide alfa group from the initial treatment to week 36 of PMA. Data for subjects who survived to week 36 of PMA and did not drop out of follow-up are shown. [Modes for carrying out the invention]

[0029] Various combinations of the elements of this disclosure, for example, combinations of elements of dependent claims that depend on the same independent claim, are included in this disclosure.

[0030] Furthermore, unless otherwise explicitly stated, it should be understood that no method described herein is ever intended to be construed as requiring its steps to be performed in a specific order. Therefore, if a claim for a method does not actually specify the order in which its steps should be followed, or if there is no other specific statement in a claim or description limiting the steps to a particular order, no order should ever be inferred in any way. This applies to all possible non-obvious grounds for interpretation, including logical matters relating to the arrangement or flow of the steps, plain meaning derived from grammatical construction or punctuation, and the number or type of embodiments described in the specification.

[0031] All publications referenced herein are incorporated herein by reference and disclose and explain methods and / or materials related to those cited herein. definition

[0032] Furthermore, it should be understood that the terms used herein are intended solely to describe specific aspects and are not intended to be restrictive. As used herein and in the claims, the term “including” includes the aspects of “consisting of” and “essentially consisting of.” Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this disclosure belongs. Several terms that should be defined herein are referred to herein and in the claims.

[0033] As used herein and in the appended claims, the singular forms “one,” “one person,” and “the” include plural referents unless the context explicitly indicates otherwise.

[0034] As used herein, the term “combination” includes blends, mixtures, alloys, reaction products, and the like.

[0035] In this specification, a range may be expressed as a range from one value (the first value) to another value (the second value). When such a range is expressed, it includes, in some embodiments, one or both of the first and second values. Similarly, when a value is expressed as an approximation using the antecedent “about,” it will be understood that a particular value forms another aspect. It will also be understood that each endpoint of a range is important both in relation to and independently of the other endpoint. Furthermore, it will be understood that multiple values ​​are disclosed in this specification, and each value is disclosed not only as the value itself but also “approximately” that particular value. For example, when the value “10” is disclosed, “about 10” is also disclosed. It will also be understood that each unit between two particular units is disclosed. For example, when 10 and 15 are disclosed, 11, 12, 13, and 14 are also disclosed.

[0036] As used herein, the terms “about” and “at or about” mean that the quantity or value in question may be approximately equal to, or nearly identical to, a specified value. As used herein, unless otherwise indicated or inferred, it is generally understood to mean a deviation of ±10% of the stated nominal value. The term is intended to convey that similar values ​​will facilitate equivalent results or effects described in the claims. That is, quantities, sizes, formulations, parameters, and other quantities and characteristics are not, and do not need to be, exact, but can be approximate and / or larger or smaller as necessary to reflect tolerances, conversion factors, rounding, measurement errors, and other factors known to those skilled in the art. In general, quantities, sizes, formulations, parameters, or other quantities or characteristics are “approximate” or “approximate,” whether explicitly stated so or not. When “about” is used before a quantitative value, unless otherwise specifically stated, it is understood that the parameter also includes the specific quantitative value itself.

[0037] As used herein, the term “effective dose” refers to an amount sufficient to achieve the desired outcome. For example, the “effective dose” of recombinant human surfactant protein D (rhSP-D) may refer to an amount sufficient to achieve a desired reduction in mechanical ventilation, a reduction in hospital stay, or a reduction in secondary complications. The specific level required as an effective dose (concentration, frequency of administration, duration of administration, etc.) depends on various factors.

[0038] Bronchopulmonary dysplasia (BPD) may be assessed when the infant reaches 36 weeks postmenstrual (PMA) (as assessed in subjects of the studies described herein). This is the point at which a premature infant is considered to have reached full term. This is calculated as 36 weeks when the sum of gestational age (time elapsed since birth) and chronological age (time elapsed since birth) is 36 weeks. Criteria for assessing BPD are described in Jensen et al. (Jensen EA, Dysart K, Gantz MG et al., The Diagnosis of Bronchopulmonary Dysplasia in Very Preterm Infants. An Evidence-based Approach. Am J Respir Crit Care Med. 2019;200(6):751-9) ("Jensen"), the disclosures of which are incorporated herein by reference in their entirety. BPD assessments of infants who have reached 36 weeks PMA are recorded as one of the following: [Table 1]

[0039] Jensen et al. (2019) recommend the following BPD definition and grading system, and all subjects who reach 36 weeks of PMA are recorded as one of the following: [Table 2]

[0040] Zelpultide alfa (formerly AT-100) is a novel biotechnology therapy under development for the prevention of bipolar disorder (BPD) in premature newborns, utilizing recombinant human surfactant protein D (rhSP-D) as its active ingredient. Current surfactant therapies for respiratory distress syndrome do not include surfactant protein D (SP-D), which is involved in the normal surfactant lipid structure and lipid recycling. SP-D helps regulate the innate immune response of the lungs by eliminating infectious pathogens and suppressing lung inflammation and inflammatory injury. It is hypothesized that treatment of premature newborns with Zelpultide alfa may reduce lung injury and inflammation, thus shortening the time required for respiratory support and potentially leading to a reduction in BPD morbidity.

[0041] The studies described herein aimed to evaluate three dose levels of zelpultide alfa that maximized the benefit-risk ratio in very premature neonates at high risk of developing bipolar disorder (BPD). The primary objective was to establish the safety and tolerability profile of the optimal dose of zelpultide alfa. Secondary objectives included evaluating preliminary efficacy outcomes, including BPD morbidity or mortality, time requiring mechanical ventilation, and complications due to preterm birth. Exploratory objectives included lung injury and changes in inflammatory mediators potentially associated with BPD. Composition of Zerpultide Alpha

[0042] The rhSP-D used in this disclosure is synthesized by recombinant DNA technology to ensure high purity and consistent bioactivity. The composition is formulated with pharmaceutically acceptable buffers and other components as shown below to make it suitable for administration to neonatal patients. As an example, zerplutide alfa is selected as a novel recombinant version of the endogenous human protein hSP-D and is synthesized and formulated for administration to premature infants. The composition contains zerplutide alfa in a pharmaceutically acceptable buffer, tailored to the sensitive physiological functions of premature infants. The formulation is designed for intratracheal administration, endotracheal administration, inhalation, spray administration, or, where possible, other routes of administration suitable for neonates.

[0043] Specifically, Zerpultide alfa is a recombinant version of the endogenous human protein hSP-D, a protein known to modulate the immune response and break the cycle of injury and inflammation while reducing lung inflammation and infection. Zerpultide alfa is manufactured as a dry powder but is reconstituted into a liquid before administration and is configured for intratracheal, endotracheal, inhalation, or spray administration. The liquid composition contains rhSP-D or its active fragment, a buffer, a sugar, and a calcium salt. The buffer is histidine, the sugar is lactose, and the calcium salt is calcium chloride (CaCl2). Specifically, Zerpultide alfa contains 4 mg / mL of rhSP-D, 5 mM histidine, 265 mM lactose, and 5 mM calcium chloride. The pH of the solution is 6.0. The dosages of zelpultide alfa described herein (e.g., 2 mg / kg, 4 mg / kg, and 6 mg / kg) refer to the amount of the active ingredient rhSP-D administered per kg of the subject's birth weight at each dose.

[0044] Specific compositions containing rhSP-D are described in International Publication No. WO2019191247, the disclosure of which is incorporated herein by reference in its entirety. Method of administration

[0045] This method involves administering rhSP-D to neonatal patients receiving mechanical ventilation. Administration can be achieved intratracheal, endotracheal, inhalation, or nebulization, and the administration regimen is optimized specifically for the neonatal population based on patient weight. Clinical effectiveness

[0046] As shown in the results provided herein, in clinical trials involving premature infants born at 29 weeks of gestation or less, it has been demonstrated that premature infants treated with rhSP-D, i.e., zerplutide alfa, had shorter hospital stays / NICU stays and shorter durations of mechanical ventilation compared to premature infants receiving standard care. Infants treated with zerplutide alfa showed improved respiratory function, including reduced morbidity and severity of BPD, and in some aspects were able to be discharged earlier. Furthermore, infants experienced reduced morbidity of complications associated with premature birth and / or mechanical ventilation (including long-term steroid use, pneumonia, pulmonary hypertension, NEC, and grade 2 intraventricular hemorrhage). Overall, health outcomes were relatively favorable. Mechanism of action

[0047] Zerpultide alfa enhances neonatal lung health by promoting maturation of underdeveloped lungs in premature infants, facilitating cell repair mechanisms, enhancing immune function, reducing systemic inflammation, mitigating infections, and improving overall lung function. This approach addresses key challenges faced by premature infants, leading to faster progress in health improvement and discharge from the hospital / NICU, more efficiently promoting the recovery of damaged lung tissue, and leading to earlier resolution of underlying respiratory distress or respiratory failure, resulting in a reduced need for prolonged mechanical ventilation. Treatment methods for premature babies at risk of developing bipolar disorder (BPD)

[0048] Aspects of this disclosure relate to a method for shortening the duration of mechanical ventilation in premature infants at risk of developing bronchopulmonary dysplasia (BPD), the method comprising administering an effective amount of recombinant human surfactant protein D (rhSP-D) to the infant.

[0049] As demonstrated in the examples provided herein, the median duration of mechanical ventilation in infants treated with standard Aersham care is 25 days, and the mean duration is 25.8 days. Thus, in some embodiments, the reduction in the duration of mechanical ventilation is at least 1 day. In further embodiments, the reduction in the duration of mechanical ventilation is 1 to 12 days, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, up to 12 days, up to 11 days, up to 10 days, up to 9 days, or up to 8 days.

[0050] In a further embodiment, the disclosure relates to a method for reducing the length of hospital stay for premature infants at risk of developing BPD, the method comprising administering an effective dose of rhSP-D to the infant.

[0051] As demonstrated in the embodiments provided herein, the median length of hospital stay for infants treated with Ayrsham standard care is 90.2 days. Therefore, in certain embodiments, the reduction in length of hospital stay is at least 1 day. In certain embodiments, the reduction in length of hospital stay is from 1 to 30 days, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, up to 30 days, up to 29 days, up to 28 days, up to 27 days, up to 26 days, up to 25 days, up to 24 days, up to 23 days, up to 22 days, up to 21 days, or up to 20 days.

[0052] In some embodiments, a method for reducing the probability that a premature infant at risk of developing BPD will develop one or more secondary complications due to premature birth includes administering an effective amount of recombinant human surfactant protein D (rhSP-D) to the infant.

[0053] One or more secondary complications due to premature birth include, but are not limited to, steroid use, radiographically confirmed pneumonia, retinopathy of prematurity (ROP), pulmonary hypertension, necrotizing enterocolitis (NEC), grade 2 intraventricular hemorrhage (IVH), or a combination thereof.

[0054] In a further embodiment, the reduction in probability is at least 10%. In a specific embodiment, the reduction in probability is at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100%. The reduction in probability may be calculated by comparing the probability that an infant receiving standard treatment develops one or more secondary complications (e.g., 90%) with the probability that an infant treated with rhSP-D according to the method described herein develops one or more secondary complications (e.g., 10%). In this example, the reduction in probability is (90-10) / 90*100, or 88%.

[0055] In some embodiments, rhSP-D is zerplutide alpha.

[0056] rhSP-D may be administered intratracheally, endotracheally, by inhalation, or by spray.

[0057] In certain aspects, premature infants at risk of developing BPD are those born at 29 weeks of gestation or earlier. In further aspects, premature infants at risk of developing BPD are those born at 28 weeks of gestation or earlier, 27 weeks or earlier, 26 weeks or earlier, 25 weeks or earlier, 24 weeks or earlier, 23 weeks or earlier, or 22 weeks or earlier.

[0058] In certain aspects, premature infants at risk of developing bipolar disorder (BPD) are those who require respiratory support after birth. In some aspects, respiratory support is invasive. An example of invasive respiratory support is the use of an endotracheal tube.

[0059] In further embodiments, the effective dose of rhSP-D includes doses ranging from 1 milligram / kilogram (mg / kg) to 10 mg / kg / day over a period of 1 to 10 days. In specific embodiments, the dose is 1 mg / kg / day, 2 mg / kg / day, 3 mg / kg / day, 4 mg / kg / day, 5 mg / kg / day, 6 mg / kg / day, 7 mg / kg / day, 8 mg / kg / day, 9 mg / kg / day, or 10 mg / kg / day. In specific embodiments, the period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 10 days. As used herein, the dose in "mg / kg" refers to the number of milligrams of the active ingredient (e.g., rhSP-D) per kilogram of birth weight of an infant.

[0060] Further aspects of this disclosure relate to pharmaceutical compositions for use in any of the methods described herein.

[0061] Further aspects of this disclosure relate to the use of a pharmaceutical composition in (1) shortening the duration of mechanical ventilation in premature infants at risk of developing bronchopulmonary dysplasia (BPD), or (2) shortening the length of hospital stay in premature infants at risk of developing BPD, wherein the pharmaceutical composition comprises recombinant human surfactant protein D (rhSP-D).

[0062] Further aspects of this disclosure relate to the use of a pharmaceutical composition in (1) shortening the duration of mechanical ventilation in premature infants at risk of developing bronchopulmonary dysplasia (BPD), (2) shortening the length of hospital stay in premature infants at risk of developing BPD, or (3) reducing the probability that premature infants at risk of developing BPD will develop one or more secondary complications due to premature birth, wherein the pharmaceutical composition comprises recombinant human surfactant protein D (rhSP-D).

[0063] Various combinations of the elements of this disclosure, for example, combinations of elements of dependent claims that depend on the same independent claim, are included in this disclosure. The nature of this disclosure

[0064] In various aspects, this disclosure relates to, and includes, at least the following aspects:

[0065] Embodiment 1 A method for shortening the duration of mechanical ventilation in a premature infant at risk of developing bronchopulmonary dysplasia (BPD), comprising administering an effective amount of recombinant human surfactant protein D (rhSP-D) to the infant.

[0066] Embodiment 2: The method according to Embodiment 1, wherein the reduction in the duration of mechanical ventilation is at least one day.

[0067] Embodiment 2A The method according to Embodiment 1 or 2, wherein the reduction is relative to the 25-day duration in infants treated with standard Aersham treatment.

[0068] Aspect 3: A method for shortening the length of hospital stay for premature infants at risk of developing bipolar disorder, comprising administering an effective amount of rhSP-D to the infant.

[0069] Embodiment 4: The method according to Embodiment 3, wherein the reduction in the length of hospital stay is at least one day.

[0070] Embodiment 4A The method according to Embodiment 3 or 4, wherein the reduction is relative to the 90-day duration in infants treated with standard Aersham treatment.

[0071] Embodiment 5 A method for reducing the probability that a premature infant at risk of developing BPD will develop one or more secondary complications due to premature birth, comprising administering an effective amount of recombinant human surfactant protein D (rhSP-D) to the infant.

[0072] Embodiment 6: The method according to Embodiment 5, wherein one or more secondary complications due to premature birth include steroid use, radiographically confirmed pneumonia, retinopathy of prematurity (ROP), pulmonary hypertension, necrotizing enterocolitis (NEC), grade 2 intraventricular hemorrhage (IVH), or a combination thereof.

[0073] Embodiment 7 The method according to Embodiment 5 or 6, wherein the probability reduction is at least 10%.

[0074] Embodiment 8 The method according to any one of Embodiments 1 to 7, wherein rhSP-D is zelpultide alpha.

[0075] Embodiment 9 The method according to any one of Embodiments 1 to 8, wherein rhSP-D is administered intratracheally, endotracheally, by inhalation, or by spray.

[0076] Embodiment 10: The method according to any one of Embodiments 1 to 9, wherein the premature infant at risk of developing BPD is an infant born at 29 weeks of gestation or less.

[0077] Embodiment 11: The method according to any one of Embodiments 1 to 10, wherein a premature infant at risk of developing BPD is an infant who requires respiratory support after birth.

[0078] Embodiment 12: The method according to Embodiment 11, wherein the respiratory support is invasive respiratory support.

[0079] Embodiment 13 The method according to Embodiment 12, wherein invasive respiratory support includes the use of an endotracheal tube.

[0080] Embodiment 14 The method according to any one of Embodiments 1 to 13, wherein the effective dose of rhSP-D is a dose ranging from 1 milligram / kilogram (mg / kg) to 10 mg / kg / day over a period of 1 to 10 days.

[0081] Applicable aspect 15 A pharmaceutical composition for use in the method described in any one of Applicable aspects 1 to 14.

[0082] Aspect 16: Use of a pharmaceutical composition in (1) shortening the duration of mechanical ventilation for premature infants at risk of developing bronchopulmonary dysplasia (BPD), (2) shortening the length of hospital stay for premature infants at risk of developing BPD, or (3) reducing the probability that premature infants at risk of developing BPD will develop one or more secondary complications due to premature birth, Use of a pharmaceutical composition containing recombinant human surfactant protein D (rhSP-D).

[0083] Embodiment 17: The use according to Embodiment 16, wherein the reduction in the duration of mechanical ventilation is at least one day.

[0084] Embodiment 18: The use described in Embodiment 16 or 17, wherein the reduction in the length of hospital stay is at least one day.

[0085] Apparatus 19: The use according to any one of Apparatus 16 to 18, wherein one or more secondary complications due to premature birth include the use of steroids, radiographically confirmed pneumonia, retinopathy of prematurity (ROP), pulmonary hypertension, necrotizing enterocolitis (NEC), grade 2 intraventricular hemorrhage (IVH), or a combination thereof.

[0086] Embodiment 20: The use according to any one of Embodiments 16 to 19, wherein the reduction in probability is at least 10%.

[0087] Embodiment 21: The use according to any one of Embodiments 16 to 20, wherein rhSP-D is zelpultide alpha.

[0088] Embodiment 22: The use of rhSP-D according to any one of Embodiments 16 to 21, wherein rhSP-D is administered intratracheally, endotracheally, by inhalation, or by spray.

[0089] Applicable aspect 23: The use described in any one of Applicable aspects 16 to 22, wherein premature infants at risk of developing BPD are infants born at 29 weeks of gestation or less.

[0090] Applicable aspect 24: The use described in any one of Applicable aspects 16 to 23, wherein a premature infant at risk of developing BPD is an infant who requires respiratory support after birth.

[0091] Embodiment 25: The respiratory support is invasive respiratory support, as described in Embodiment 24.

[0092] Embodiment 26: The use of invasive respiratory support as described in Embodiment 25, including the use of an endotracheal tube.

[0093] Embodiment 27: The use of rhSP-D as described in any one of Embodiments 16 to 26, in which the dose is administered over a period of 1 to 10 days at a dose of 1 milligram / kilogram (mg / kg) to 10 mg / kg / day. Examples

[0094] The following examples are provided to give a complete disclosure and description of how the compounds, compositions, articles, apparatus, and / or methods claimed herein are constructed and evaluated, and are purely illustrative and not intended to limit the disclosure. While efforts have been made to ensure accuracy with respect to numerical values ​​(e.g., quantities, temperatures, etc.), some errors and deviations should be taken into account. Unless otherwise indicated, parts are parts by weight, temperatures are °C or ambient temperature, and pressures are atmospheric pressure or near atmospheric pressure. Unless otherwise indicated, percentages of a composition are given in wt%.

[0095] Reaction conditions, such as component concentrations, desired solvents, solvent mixtures, temperature, pressure, and other reaction ranges and conditions, have numerous variations and combinations that can be used to optimize the purity and yield of the product obtained from the described process. Optimizing such process conditions requires only reasonable and conventional experiments.

[0096] This example relates to a study titled "Phase Ib Randomized Multicenter Dose-Determining Study of Zelpultide Alfa (rhSP-D) in Premature Neonatal Patients at High Risk of Developing Bronchopulmonary Dysplasia (BPD)."

[0097] The objective of the Phase 1b study (clinical safety study) was to evaluate the safety and tolerability of different doses of zelpultide alfa in addition to standard care, compared to aersham, in premature neonates at risk of bronchopulmonary dysplasia (BPD). Efficacy was a secondary outcome.

[0098] This study was designed as a randomized, double-blind, dose-determining study enrolling premature neonates who required at least one surfactant treatment within 96 hours of birth and underwent intubation and mechanical ventilation. Initially, eight subjects (gestational age 25–28 weeks 6 / 7 days) were randomized in a 3:1 ratio to receive either intratracheal administration of zerplutide alfa at each dose level (2, 4, or 6 mg / kg) or air sham, up to two times at 24-hour intervals. Twelve additional subjects (gestational age 23–28 weeks 6 / 7 days) were randomized in a 3:1 ratio to receive either the maximum tolerable dose of zerplutide alfa or air sham once daily for up to seven days.

[0099] Thirty-seven subjects were randomized and treated. Zelpultide alfa 6 mg / kg was safe and well-tolerated. 92.9% of zelpultide alfa subjects and 100.0% of aersham subjects experienced one or more adverse events. The mortality rate was 21%, all of which were in the zelpultide alfa group, but there were no deaths related to the study drug. Compared to aersham subjects, zelpultide alfa subjects showed favorable outcomes, including lower morbidity of bipolar disorder (BPD) (32.1% vs. 66.7%), lower morbidity or mortality of grade 2 or 3 BPD (39% vs. 56%), and shorter time requiring mechanical ventilation (17.7 days vs. 25.8 days).

[0100] As will be explained in more detail, this study supports the safety and tolerability of zelpultide alfa, confirming that 6 mg / kg (within 7 days) was safe and well-tolerated. Zelpultide alfa improved efficacy outcomes, demonstrating that this new drug is a promising therapy for the prevention of bipolar disorder (BPD).

[0101] The registration numbers for this clinical trial are NCT04662151 and EudraCT2021-005752-10.

[0102] The following abbreviations are used in reporting the results. List of abbreviations [Table 3]

[0103] Test design

[0104] This study was conducted at 12 sites in the United States and 10 sites in Spain. The study was designed, conducted, documented, and reported in accordance with the principles of the Guidelines for the Implementation of Clinical Trials of Pharmaceuticals, and monitored by an appropriate Data Safety Monitoring Committee (DSMC). This study evaluated the safety and tolerability of zelpultide alfa compared to aersham in premature neonates at high risk of developing bipolar disorder (BPD). The primary objective of this study was to establish the safety profile of the optimal dose of zelpultide alfa.

[0105] This study had two phases. In the first phase, very premature neonates (born between 25 weeks and 28 weeks 6 / 7 days GA) were randomized in a 3:1 ratio in a sequential collective cohort approach according to a conventional dose-determining study design. Six received standard care (SOC) and intratracheal administration of zelpultide alfa starting at 2 mg / kg and progressing to each dose level (2 mg / kg, 4 mg / kg, or 6 mg / kg, see Figure 1A). Two received SOC and an air sham (1 mL of air aspirated into the administration syringe for intratracheal infusion). Randomized subjects, if still intubated at the time of the second administration, received up to two study treatments at 24-hour (±1-hour) intervals. The initial dose of zelpultide alfa or air sham was administered via an endotracheal tube (ETT) at least 15 minutes after treatment with Curosurf® surfactant and within 96 hours postnatally. In the second phase, after confirming the maximum tolerable dose, very premature neonates (born between 23 weeks and 28 weeks 6 / 7 days GA) were simultaneously enrolled and randomized in a 3:1 ratio to receive either zelpultide alfa or airsham, with 9 receiving either and 3 receiving airsham. Subjects, if still intubated according to standard care, received up to 7 doses of either zelpultide alfa or airsham at approximately 24-hour (±1-hour) intervals.

[0106] Dose-restriction toxicity (DLT) was a determinant of whether new subjects could receive relatively high doses of zerplutide alfa and whether additional subjects would be enrolled in the study thereafter. If a DLT event occurred, continued administration to the subject was temporarily suspended, and the subject was transferred to a DSMC (Distributed Service Management Center). All subjects received a State of Care (SOC) including, but not limited to, pulmonary surfactant, respiratory support, and nutrition, in accordance with local hospital clinical guidelines. Participation in the study did not affect the SOC, and the clinical management of enrolled subjects was also modified. Follow-up was conducted for all subjects at day 28, week 36 of post-operative care (PMA), discharge, and at 6 and 12 months of age (data for 6 and 12 months are not reported in this publication). The medical team, principal investigator, subjects, and their parents were blinded for randomization. However, due to the nature of endotracheal treatment in the NICU, staff responsible for preparing and administering doses of zerplutide alfa and Aersham were aware of the randomization assignment. These individuals performed the administration process in an inconspicuous location, and were instructed not to expose the randomization of each subject to blinded staff.

[0107] Research subjects

[0108] Phase 1 of the trial (including dose escalation and treatment for up to 2 days) was planned to enroll 24 subjects born between 25 weeks and 28 weeks 6 / 7 days GA. Phase 2 of the trial (trial of treatment for up to 7 days) was planned to enroll 12 subjects born between 23 weeks and 28 weeks 6 / 7 days GA. Due to an error in the randomization system, one additional subject was randomized to the Phase 1 2 mg / kg zelpultide alfa treatment group. After randomization, one subject was removed from the study and replaced because they no longer met the eligibility criteria before treatment administration. Thus, a total of 38 subjects were randomized, and 37 received treatment (Figure 1B). Eligibility criteria included endotracheal intubation, mechanical ventilation, and receipt of at least one surfactant treatment (Curosurf®) as part of the postnatal SOC. To reduce variability associated with surfactant selection, the study population was limited to subjects who received Curosurf®. Subjects were excluded if their birth weight was less than 400g or greater than 1,800g, or if they had significant congenital abnormalities affecting cardiovascular or pulmonary function. Subjects were also excluded if their birth mother had hepatitis B, C, or E, or HIV, was undergoing chemotherapy, had a history of active cytomegalovirus, COVID-19, or a sexually transmitted infection, or had a history of alcohol or drug abuse. The 37 subjects who were randomized and received treatment were included in the treatment intention population.

[0109] Outcome

[0110] The primary outcomes were safety and tolerability of zelpultide alfa. Safety outcomes included the incidence of adverse events (AEs), serious adverse events (SAEs), and abnormalities in hematological and serological tests. The DSMC evaluated AEs and DLTs for any zelpultide alfa-related safety impacts and made recommendations regarding dose escalation and subsequent enrollment, including termination of enrollment where appropriate. DLTs were distinguished from AEs if all of the following criteria were met. If the AE was possibly, likely, or directly related to the administration of zelpultide alfa, if the AE occurred at any point in time between the first and last doses of zelpultide alfa (+72 hours), if the AE was not directly related to surfactant administration or ETT placement error, if the AE was not directly related to surfactant administration or ETT placement error, or if the AE resulted in instability or death-related symptoms after medical intervention (hemodynamic instability, shock or severe hypertension, carbon dioxide partial pressure <25 or >65 mmHg, apnea, ETT / airway obstruction requiring immediate removal of ETT, hypoxia, death-related extubation / reintubation, or anaphylaxis).

[0111] Secondary outcomes included preliminary efficacy outcomes and complications due to preterm birth. Primary efficacy outcomes included the morbidity or mortality rate of bilateral dysplasia (BPD) at 36 weeks postpartum (PMA), and the duration (days) of mechanical ventilation from birth to 36 weeks postpartum. The definition and classification of BPD were based on Jensen et al., 2019 (Jensen EA, Dysart K, Gantz MG et al., The Diagnosis of Bronchopulmonary Dysplasia in Very Preterm Infants. An Evidence-based Approach. Am J Respir Crit Care Med. 2019;200(6):751-9). The duration of mechanical ventilation was defined as 12 hours or more of mechanical ventilation per calendar day. Other secondary outcomes included steroid use, length of hospital stay, immunogenicity, pharmacokinetic analysis, pneumonia, hematological infections, morbidity of retinopathy of prematurity (ROP), pulmonary hypertension, PDA, necrotizing enterocolitis (NEC), or grade 2 intraventricular hemorrhage (IVH). Exploratory endpoints included changes in inflammatory mediators potentially associated with lung injury and bipolar disorder over 36 weeks.

[0112] As this was a Phase 1b study, the sample size lacked statistical power for outdoor safety and efficacy assessments; therefore, inferential statistics were not planned, and the analysis of safety and efficacy endpoints was descriptive only. Continuous variables were summarized by mean, standard deviation (SD), median, minimum, and maximum. Categorical variables were reported by the number and proportion of subjects. Baseline results were defined as the most recent measurement taken before the first dose of the study drug.

[0113] result

[0114] This study was conducted in two parts. The first part examined the primary endpoint of safety and tolerability of zelpultide alfa, and the completion of the study included a long-term follow-up endpoint (up to 12 months of age). Of the very premature neonates treated (Phase 1: zelpultide alfa 2 mg / kg, n=7; zelpultide alfa 4 mg / kg, n=6; zelpultide alfa 6 mg / kg, n=6; and Ayrsham n=6; Phase 2: zelpultide alfa 6 mg / kg, n=9; and Ayrsham n=3), 36 reached the PMA 36 week or death endpoint (Figure 1B). One subject discontinued the study before PMA 36 weeks due to withdrawal of consent (in Phase 1, zelpultide alfa 2 mg / kg, n=1).

[0115] Most subjects were male and of non-Hispanic / Latino and Caucasian descent. Mean baseline height, weight, and head circumference were generally similar between the groups (see Table I, Figure 3). The mean baseline GA in the Ayrsham treatment group was slightly younger than in the zelpultide alfa group, but the median age was numerically similar between the two groups (Ayrsham: 25.6 [minimum, maximum, 24, 28]; zelpultide alfa: 26.1 [minimum, maximum, 23, 29]). The proportion of Black / African American infants (17.9%) and the incidence of birth defects (32.1%) were higher in the zelpultide alfa treatment group than in the Ayrsham group (both 11.1%).

[0116] Safety Outcomes

[0117] Treatment with zelpultide alfa was safe and well-tolerated. Dose escalation was carried out up to the maximum dose, and no dose-limiting trials (DLTs) were reported. Therefore, in the second phase of the study, 6 mg / kg was selected as the most well-tolerated and safest dose. Overall, 92.9% of subjects treated with zelpultide alfa experienced at least one adverse event (AE), compared to 100% of subjects treated with aersham (Table II, Figure 4). Across all treatment groups, the most frequently reported AEs were anemia, PDA, ROP, hyperbilirubinemia, hyperglycemia, and hypotension (Tables III.A and III.B, Figures 5A and 5B).

[0118] Four subjects in the zelpultide alfa group in Phase 1 of the trial (2 mg / kg, n=2; 4 mg / kg, n=2) and three subjects in Phase 2 (6 mg / kg, up to 7 doses, n=3) experienced a total of nine adverse events (AEs) thought to be related to zelpultide alfa. Of these AEs, eight were thought to be potentially treatment-related, and one was thought to be likely treatment-related (hypoxia). No treatment-related AEs were reported in the zelpultide alfa 6 mg / kg group or the Aersham treatment group in Phase 1 of the trial. Seventeen subjects experienced 26 serious adverse events (SAEs). Only two SAEs (both pulmonary hemorrhage cases) were thought to be potentially treatment-related by the principal investigator, but due to the nature of premature birth and associated complications, these events were considered unrelated by the study and sponsor medical monitoring. The other 24 SAEs were unrelated to the study drug. In this study, there were six fatal adverse events (AEs), but none were considered treatment-related by the principal investigator, study medical monitor, or sponsor medical monitor. Five of these were due to non-respiratory conditions, including enterobacter sepsis, sepsis, PDA, intestinal perforation, and IVH (Table IV, Figure 6). One subject died from respiratory failure. Four subjects treated with zerplutide alfa experienced SAEs (pulmonary hemorrhage, respiratory failure, enterobacter sepsis, and IVH) that led to discontinuation of the study drug, and the majority of these (n=3) were considered treatment-related.

[0119] Regarding immunogenicity as determined by the presence of anti-SP-D antibodies, no anti-Zelpultide alfa antibodies were observed in subjects treated with Zelpultide alfa up to week 36 of PMA. In pharmacokinetic analysis, subjects treated with Zelpultide alfa showed a dose-dependent increase in serum SP-D concentration within 24 hours after the first treatment compared to baseline, with the highest increase observed at a dose of 6 mg / kg (Table VII, Figure 9).

[0120] Given the relatively low incidence of adverse events (AEs) and serious adverse events (SAEs), the absence of fatal zerplutide alfa-related AEs, and the lack of reported DLTs, treatment with zerplutide alfa was considered safe and well-tolerated.

[0121] Effectiveness outcome

[0122] Zelpultide alfa improved overall outcomes in very premature neonates in several clinically significant respiratory outcomes, including reduced biparietal diameter (BPD) and shorter time requiring mechanical ventilation. Subjects treated with zelpultide alfa showed lower BPD morbidity (32.1% vs. 66.7%), lower BPD morbidity or mortality (53.6% vs. 66.7%), lower grade 2 or 3 BPD morbidity or mortality (39% vs. 56%), and no cases of grade 3 BPD (0% vs. 11.1%) (Table V, Figure 7). Time requiring mechanical ventilation was reduced (mean: 17.7 days vs. 25.8 days, Figure 2A), and the proportion of subjects requiring mechanical ventilation at PMA 36 weeks was lower compared to airsham (Figure 2B).

[0123] Additional Outcomes

[0124] In this Phase 1b study, several notable findings were observed from additional analyses of secondary and exploratory outcomes. Steroid use, as defined as steroid adjuncts used to treat postnatal lung disease, was numerically lower in subjects treated with zelpultide alfa compared to aersham (17.9% vs. 33.3%, Table VI, Figure 8). The mean length of hospital stay from baseline to discharge, excluding data from six subjects who died by week 36 of PMA, was 87.2 days (±24.1, n=21) in the overall zelpultide alfa group and 90.2 days (±21.1, n=9) in the aersham group. The morbidity of ROP, pulmonary hypertension, and NEC was also numerically lower in subjects treated with zelpultide alfa compared to aersham (39.3% vs. 44.4%, 7.1% vs. 11.1%, and 3.6% vs. 11.1%, respectively, Table VI).

[0125] Discussion

[0126] This Phase 1b randomized clinical trial demonstrated that the maximum study dose of zelpultide alfa (6 mg / kg, administered for up to 7 days) was safe and well-tolerated when added to status of care (SOC) for very premature neonates at high risk of developing bipolar disorder (BPD). No DLTs were reported in subjects treated with zelpultide alfa. The DSMC assessed the 6 mg / kg dose as safe and recommended further research. Subjects treated with zelpultide alfa also showed improvements in several clinically significant respiratory outcomes compared to those treated with aersham. Morbidity or mortality of BPD at PMA 36 weeks, morbidity or mortality of grade 2 or 3 BPD, and time requiring mechanical ventilation were numerically shorter in subjects treated with zelpultide alfa compared to those treated with aersham. These improved outcomes were accompanied by reduced steroid use, and lower morbidities of ROP, pulmonary hypertension, and NEC at PMA 36 weeks. The zelpultide alfa treatment group had a higher proportion of Black / African American infants. Racial and ethnic disparities in neonatal comorbidities and mortality have been reported in the literature (including relatively higher infant mortality rates associated with Black / African Americans). However, findings from different studies are inconsistent, and the factors contributing to these racial and ethnic disparities have not been fully identified. Nevertheless, if this is considered a potential factor in poor prognosis, the positive outcomes associated with zelpultide alfa should be considered more noteworthy.

[0127] Because there are no optimal standard outcome measures for improvement in lung function in very premature neonates, secondary efficacy outcomes were designed to determine whether zelpultide alfa therapy leads to changes in composite outcomes of BPD and mortality, and whether it affects the time spent receiving respiratory support throughout 36 weeks of premature birth (PMA). Grade 2 and 3 BPD (moderate to severe) were selected as outcomes because infants in these categories face the highest risk of broad morbidity, the worst long-term outcomes, and a significant burden on intensive care services. Importantly, none of the 28 subjects treated with zelpultide alfa developed grade 3 BPD. The data also showed a relative 30% reduction in the risk of grade 2 or 3 BPD or death in subjects treated with zelpultide alfa. Furthermore, an analysis excluding deaths before 14 days of birth was also performed. This was a meaningful analysis because mortality is higher during this period as a result of comorbidities associated with premature birth. Zelpultide alfa demonstrated a 55% reduction in the risk of grade 2 or 3 BPD or death in infants who survived more than 14 days. This suggests that the zelpultide alfa treatment group showed a more significant improvement compared to aersham.

[0128] In recent years, there has been a growing emphasis on avoiding unnecessary invasive ventilation to prevent long-term lung injury in premature neonates. Although ventilation strategies have improved, mechanically ventilated lungs are still exposed to artificial hyperdistension caused by the pressure and tidal volume set on the ventilator. This increases lung tissue damage, inhibits secondary alveolar septal formation, increases the risk of ventilation-associated pneumonia, activates a pro-inflammatory cascade, and increases the risk of developing bipolar disorder (BPD). Therefore, it is desirable to reduce the time spent on mechanical ventilation in any way. For this reason, the time spent on mechanical ventilation was included as a secondary endpoint to determine whether zerplutide alfa resulted in improved respiratory function that reduced the need for invasive mechanical ventilation. Zerplutide alfa reduced the time spent on mechanical ventilation by approximately 8 days compared to airsham (see Figures 2A, 2B and Table XI (Figure 12)).

[0129] As shown in Table IX (Figure 11), more deaths were observed in the zerplutide alfa 6 mg / kg group during the second phase of the trial, which was due to the enrollment of very premature infants at 23 weeks gestational age during the second phase. The mortality rate in the zerplutide alfa group was 21.4%, which is consistent with recently published mortality rates for premature neonates (15-50%). Notably, the majority of deaths occurred in low-gestational-age infants (below 25 weeks gestational age), which is consistent with previous findings that subjects in this age group have a lower survival rate. Also, 5 out of 6 deaths were unrelated to respiratory events (only one death was due to respiratory failure, and this subject had co-existing PDA). On the other hand, there were no deaths in the ayrsham group during the observation period. This may be considered a statistical anomaly, likely due to the smaller sample size in the Ayrsham group (n=9) compared to the 28 subjects in the zerplutide alfa group, and the 3:1 randomization scheme resulting in a greater chance of events occurring in the larger zerplutide alfa group. While the small sample size was appropriate given that safety was the primary outcome in this Phase 1b study, it limited the assessment of statistical significance for efficacy outcomes.

[0130] As an exploratory endpoint, we measured levels of pro-inflammatory and anti-inflammatory cytokines, given that inflammation plays a crucial role in lung injury and the development and progression of bipolar disorder (BPD). Zelpultide alfa may potentially play a role in modulating these inflammatory pathways. Unfortunately, inflammatory biomarker data were limited due to ethical guidelines regarding the amount of blood that could be collected from very premature neonates. Furthermore, comparison with Ayrsham was not possible due to non-uniform baselines. Due to these data limitations and baseline variability, we were unable to draw clinically relevant conclusions about this outcome.

[0131] This trial has several design limitations. Blinded clinical trials are the optimal standard for limiting bias in study design. However, blinding treatment is difficult when using intratracheal products such as zerplutide alfa within a limited timeframe in the NICU. The use of a placebo also limits bias in any study design. However, intratracheal placebo administration in a NICU setting is not ethical or practical. Therefore, this trial selected a SOC using airsham as a comparison. While airsham is not entirely without risks associated with intratracheal use, the risk to subjects was considered minimal. Therefore, it was intended that the individuals preparing and administering the doses were aware of the treatment, but other NICU medical staff, the principal investigator, subjects, and their parents remained blinded to the treatment. There has been a trend towards early extubation and early transition to non-invasive ventilation over the past decade. The number of treatment doses a subject could receive was determined by the study protocol and depended on the presence of an ETT for mechanical ventilation according to the SOC. Therefore, the number of treatment doses received by each subject varied according to the timing of extubation based on the State of Care Unit (SOC). In the second phase, treatment could be administered for up to 7 days, and more than 66% of subjects received 5 or more doses (see Tables VIII.A and VIII.B, Figures 10A and 10B). This limitation was difficult to overcome because the aim of this study was not to interfere with the SOC in the subjects' respiratory management.

[0132] conclusion

[0133] Intratracheal administration of zelpultide alfa at a dose of 6 mg / kg for up to 7 days to very premature neonates has been established as a safe and tolerable dose, and is the dose recommended by the DSMC for future research based on the observed safety profile. Although this study did not have statistical power for efficacy, the efficacy endpoints assessed after zelpultide alfa treatment showed improvement, indicating a reduction in the incidence of BPD or death and the number of days requiring mechanical ventilation. This supports the promising clinical profile of zelpultide alfa for BPD prevention, especially considering the challenges and comorbidities of very premature neonates at the start of the study.

[0134] The above description is illustrative and not restrictive. For example, the embodiments (or one or more embodiments thereof) described above may be used in combination with each other. For example, other embodiments may be used by those skilled in the art by reading the above description. This abstract is provided in accordance with 37 C. FR § 1.72(b) to enable the reader to quickly ascertain the nature of this technical disclosure. It is submitted with the understanding that it is not to be used to interpret or limit the scope or meaning of the claims. Also, in the above detailed description, various features may be grouped together for the sake of efficiency in this disclosure. This should not be interpreted as meaning that a disclosed but unclaimed feature is essential to any claim. Rather, the subject matter of the invention may be based on some, but not all, features of a particular disclosure. Accordingly, the following claims are incorporated into the detailed description as embodiments or embodiments, and each claim is positioned as an independent embodiment, and such embodiments are considered to be able to be combined in various combinations or permutations. The scope of this disclosure should be determined together with the entire scope of the appended claims and the equivalents encompassed therein.

Claims

1. A method for shortening the duration of mechanical ventilation in a premature infant at risk of developing bronchopulmonary dysplasia (BPD), comprising administering an effective amount of recombinant human surfactant protein D (rhSP-D) to the infant.

2. The method according to claim 1, wherein the reduction in the duration of the mechanical ventilation is at least one day.

3. A method for shortening the length of hospital stay for premature infants at risk of developing bipolar disorder (BPD), comprising administering an effective amount of rhSP-D to the infant.

4. The method according to claim 3, wherein the reduction in the number of days of hospitalization is at least one day.

5. A method for reducing the probability that a premature infant at risk of developing BPD will develop one or more secondary complications due to premature birth, comprising administering an effective amount of recombinant human surfactant protein D (rhSP-D) to the infant.

6. The method according to claim 5, wherein one or more secondary complications due to premature birth include steroid use, radiographically confirmed pneumonia, retinopathy of prematurity (ROP), pulmonary hypertension, necrotizing enterocolitis (NEC), grade 2 intraventricular hemorrhage (IVH), or a combination thereof.

7. The method according to claim 5 or 6, wherein the reduction in the aforementioned probability is at least 10%.

8. The method according to any one of claims 1 to 7, wherein the rhSP-D is zelpultide alpha.

9. The method according to any one of claims 1 to 8, wherein the rhSP-D is administered intratracheally, endotracheally, by inhalation, or by spray.

10. The method according to any one of claims 1 to 9, wherein the premature infant at risk of developing BPD is an infant born at 29 weeks of gestation or less.

11. The method according to any one of claims 1 to 10, wherein the premature infant at risk of developing BPD is an infant who requires respiratory support after birth.

12. The method according to claim 11, wherein the respiratory support is invasive respiratory support.

13. The method according to claim 12, wherein the invasive respiratory support includes the use of an endotracheal tube.

14. The method according to any one of claims 1 to 13, wherein the effective dose of rhSP-D comprises a dose of 1 milligram / kilogram (mg / kg) to 10 mg / kg / day over a period of 1 to 10 days.

15. A pharmaceutical composition for use in the method according to any one of claims 1 to 14.

16. (1) the use of a pharmaceutical composition to shorten the duration of mechanical ventilation in premature infants at risk of developing bronchopulmonary dysplasia (BPD), (2) the length of hospital stay in premature infants at risk of developing BPD, or (3) the probability of a premature infant at risk of developing BPD developing one or more secondary complications due to premature birth, The pharmaceutical composition comprises recombinant human surfactant protein D (rhSP-D) for use.

17. The use according to claim 16, wherein the reduction in the duration of the mechanical ventilation is at least one day.

18. The use according to claim 16 or 17, wherein the reduction in the length of hospital stay is at least one day.

19. The use according to any one of claims 16 to 18, wherein one or more secondary complications due to premature birth include the use of steroids, radiographically confirmed pneumonia, retinopathy of prematurity (ROP), pulmonary hypertension, necrotizing enterocolitis (NEC), grade 2 intraventricular hemorrhage (IVH), or a combination thereof.

20. The use according to any one of claims 16 to 19, wherein the reduction in the aforementioned probability is at least 10%.

21. The use according to any one of claims 16 to 20, wherein the rhSP-D is zelpultide alpha.

22. The use of rhSP-D according to any one of claims 16 to 21, wherein the rhSP-D is administered intratracheally, endotracheally, by inhalation, or by spray.

23. The use according to any one of claims 16 to 22, wherein the premature infant at risk of developing BPD is an infant born at 29 weeks of gestation or less.

24. The use according to any one of claims 16 to 23, wherein the premature infant at risk of developing BPD is an infant who requires respiratory support after birth.

25. The use according to claim 24, wherein the respiratory support is invasive respiratory support.

26. The use according to claim 25, wherein the invasive respiratory support includes the use of an endotracheal tube.

27. The use of rhSP-D according to any one of claims 16 to 26, wherein rhSP-D is administered at a dose of 1 milligram / kilogram (mg / kg) to 10 mg / kg / day over a period of 1 to 10 days.

Images