Exploring Potential New Avenues for Bronchopulmonary Dysplasia Treatment

Bronchopulmonary Dysplasia is the most common long-term respiratory morbidity of low-weight or premature infants, with the risk of development proportional to the degree of prematurity. It is also referred to as chronic lung disease of premature babies. It is a chronic respiratory disease that often occurs in low-weight or premature infants who have received supplemental oxygen or have spent long periods on a breathing machine (mechanical ventilation), such as infants with acute respiratory distress syndrome. Bronchopulmonary Dysplasia occurs in older infants who experience abnormal lung development, an antenatal infection, placental abnormalities (like preeclampsia), or chorioamnionitis. Babies are not born with Bronchopulmonary Dysplasia, also referred to as chronic lung disease of prematurity, it is associated with how a baby’s lung tissue develops.

Bronchopulmonary Dysplasia risk development increases the earlier a baby is born and the lower the birth weight. Affected infants have rapid, labored breathing, tachypnea, cyanosis, feeding difficulties, and recurrent lung infection. Bronchopulmonary Dysplasia pathopysiology remains complex and poorly understood. It results from various factors that injure small airways and can interfere with alveolarization, leading to alveolar simplification with a reduction in the overall surface area for gas exchange. The developing pulmonary microvasculature is also injured. Damage to the lung during a critical stage of lung growth results in clinically significant pulmonary dysfunction. Bronchopulmonary Dysplasia treatment is on a rise due to increasing cases, because of modern advances in medicine, which have enabled doctors to keep more low birth weight, premature babies alive than in the past.

“As per the Delveinsight analysis, most infants with extremely low birth weight are born at <28 weeks gestational age (GA). Also, the risk of Bronchopulmonary Dysplasia is very high in this GA compared to normal-term birth. In the United States, maximum incident cases of Bronchopulmonary Dysplasia are in ≤750 g birth weight group preterm infants, followed by 751–1000 g, 1001–1250 g, and ≥1250 g weight group preterm infants. Thus, the lower the GA and the birth weight, the higher is the incidence of Bronchopulmonary Dysplasia.”

Infants with Bronchopulmonary Dysplasia show substantial heterogeneity in clinical presentation and long-term outcomes. The manner and precision with which Bronchopulmonary Dysplasia is defined have far-reaching consequences for translational and clinical research.

Bronchopulmonary Dysplasia diagnostic criteria in infants indicate substantial clinical presentation and long-term outcomes heterogeneity. The manner and precision with which Bronchopulmonary Dysplasia is defined have far-reaching consequences for translational and clinical research. Bronchopulmonary Dysplasia diagnosis is based on identifying characteristic symptoms, detailed patient history, thorough clinical evaluation, and a variety of specialized tests, including blood tests, chest x-rays, and echocardiograms. Many infants now, who went through Bronchopulmonary Dysplasia diagnosis, are born at an earlier gestational age than before. These cases are sometimes referred to as “new Bronchopulmonary Dysplasia.” They generally have less inflammation and scarring than classic Bronchopulmonary Dysplasia.

Bronchopulmonary Dysplasia grades are divided into three types (mild, moderate, or severe) based on respiratory support needs at 36 weeks postmenstrual age (PMA). The severity‐specific data reveal that the highest number of preterm infants have mild Bronchopulmonary Dysplasia.  The exact underlying mechanisms that cause classic or new Bronchopulmonary Dysplasia are complex and not fully understood. Bronchopulmonary Dysplasia caused in one infant may differ from the causes in another. Most likely, multiple different environmental and genetic factors all play a role in the development of the disorder.

Though the exact sequence of events leading to the Bronchopulmonary Dysplasia development has not been fully elucidated and likely varies among patients, it is thought to result from an inflammatory and mechanical injury from chronic ventilator support in premature lungs that are fragile and susceptible to injury. Bronchopulmonary Dysplasia occurs in newborns who received supplemental oxygen or have spent long periods on mechanical ventilation, such as infants with acute respiratory distress syndrome. Bronchopulmonary Dysplasia often results in the poor growth and development of these newborns. Bronchopulmonary Dysplasia can also occur in older infants who experienced abnormal lung development or infants with an infection before birth (antenatal infection) or placental abnormalities. 

Bronchopulmonary Dysplasia Treatment

Once Bronchopulmonary Dysplasia develops, adequate respiratory support and nutrition for the promotion of optimal lung growth is the primary goal of Bronchopulmonary Dysplasia. Multiple pharmacologic and non-pharmacologic Bronchopulmonary Dysplasia treatment strategies have been proposed to support survival, minimize further lung injury, and facilitate recovery. Respiratory therapies range widely from a noninvasive ventilator to support mechanical ventilation with a tracheostomy. Most infants with mild Bronchopulmonary Dysplasia usually require only oxygen support to improve lung capacity and help them breathe without any pharmacological intervention. Several pharmacologic therapies involved in Bronchopulmonary Dysplasia treatment include bronchodilators, diuretics, antibiotics, surfactants, and corticosteroids.

To date, there is no specific Bronchopulmonary Dysplasia cure, and the focus is on minimizing lung damage and providing support for the lung to heal and grow. But recent, advanced and proper Bronchopulmonary Dysplasia treatment includes mechanical ventilation and supplemental oxygen to improve lung capacity and help them breathe. Antenatal steroid treatment before preterm birth and early treatment with surfactant reduces the need for high levels of respiratory support after birth. Infants are also given different medications, including bronchodilators, diuretics, antibiotics, and steroids, to reduce lung inflammation and congestion. Proper nutrition management ensures healthy lung development. Current strategies for Bronchopulmonary Dysplasia prevention can broadly be divided into antenatal pharmacologic interventions such as maternal progesterone and antenatal steroids and postnatal pharmacologic interventions. Though Bronchopulmonary Dysplasia management has improved with the advent of new and effective perinatal strategies, it still is the most common complication associated with prematurity and the major cause of respiratory morbidities. Its prevention and management remain a major challenge for neonatologists, especially with the increasing survival of extremely premature infants.

“There is no labeled therapy available in the US, EU, and JP for the treatment of Bronchopulmonary Dysplasia.  Synagis (MedImmune) is a respiratory syncytial virus (RSV) F-protein inhibitor, monoclonal antibody indicated for the prevention of serious lower respiratory tract disease caused by a respiratory syncytial virus (RSV) in pediatric patients with Bronchopulmonary Dysplasia that require medical treatment within the previous 6 months and who are 24 months of age or younger at the beginning of RSV season.”

Corticosteroids like dexamethasone, prednisolone, and others are used for Bronchopulmonary Dysplasia treatment. Although corticosteroids have been widely used for prevention and Bronchopulmonary Dysplasia treatment due to their anti-inflammatory properties, systemic steroids have been associated with serious short and long-term adverse effects. Prenatal steroids, surfactants, ventilators, and improved resuscitation protocols have increased the survival rate of premature infants; however, there has been little progress in protecting their not fully developed organs from the trauma of life-saving measures at birth including supplemental oxygen and breathing machines. To cater to the current unmet needs in Bronchopulmonary Dysplasia treatment, new approaches in assisted ventilation, optimal nutrition, and pharmacologic interventions to ameliorate or prevent Bronchopulmonary Dysplasia continue to be investigated.

The Bronchopulmonary Dysplasia pipeline is currently limited, consisting of only a few drugs which include OHB607 (mecasermin rinfabate), and Pneumostem (Human Umbilical Cord Blood Derived-Mesenchymal Stem Cells) being developed by Medipost, AT-100 (Airway Therapeutics), and others. 

OHB607 (mecasermin rinfabate) an intravenous infusion being developed by Oak Hill, seems to be a potential key asset to treat Bronchopulmonary Dysplasia. The company licensed the asset from Takeda. OHB607 is a proprietary, recombinant version of insulin-like growth factor 1 (IGF-1), the natural version of which is a key driver of fetal growth and development in utero, and its binding protein, IGFBP-3. The drug has been evaluated in both preclinical and clinical studies. A Phase IIa clinical trial showed a statistically significant improvement in preventing severe Bronchopulmonary Dysplasia. 

Chiesi Farmaceutici is evaluating CHF5633 for Bronchopulmonary Dysplasia treatment. It is the first fully synthetic surfactant enriched by peptide analogs of two human surfactant proteins. The drug is in the early clinical stage of development for Bronchopulmonary Dysplasia. Through the clinical success of porcine surfactant (Poractant alfa, Curosurf) in treating neonatal respiratory distress syndrome (RDS), Chiesi has established an impressive platform in neonatology. CHF5633 completed its evaluation in Phase II compared to Curosurf in treating preterm neonates with RDS. The drug is presently being evaluated in early clinical-stage development for Bronchopulmonary Dysplasia treatment.

Analyst key points –

• Bronchopulmonary Dysplasia remains an important cause of neonatal mortality and morbidity despite newer and considerate ventilation modes.
• Despite significant advancements in the understanding of the pathogenesis and course of Bronchopulmonary Dysplasia, neonatologists continue to face significant challenges in the prevention and treatment of this condition.
• Most Bronchopulmonary Dysplasia prevention and treatment options lack evidence and have long-term adverse events. Theoretically effective strategies have failed to transition to clinical settings. 
• There is no approved therapy by the US FDA to prevent or treat Bronchopulmonary Dysplasia in infants. Future meta-analyses and prospective randomized controlled studies that aim to measure clinically significant outcomes are still needed.  
• There is a dire need for trials assessing this population’s safety, effectiveness, and dosage of pharmacologic agents.
• A recent study published in the American Journal of Respiratory and Critical Care Medicine depicted tiny particles released by MSCs called extra-cellular vesicles, which are useful for the prevention of Bronchopulmonary Dysplasia.
• Macrolide therapy is a treatment for infants at risk of Bronchopulmonary Dysplasia who have Ureaplasma colonization. As a way to prevent Bronchopulmonary Dysplasia, a major double-blind placebo-controlled experiment in preterm infants is currently testing azithromycin, which has anti-inflammatory characteristics in addition to its antibacterial benefits.

With all other drugs in the early stages of development, until now, OHB607 seems to be the most promising candidate in the clinical pipeline of Bronchopulmonary Dysplasia. The market is expected to react positively to OHB607, aiding it in solidifying its position as a leading therapy for this indication, as no other therapy has been able to pave its way to approval yet. The expected approval of emerging therapy and the improving understanding of the disease due to advancing techniques will allow the Bronchopulmonary Dysplasi market to rise at a significant rate.