Discovery Laboratories, Inc. (Nasdaq: DSCO)
Discovery Laboratories, Inc. is creating a fully-integrated biotechnology company committed to the development and commercialization of novel Surfactant Replacement Therapies (SRTs™) with potential application across the respiratory disease continuum. Surfactant is produced naturally in the lungs and is essential for normal breathing throughout life. Our product platform is based on a novel pulmonary surfactant technology intended to establish a completely new, therapeutic approach in the treatment of respiratory disease, with a targeted initial application in premature infants.
Pulmonary surfactant is essential for viability at birth and throughout life. In many pulmonary diseases including, respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), acute respiratory failure (ARF) and acute lung injury (ALI), surfactant produced by cells within the respiratory tract is either deficient or may fail to function properly. This deficiency leads to difficulty in breathing, and in severe cases, requires respiratory support via mechanical ventilation in the intensive care unit of a hospital. 42,43 ,92
Our precision-engineered, peptide-containing pulmonary surfactant technology is designed to mimic the essential function of human pulmonary surfactant. The heritage of this technology began at The Scripps Research Institute, where our platform was invented, then exclusively licensed to Discovery Labs.
SURFAXIN® (lucinactant) for intratracheal suspension, our first product, has received an approvable letter from the US FDA for the prevention of RDS in premature infants. SURFAXIN represents the first of many potential products through the use of our novel technology platform. Our aerosolized SRT™ product, AEROSURF™ (lucinactant) for inhalation, is being developed to treat the broader population of infants in the NICU with respiratory failure -- potentially avoiding the complications associated with traditional mechanical ventilation.
Surfactants
Pulmonary surfactant produced in the lungs is critical for proper respiratory function. The primary role of pulmonary surfactant is to reduce surface tension in the lung - this effect is necessary to prevent the collapse of the alveoli and distal airways and promote gas exchange. Additionally, surfactant reduces the effort needed to expand the lungs during inspiration, thus reducing the work of breathing. The absence of sufficient surfactant leads to alveolar or distal airway collapse and compromised pulmonary function.44
Lung surfactant has additional beneficial properties:78 79
Acts as physical barrier to inhaled particles and noxious agents
Enhances particle clearance
Provides host defense against infection
Possesses anti-inflammatory properties
Surfactants are a complex mixture of phospholipids and proteins. Phospholipids are the primary surface tension-lowering component of pulmonary surfactants. The surfactant proteins play a critical role in a variety of functions related to respiratory health and development. Currently, researchers have identified 4 distinct surfactant-associated proteins designated as: SP-A; SP-B; SP-C; and, SP-D. The role of each of these proteins in surfactant function and pulmonary function has been clarified in various in vivo and in vitro studies. One of the key differentiating factors for these proteins is their affinity for water. SP-A and SP-D proteins are hydrophilic -- they have a strong affinity to water and have been shown to be involved in the innate immunity of the lungs. SP-B and SP-C are both hydrophobic -- they have no affinity to water molecules, which supports their ability to interact with phospholipids and lower surface tension.
Over the past 25 years, since surfactant replacement therapy was first used, it has become commonly accepted that both SP-B and SP-C, when combined with surfactant phospholipids, produce exogenous replacement surfactants that possess the properties needed to promote the formation and stability of the surfactant film leading to lowering of surface tension in the lungs.1 Studies have shown that SP-B is the most important for the lowering of surface tension. SP-B gene-knockout mice (i.e., mice lacking the SP-B protein) die of respiratory failure soon after birth, whereas those mice lacking SP-C (i.e., SP-C gene-knockout) survive the neonatal period, but may develop various forms of interstitial lung disease much later in life. This same lethal respiratory failure has been documented in human newborns that lack SP-B. 80 81
There are many respiratory diseases associated with the absence of surfactant or loss of its function. These diseases affect both infant and adult populations, and include: 43 82 83 84 85
Neonatal Respiratory Disease
Respiratory Distress Syndrome (RDS)
Bronchopulmonary Dysplasia (BPD)
Acute Respiratory Failure (ARF)
Bronchiolitis
Pneumonia
Diaphragmatic Hernia
Hypoxemia
Pulmonary Hypertension
Transient Tachypnea
Pediatric and Adult Respiratory Disease
Acute Lung Injury (ALI)
Acute Respiratory Distress Syndrome (ARDS)
Cystic Fibrosis
Pneumonia
Bronchiolitis
COPD
Asthma
Idiopathic Pulmonary Fibrosis (IPF)
Upper Airway Disorders - Otitis Media; Sinusitis; Rhinitis
Many of these diseases are the result of surfactant deficiency or degradation. The goal of Surfactant Replacement Therapy (SRT™) is to replace and restore surfactant function.
Currently, exogenous therapeutic surfactants are approved only for use as prophylactic (prevention) or rescue treatment for RDS in premature infants. Commercially available surfactants predominantly in use today are derived from animal sources. Animal-derived surfactants contain low levels of SP-B relative to human surfactant. Concentration of this protein varies considerably between lots of the animal derived surfactants. There is also a theoretical risk of transmitting known and yet to be discovered animal-borne disease. Additionally, cultural or other sensitivities become an important consideration when using animal derived products. Finally, despite many years of research with animal-derived surfactants, the only currently approved administration approach in the United States and Europe entails invasive mechanical ventilation. 39 40 44
KL4
The substantial unmet need for improved surfactant therapies and recognition of the importance of SP-B led to the discovery of the peptide, KL4 (also known as sinapultide). KL4 is precision-engineered to mimic the essential properties of human SP-B, the most important surfactant protein for lowering surface tension and promoting oxygen exchange. Data show that a pulmonary surfactant containing KL4 is highly effective in lowering surface tension and, unlike larger animal surfactant proteins, demonstrates significant resistance to degradation in multiple in-vitro models. 1 7 12 15
Chemically, KL4 consists of 21 amino acid residues where "K" is the amino acid lysine and "L" is the amino acid leucine.1 KL4-based surfactants contain the key peptide KL4, the lipids dipalmitoylphosphatidylcholine (DPPC) and palmitoyl-oleyl phosphatidylglycerol (POPG), plus the fatty acid, palmitic acid (PA).
Existing Data for KL4 based surfactant demonstrates the following:
Demonstrable anti-inflammatory capability4
Resistance to proteolytic degradation and oxidation7 12 15
Avoids potential risk of transmitting animal-borne diseases44 78
No evidence of immunogenicity 44 78
Compatibility with a variety of formulations (i.e. liquid instillate, aerosol, lyophilized form) 70 71 73
The novel attributes of KL4-surfactants allow Discovery Labs to potentially address a wide range of respiratory diseases in several unique patient populations. To date, approximately 1,000 neonatal and adult patients have been treated with KL4-surfactant. Additionally, a wealth of scientific and clinical literature regarding KL4-surfactant has been published addressing the pharmacology, safety and efficacy of the use of KL4-surfactant in multiple respiratory diseases.
Pipeline Overview
Discovery Labs is developing its SRT™ platform with the intent to create a completely new therapeutic approach in the treatment of respiratory disease.
Product introduction begins with anticipated U.S. FDA approval of SURFAXIN®, followed by the potential launch of multiple line extensions involving a variety of dosage forms and novel indications of usage.
AEROSURF™, Discovery Labs' aerosolized surfactant candidate, represents a potential transformation in respiratory critical care by reducing or eliminating complications associated with mechanical ventilation.
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