Periodic Reporting for period 1 - LIFT (Liquid Foam Therapy (LIFT) for Acute Respiratory Distress Syndrome (ARDS))
Okres sprawozdawczy: 2018-10-01 do 2020-03-31
Podsumowanie kontekstu i ogólnych celów projektu
The respiratory pathway represents an attractive route for direct topical treatment of lung diseases. This is most relevant for critical conditions such as acute respiratory distress syndrome (ARDS). Despite such potential, common inhalation devices (e.g. inhalers, nebulizers, etc.) are very limited in their delivery abilities: only very small particles can be inhaled (<10 µm) and inhalable doses remain low (<<1 ml for inhalers and <1 ml/hour for nebulizers). Furthermore, lung diseases are typically associated with airway narrowing and obstructions, which favor instead airflow and consequently aerosol deposition in the more accessible healthy regions. These drawbacks are directly associated with poor treatment outcomes as well as an ongoing lack of treatment for critical lung conditions as in ARDS. Endotracheal liquid instillation has been previously suggested to overcome the shortcomings of inhalation devices, which have been shown to be effective for pulmonary therapies in premature babies. However, due to stark differences in lung size, this clinical strategy is ineffective in older populations. Liquid instillations are strongly affected by gravity and thus quickly drain into pools, drowning some lung regions while leaving others untreated. Together with the aforementioned limitations of inhalation devices, current administration methods for critical lung diseases (e.g. ARDS) in children and adults remain sorely inadequate, leaving some diseases not treatable.
To overcome these challenges, we propose using liquid foam as a carrier for therapeutic delivery to the lungs (i.e. LIquid Foam Therapy or LIFT – patent pending6). Such an approach represents a paradigm shift in the field of pulmonary drug delivery. Unlike liquid installations, foam is “gravity defiant”: LIFT distributes homogeneously throughout the lungs with capabilities of delivering doses of >100 ml to each lung. Moreover, and in stark contrast to aerosols and liquid boluses, LIFT can flow through narrowed airways and penetrate beyond obstructions. To deliver LIFT, our device (under construction, Fig. 2) is intended for clinical use under the supervision of a physician, and can be deployed in either intubated or ventilated patients, through bronchoscopy, laryngeal mask, or voluntary inhalation (after local anesthesia, suppressing cough reflex). Our device incorporates loading proprietary drug capsules containing chemically inert foaming material capable of carrying various drugs. Alternatively, as in the case of ARDS, elaborated below, the drug itself is foamed. Briefly, after loading of the capsule (i) the device foams its content and (ii) pushes the foam out of the device through an outlet tube, using a syringe pump mechanism. In parallel, (iii) a second syringe pushes an interchangeable therapeutic solution through the same outlet tube. (iv) The foam and therapeutic solution mix in the outlet tube and enter the respiratory system of the patient as medicinal foam. Subsequently, (v) a third syringe pump pushes air into the patient’s lungs, effectively translocating the medicinal foam distally into the alveolar regions. Due to the large volume of the lungs’ alveolar regions (~2.5 L at exhalation), the foam (~0.5 L) will neither flow back nor obstruct the patient’s airways. This entire process is timed to last a mere few seconds, after which the patient is immediately able to breathe (or mechanical ventilation may proceed).
Acute Respiratory Distress Syndrome (ARDS) embodies the optimal combination of both large market potential and an easier regulatory pathway. ARDS is a life-threatening inflammatory lung condition, which affects patients across all age groups and may be triggered by sepsis, pneumonia, drowning, head or chest injury amongst other. One of the hallmarks of ARDS is the depletion of the inner “soapy” liquid lining of the lungs, known as pulmonary surfactant. Surfactant reduces surface tension forces at the interface between the alveolar cavity walls and air, thus easing the act of breathing and maintaining healthy lung compliance7,8. The clinical syndrome was first described by Ashbaugh et al., and 50 years on, there is still no effective therapeutic delivery method in children and adults. Surfactant Replacement Therapy (SRT) exists and is a life-saving clinical procedure in treating Infant Respiratory Distress Syndrome (IRDS) in preterm neonates. Born before the 28th week of gestation (780,000/yr. worldwide), these babies’ immature lungs lack pulmonary surfactant. In IRDS, SRT is based on endotracheal administration of liquid surfactant instillations. However, due to stark differences in lung size, this clinical strategy is ineffective in older populations.
LIFT’s long-term vision is to overcome the challenges of ineffective therapeutic delivery to the lungs that continue to impede successful SRT for ARDS. While alternative pharmacological solutions for ARDS treatment have been examined, none are known to be effective7,8. This includes intravenous injections (e.g. glucocorticoids, Methylprednisolone), enteral administration (e.g. n-3 fatty acids, γ-linolenic acid, and antioxidants) and aerosol inhalation (e.g. heparin, rosuvastatin, ketoconazole). LIFT is anticipated not only to help reduce mortality rates, but also bring down healthcare costs by shortening hospitalization and rehabilitation periods. From a financial viability standpoint, generic versions of the necessary therapeutic agent for SRT are broadly available (i.e. pulmonary surfactant). LIFT can prove scalable preferably through future partnering with existing FDA approved surfactant manufacturers (Chiesi, Abbvie, ONY among others), or via in-house implementation of established surfactant manufacturing techniques. In parallel, the high direct costs associated with ARDS hospitalization in the ICU (mean cost of $80,000 per patient in the US) offer an opportunity for attractive margins of profitability and a sustainable business model.
To overcome these challenges, we propose using liquid foam as a carrier for therapeutic delivery to the lungs (i.e. LIquid Foam Therapy or LIFT – patent pending6). Such an approach represents a paradigm shift in the field of pulmonary drug delivery. Unlike liquid installations, foam is “gravity defiant”: LIFT distributes homogeneously throughout the lungs with capabilities of delivering doses of >100 ml to each lung. Moreover, and in stark contrast to aerosols and liquid boluses, LIFT can flow through narrowed airways and penetrate beyond obstructions. To deliver LIFT, our device (under construction, Fig. 2) is intended for clinical use under the supervision of a physician, and can be deployed in either intubated or ventilated patients, through bronchoscopy, laryngeal mask, or voluntary inhalation (after local anesthesia, suppressing cough reflex). Our device incorporates loading proprietary drug capsules containing chemically inert foaming material capable of carrying various drugs. Alternatively, as in the case of ARDS, elaborated below, the drug itself is foamed. Briefly, after loading of the capsule (i) the device foams its content and (ii) pushes the foam out of the device through an outlet tube, using a syringe pump mechanism. In parallel, (iii) a second syringe pushes an interchangeable therapeutic solution through the same outlet tube. (iv) The foam and therapeutic solution mix in the outlet tube and enter the respiratory system of the patient as medicinal foam. Subsequently, (v) a third syringe pump pushes air into the patient’s lungs, effectively translocating the medicinal foam distally into the alveolar regions. Due to the large volume of the lungs’ alveolar regions (~2.5 L at exhalation), the foam (~0.5 L) will neither flow back nor obstruct the patient’s airways. This entire process is timed to last a mere few seconds, after which the patient is immediately able to breathe (or mechanical ventilation may proceed).
Acute Respiratory Distress Syndrome (ARDS) embodies the optimal combination of both large market potential and an easier regulatory pathway. ARDS is a life-threatening inflammatory lung condition, which affects patients across all age groups and may be triggered by sepsis, pneumonia, drowning, head or chest injury amongst other. One of the hallmarks of ARDS is the depletion of the inner “soapy” liquid lining of the lungs, known as pulmonary surfactant. Surfactant reduces surface tension forces at the interface between the alveolar cavity walls and air, thus easing the act of breathing and maintaining healthy lung compliance7,8. The clinical syndrome was first described by Ashbaugh et al., and 50 years on, there is still no effective therapeutic delivery method in children and adults. Surfactant Replacement Therapy (SRT) exists and is a life-saving clinical procedure in treating Infant Respiratory Distress Syndrome (IRDS) in preterm neonates. Born before the 28th week of gestation (780,000/yr. worldwide), these babies’ immature lungs lack pulmonary surfactant. In IRDS, SRT is based on endotracheal administration of liquid surfactant instillations. However, due to stark differences in lung size, this clinical strategy is ineffective in older populations.
LIFT’s long-term vision is to overcome the challenges of ineffective therapeutic delivery to the lungs that continue to impede successful SRT for ARDS. While alternative pharmacological solutions for ARDS treatment have been examined, none are known to be effective7,8. This includes intravenous injections (e.g. glucocorticoids, Methylprednisolone), enteral administration (e.g. n-3 fatty acids, γ-linolenic acid, and antioxidants) and aerosol inhalation (e.g. heparin, rosuvastatin, ketoconazole). LIFT is anticipated not only to help reduce mortality rates, but also bring down healthcare costs by shortening hospitalization and rehabilitation periods. From a financial viability standpoint, generic versions of the necessary therapeutic agent for SRT are broadly available (i.e. pulmonary surfactant). LIFT can prove scalable preferably through future partnering with existing FDA approved surfactant manufacturers (Chiesi, Abbvie, ONY among others), or via in-house implementation of established surfactant manufacturing techniques. In parallel, the high direct costs associated with ARDS hospitalization in the ICU (mean cost of $80,000 per patient in the US) offer an opportunity for attractive margins of profitability and a sustainable business model.