Aerosolized Chemically Modified Tetracycline Nanoformulation for the Treatment of Acute Respiratory Distress Syndrome

PROJECT SUMMARY/ABSTRACT CMTx Biotech is a drug development company working to rescue, develop and commercialize a proprietary clinical-stage drug candidate, incyclinide (CMT-3 / COL-3), for the treatment of sepsis patients at risk of acute respiratory distress syndrome (ARDS). According to the U.S. Centers for Disease Control (CDC), at least 1.7 million American adults develop sepsis annually, resulting in nearly 270,000 deaths. Sepsis accounts for more than 50% of hospital deaths, and mortality increases dramatically with greater disease severity: 10–20% for sepsis, 20–40% for severe sepsis, and 40–80% for septic shock. Sepsis is a medical emergency characterized by severe immune dysregulation with a very complex immunopathogenesis. ARDS is a devastating complication of severe sepsis, both with similar underlying mechanisms characterized by inflammation and endothelial dysfunction. Sepsis is the leading cause of ARDS and accounts for 32% of the etiology of the condition. Approximately 6-7% of sepsis patients rapidly progress to ARDS, which is associated with a significantly increased risk of in-hospital mortality. There is currently no specific treatment for sepsis-induced ARDS. Moreover, researchers have not yet elucidated the multifactorial mechanisms by which sepsis induces ARDS, or why the inflammatory cytokine storm eventually induces diffuse alveolar damage and severe hypoxia. Though advances in treatment modalities have improved the outcome over recent decades, including lung protective ventilation, prone positioning, use of neuromuscular blockade, and extracorporeal membrane oxygenation, the mortality rate still remains high. There remains a critical unmet need for the development of safe and efficacious therapeutics to prevent the onset of sepsis-induced ARDS, protect against lung injury and improve survival. CMTx Biotech is working to develop and commercialize a novel and proprietary nanoformulation of incyclinide (nCMT-3) that can be aerosolized, and which can be delivered to specifically target the lung and treat sepsis- induced ARDS while limiting systemic toxicity. Incyclinide is a clinical-stage, non-antibiotic, chemically-modified tetracycline that belongs to a class of pleiotropic matrix metalloproteinase (MMP) modulators which inhibit pathologically-excessive collagenolysis and resolve systemic inflammation. Importantly, the safety of incyclinide has already been demonstrated in Investigational New Drug (IND)-enabling studies, and incyclinide has been evaluated in a number of human clinical trials for the treatment of diseases as disparate as AIDS-related Kaposi’s sarcoma, recurrent high-grade gliomas, refractory metastatic cancer, acne, rosacea and periodontitis. Published pre-clinical efficacy studies have shown that systemic administration of incyclinide prevents the development of ARDS and septic shock, and improves survival in several chronic insidious onset animal models of ARDS across several species, including mice, rats, pigs, and sheep. Our long-term goal is to obtain regulatory approval from the FDA and comparable international regulatory authorities to market aerosolized nCMT-3 for the treatment and prevention of sepsis-induced ARDS. We strongly anticipate that nCMT-3 will inhibit disease progression, mitigate acute lung injury and respiratory distress, reduce the need for intensive care and intubation, and improve clinical outcomes for sepsis patients, including overall survival. Our specific aims are (a) to determine the pharmacokinetics, biodistribution, and safety of aerosolized nCMT-3 in mechanically ventilated pigs with healthy lungs, (b) to demonstrate the efficacy of aerosolized nCMT-3 in reducing the incidence and mortality of sepsis- mediated ARDS in a high-fidelity, clinically applicable porcine sepsis-induced ARDS model, and (c) to demonstrate the efficacy of aerosolized nCMT-3 at reducing local and systemic inflammation. Successful completion of these studies will allow CMTx Biotech to advance nCMT-3 towards human clinical trials for the treatment of ARDS patients.