SBIR-STTR Award

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality worldwide. The currently available treatments are largely palliative and have minimal impact on the inflammatory process in COPD that inexorably leads to a decline in lung function. Unlike asthma, for which inhaled corticosteroids are a highly effective treatment, COPD appears to be a largely steroid- resistant disease. Therefore, there is a pressing need to develop drugs that also target other components of the disease, mainly airway inflammation and remodeling. By reducing airway resistance and aspects of inflammation, Rho kinase inhibitors represent a novel approach to provide symptomatic improvement and slow the progression of the disease. Our overall objective is to develop an inhaled, safe and efficacious ROCK inhibitor as maintenance therapy for airflow obstruction in patients with COPD, including chronic bronchitis and emphysema. Theron has identified a highly potent inhibitor of the human ROCK-1 and ROCK-2 isoenzymes. The purpose of this proposal is to further characterize the lead inhibitor TRN-101 in models that are relevant to airway resistance, inflammation and remodeling. The specific aims of this phase I proposal are: 1) to demonstrate the bronchoprotective effect of an inhaled ROCK inhibitor, TRN-101, against methacholine-induced bronchospasm in anaesthetized rats; and 2)to evaluate the effects of TRN-101 on airway inflammation using an in vivo mouse model of COPD exacerbation. The latter study will focus on the effects of an inhaled ROCK inhibitor on neutrophil trafficking in the airways of mice challenged with lipopolysaccharide (LPS). By achieving the specific aims outlined above, we believe Theron Pharmaceuticals can advance a novel pharmacological treatment for COPD. Because of the potential anti-inflammatory activity and impact on tissue remodeling, ROCK inhibitors could offer unprecedented benefits for the treatment of this disease.

Public Health Relevance:
Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality worldwide. The current available treatments are largely palliative and have minimal impact on the inflammatory process in COPD that leads to an inexorable decline in lung function. By reducing airway resistance and aspects of inflammation, Rho kinase inhibitors represent a novel approach to provide symptomatic improvement and to slow the progression of the disease. Our overall objective is to develop an inhaled, safe and efficacious ROCK inhibitor as maintenance therapy for airflow obstruction in patients with COPD, including chronic bronchitis and emphysema.

Thesaurus Terms:
"2-(Acetyloxy)-N,N,N-Trimethylethanaminium; Acetylcholine; Acidophilic Leukocyte; Actins; Address; Adrenal Cortex Hormones; Agonist; Airway Resistance; Anti-Inflammatories; Anti-Inflammatory Agents; Anti-Inflammatory; Antiinflammatories; Antiinflammatory Agents; Aspiration, Respiratory; Asthma; Blood Eosinophil; Blood Neutrophil; Blood Polymorphonuclear Neutrophil; Blood Segmented Neutrophil; Body Tissues; Breathing; Bronchial Asthma; Bronchial Constriction; Bronchial Spasm; Bronchial-Constricting Agents; Bronchial-Dilating Agents; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Bronchoconstrictor Agents; Bronchoconstrictors; Bronchodilator Agents; Bronchodilators; Bronchospasm; Coad; Copd; Caliber; Cavia; Cell Communication And Signaling; Cell Signaling; Cells; Characteristics; Chemotaxis; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Chronic Obstructive Lung Disease; Combined Modality Therapy; Common Rat Strains; Corticoids; Corticosteroids; Cytokines, Chemotactic; Development; Diameter; Disease; Disease Progression; Disease Resistance; Disorder; Drugs; Emphysema; Environmental Air Flow; Eosinophilic Granulocyte; Eosinophilic Leukocyte; Esteroproteases; Ethanaminium, 2-(Acetyloxy)-N,N,N-Trimethyl-; Goals; Granulocyte Elastase; Guinea Pigs; Heterophil Granulocyte; Homologous Chemotactic Cytokines; Human; Human, General; Ic50; Inflm; Infiltration; Inflammation; Inflammatory; Inhalation; Inhaling; Inhibitory Concentration 50; Inspiration, Respiratory; Intercrines; Intracellular Communication And Signaling; Isoenzymes; Isozymes; Lps; Lead; Leukocyte Elastase; Lipopolysaccharides; Lung; Lysosomal Elastase; Maintenance Therapy; Mammals, Guinea Pigs; Mammals, Mice; Mammals, Rats; Man (Taxonomy); Man, Modern; Marrow Eosinophil; Marrow Neutrophil; Measures; Medication; Mice; Modeling; Molecular; Mono-S; Monos; Morbidity; Morbidity - Disease Rate; Mortality; Mortality Vital Statistics; Multimodal Therapy; Multimodal Treatment; Multimodality Treatment; Murine; Mus; Muscle Relaxation; Muscle Relaxation Phase; Muscle, Involuntary; Muscle, Smooth; Neutrophil Elastase; Neutrophil Infiltration; Neutrophil Recruitment; Neutrophilic Granulocyte; Neutrophilic Leukocyte; Obstruction; P160rock; Pmn Elastase; Pathogenesis; Patients; Pb Element; Peptidases; Peptide Hydrolases; Pharmaceutic Preparations; Pharmaceutical Agent; Pharmaceutical Preparations; Pharmaceuticals; Pharmacologic Substance; Pharmacological Substance; Pharmacological Treatment; Phase; Play; Polymorph; Polymorphonuclear Cell; Polymorphonuclear Leukocyte Elastase; Polymorphonuclear Leukocytes; Polymorphonuclear Neutrophils; Pressure; Pressure- Physical Agent; Process; Prostaglandins; Prostanoids; Proteases; Protein-Serine Kinase; Protein-Serine-Threonine Kinases; Protein-Threonine Kinase; Proteinases; Proteolytic Enzymes; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Rock1; Rock1 Gene; Rat; Rattus; Regulatory Pathway; Research Design; Resistance, Disease; Respiratory System, Lung; Respiratory Physiology; Rho-Associated Kinase; Rho-Kinase; Role; Sis Cytokines; Serine Kinase; Serine-Threonine Kinases; Side; Signal Transduction; Signal Transduction Systems; Signaling; Smooth Muscle (Tissue); Source; Steroid Resistance; Steroid Resistant; Stimulus; Study Type; Symptoms; Therapeutic Corticosteroid; Therapeutic Effect; Threonine Kinase; Time; Tissues; Ventilation; Airway Epithelium Infalmmation; Airway Inflammation; Airway Smooth Muscle; Biological Signal Transduction; Chemoattractant Cytokine; Chemokine; Combination Therapy; Combined Modality Treatment; Combined Treatment; Cytokine; Disease/Disorder; Drug/Agent; Effective Therapy; Eosinocyte; Eosinophil; Experience; Heavy Metal Pb; Heavy Metal Lead; In Vivo; Inhibitor; Inhibitor/Antagonist; Inspiration; Kinase Inhibitor; Lead Series; Lipid Mediator; Lumen Dilator; Lung Function; Methacholine; Methylxanthine; Migration; Mouse Model; Multimodality Therapy; Neutrophil; New Approaches; Novel; Novel Approaches; Novel Strategies; Novel Strategy; Palliative; Pressure; Prototype; Public Health Relevance; Pulmonary; Residence; Resistance To Disease; Resistant Disease; Resistant To Disease; Respiratory Function; Respiratory Smooth Muscle; Response; Rho; Rho G-Proteins; Rho Gtp-Binding Proteins; Rho Gtpases; Rho Protein P21; Rho Small Gtp-Binding Proteins; Social Role; Study Design; Symptomatic Improvement; Trafficking"

Our overall objective is to develop an inhaled, safe and efficacious Rho kinase (ROCK) inhibitor as novel maintenance therapy for patients with chronic obstructive pulmonary disease (COPD), with the unique potential to slow disease progression. COPD is one of the leading causes of morbidity and mortality worldwide due to high disease prevalence and ineffective therapies. COPD is the 3rd leading cause of death in the United States and is responsible for billions of dollars in annual healthcare costs. Current treatments are largely palliative and have minimal impact on the key inflammatory processes in COPD that inexorably lead to disease progression and associated decline in lung function. Therefore, there is an urgent need to develop drugs that target components of COPD not affected by present medicines. There is increasing evidence that the ROCK isoforms, ROCK1 and ROCK2, play an important role in the maintenance of airways tone and in lung inflammation and remodeling, suggesting that ROCK inhibitors may represent a novel approach for COPD. Theratrophix (TRX) has identified potent inhibitors of the human ROCK1 and ROCK2 isoenzymes, including the lead TRX-101, that are more potent than the prototype ROCK inhibitors, fasudil and Y-27632. The results of the previous Phase 1 SBIR (1R43HL104902-01) demonstrated that TRX-101 had bronchoprotective, anti-inflammatory and anti-fibrotic effects in rodent systems in vitro and in vivo. In this proposal we outline a series of decision-making preclinical studies to evaluate and progress an inhaled ROCK inhibitor, TRX-101 or analog, to the preclinical development phase as a potential novel therapeutic for COPD; the profiling is underpinned by investigation in several disease-relevant systems. The specific aims of this Phase 2 proposal are: Aim 1: Developability profile of TRX-101 and analogs, including pharmacokinetic (PK) characteristics - to determine which compound has the desired characteristics for a long-acting, inhaled compound, including sustained lung retention and pharmacodynamic activity, and the physicochemical characteristics for inhaled delivery; Aim 2: Assessment of bronchodilator and anti-inflammatory effects of selected TRX-compound in human lung systems - A series of key translational medicine studies will be conducted using human precision-cut lung slices and human airway smooth muscle cells, and human lung fibroblasts; Aim 3: Evaluation of inhaled TRX- compound in mouse models of cigarette smoke-induced COPD, to determine the in vivo effects in a disease-relevant animal model that is resistant to corticosteroids. By achieving the specific aims outlined it is anticipated that Theratrophix will have identified a quality inhaled ROCK inhibitor which will be ready to enter IND-enabling studies as a critical step towards initiation of clinical trials in COPD. Based upon the ability to produce potent bronchodilation, anti-inflammatory activity and an impact on tissue remodeling in a single molecular entity, an inhaled ROCK inhibitor has the potential to have a unique profile which could offer unprecedented therapeutic benefits in COPD, in particular slowing disease progression.

Public Health Relevance Statement:


Public Health Relevance:
Chronic obstructive pulmonary disease (COPD) is a very serious, common lung disease which is a global problem and does not have good medicines to treat it. COPD is the 3rd leading cause of death in the United States and is responsible for billions of dollars in annual healthcare costs. Current treatment for COPD improves some symptoms but does not impact the progressive damage to the airways and decline in lung function. This research proposal seeks to investigate whether a potential new type of COPD drug we have identified (called a Rho kinase or ROCK inhibitor) will likely have benefit and be safe to test in humans. The overall goal is to progress an inhaled ROCK inhibitor to clinic trials with the hope that it will become a breakthrough medicine for COPD, with a unique profile by both improving symptoms and slowing the progression of the disease.

NIH Spending Category:
Chronic Obstructive Pulmonary Disease; Lung

Project Terms:
absorption; Adrenal Cortex Hormones; Affect; Aftercare; Agonist; airway hyperresponsiveness; analog; Animal Model; Anti-inflammatory; Anti-Inflammatory Agents; base; Biological; Breathing; Bronchodilation; Bronchodilator Agents; Cardiotoxicity; Cause of Death; Characteristics; Chronic Obstructive Airway Disease; cigarette smoke-induced; Clinic; Clinical; Clinical Trials; Contracts; cytokine; Data; Decision Making; Deposition; Development; Disease; Disease Progression; Dose; Drug Interactions; Drug Kinetics; drug metabolism; Drug Targeting; Ensure; environmental tobacco smoke exposure; Evaluation; Excretory function; fasudil; Fibroblasts; Goals; Health Care Costs; Human; human disease; improved; In Vitro; in vitro Assay; in vivo; in vivo Model; Individual; Inflammatory; inhibitor/antagonist; Intravenous; Investigation; Isoenzymes; Lead; Link; Lung; Lung diseases; Lung Inflammation; Maintenance; Maintenance Therapy; Medical; Medicine; Metabolic; Metabolism; migration; Modeling; Molecular; Morbidity - disease rate; Mortality Vital Statistics; mouse model; novel; novel strategies; novel therapeutics; Oral Administration; ozone exposure; palliative; Patients; Pennsylvania; Pharmaceutical Preparations; Pharmacodynamics; pharmacokinetic characteristic; Phase; Phosphotransferases; Plasma Proteins; Platelet-Derived Growth Factor; Play; pre-clinical; preclinical study; Prevalence; Process; Property; Prophylactic treatment; Protein Binding; Protein Isoforms; prototype; public health relevance; pulmonary function; Research Proposals; research study; Resistance; Respiratory physiology; respiratory smooth muscle; Rho-associated kinase; Risk; ROCK1 gene; Rodent; Role; Route; Safety; Series; Slice; Small Business Innovation Research Grant; Smooth Muscle Myocytes; Symptoms; System; Testing; Therapeutic; Tissues; translational medicine; United States