SBIR-STTR Award

A Novel Combination Therapy to Treat Biofilm-Based Pneumonia Infections
Award last edited on: 12/29/2023

Sponsored Program
STTR
Awarding Agency
NIH : NIAID
Total Award Amount
$569,780
Award Phase
2
Solicitation Topic Code
855
Principal Investigator
Elke Lipka

Company Information

TSRL Inc (AKA: Therapeutic Systems Research Laboratories)

540 Avis Drive Suite A
Ann Arbor, MI 48108
   (734) 663-4233
   info@tsrlinc.com
   www.tsrlinc.com

Research Institution

Michigan State University

Phase I

Contract Number: 1R41AI143098-01A1
Start Date: 3/6/2019    Completed: 2/28/2021
Phase I year
2019
Phase I Amount
$299,733
Bronchiectasis is a lung pathology characterized by a permanent dilation of the bronchi and is associated with a chronic cough, sputum production and recurrent respiratory infections. Cystic fibrosis (CF) is one of the best understood inherited conditions that leads to progressive bronchiectasis, chronic bacterial infection and premature mortality. Both non-CF bronchiectasis (NCFB) and CF have increased in prevalence and present a significant burden on healthcare systems worldwide, with an estimated prevalence of NCFB of about 213 cases per 100,000 persons. These data suggest that between 340,000 and 522,000 adults were receiving treatment for NCFB in 2013 and that 70,000 adults were newly diagnosed that year. CF, affects 70,000 people worldwide. Both CF and NCFB are associated with bacterial biofilms, which are difficult to clear with standard antibiotics as bacteria residing in a bio?lm have increased basal resistance or tolerance to antibiotics, often at 1000X the level of their planktonic counterparts. Therefore, many biofilm-based infections, such as CF and NCFB, are never cleared by antibiotic therapy, and chronic infections are now recognized as a bio?lm-based disease. Developing new therapeutic interventions that potentiate the ability of antibiotics to sterilize biofilms would be highly significant in the clinic to prevent and resolve these infections. This Phase I SBIR proposes experiments to further develop a novel antimicrobial combination therapeutic for the treatment of CF and NCFB by pulmonary delivery. We previously designed and carried out a high-throughput screen to identify small molecules that enhances tobramycin killing of P. aeruginosa biofilms. This screen led us to discover that the commonly used antimicrobial agent triclosan, when combined with tobramycin, increases biofilm eradication by over 100-fold compared to either treatment alone. This combination also shows activity against Gram-positive biofilm formers. Based on the extensive safety studies of triclosan and an acceptable safety profile, this combination, delivered directly to the lung, has significant clinical potential. Our team of the Waters laboratory at Michigan State University and the TSRL Preclinical Accelerator brings together diverse expertise in biofilm formation, animal models of efficacy, PK/PD studies, and product development to perform the pre-clinical studies necessary to initiate a pre-IND meeting with the FDA.

Public Health Relevance Statement:
Project Narrative TSRL and its collaborators at Michigan State University are developing a novel combination antibiotic drug product for the treatment of, initially, bacterial infections in cystic fibrosis and non-cystic fibrosis bronchiectasis patients. The proposed research will establish the proof-of-concept that effective treatment of pulmonary bacterial infections can be achieved with this novel combination product, without rendering significant treatment limiting toxic effects.

Project Terms:
Adult; Affect; Age; Animal Model; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; antibiotic tolerance; Antibiotics; antimicrobial; antimicrobial drug; Bacteria; Bacterial Infections; Bacteriology; base; Bronchi; Bronchiectasis; Cessation of life; Chronic; chronic infection; Chronic Obstructive Airway Disease; Clinic; Clinical; clinical development; Combined Antibiotics; Combined Modality Therapy; Communicable Diseases; cost; Coughing; Coupled; Cystic Fibrosis; cystic fibrosis infection; cystic fibrosis patients; Data; design; Diagnosis; Disease; Dose; Drug Combinations; Drug Kinetics; Economic Burden; effective therapy; efflux pump; Ensure; Evaluation; Exhibits; experience; experimental study; Formulation; Foundations; Healthcare Systems; high throughput screening; Hospitalization; hospitalization rates; improved; in vitro activity; in vivo; Infection; Inflammation; Inflammatory Response; Inhalation; Inherited; Laboratories; Lead; Length of Stay; Licensing; Lung; lung basal segment; Lung diseases; Lung infections; medication safety; meetings; Michigan; Microbe; Microbial Biofilms; Microbiology; Morbidity - disease rate; mortality; Mus; Nebulizer; Newly Diagnosed; novel; novel therapeutic intervention; Outcome; patient registry; Patients; Persons; Pharmaceutical Preparations; Pharmacodynamics; pharmacokinetics and pharmacodynamics; Phase; Pneumonia; Powder dose form; pre-clinical; preclinical efficacy; preclinical study; Premature Mortality; Prevalence; prevent; product development; Production; Proton-Motive Force; Pseudomonas aeruginosa; pulmonary function; Pulmonary Pathology; Quality of life; Recurrence; Research; Resistance; Respiratory Tract Infections; response; Safety; safety study; Small Business Innovation Research Grant; small molecule; Sputum; survival prediction; Technology; Therapeutic; Tissues; Tobramycin; Toxic effect; Toxicology; Treatment Efficacy; Treatment outcome; Triclosan; United States; Universities; Water

Phase II

Contract Number: 5R41AI143098-02
Start Date: 3/6/2019    Completed: 2/28/2021
Phase II year
2020
Phase II Amount
$270,047
Bronchiectasis is a lung pathology characterized by a permanent dilation of the bronchi and is associated with a chronic cough, sputum production and recurrent respiratory infections. Cystic fibrosis (CF) is one of the best understood inherited conditions that leads to progressive bronchiectasis, chronic bacterial infection and premature mortality. Both non-CF bronchiectasis (NCFB) and CF have increased in prevalence and present a significant burden on healthcare systems worldwide, with an estimated prevalence of NCFB of about 213 cases per 100,000 persons. These data suggest that between 340,000 and 522,000 adults were receiving treatment for NCFB in 2013 and that 70,000 adults were newly diagnosed that year. CF, affects 70,000 people worldwide. Both CF and NCFB are associated with bacterial biofilms, which are difficult to clear with standard antibiotics as bacteria residing in a bio?lm have increased basal resistance or tolerance to antibiotics, often at 1000X the level of their planktonic counterparts. Therefore, many biofilm-based infections, such as CF and NCFB, are never cleared by antibiotic therapy, and chronic infections are now recognized as a bio?lm-based disease. Developing new therapeutic interventions that potentiate the ability of antibiotics to sterilize biofilms would be highly significant in the clinic to prevent and resolve these infections. This Phase I SBIR proposes experiments to further develop a novel antimicrobial combination therapeutic for the treatment of CF and NCFB by pulmonary delivery. We previously designed and carried out a high-throughput screen to identify small molecules that enhances tobramycin killing of P. aeruginosa biofilms. This screen led us to discover that the commonly used antimicrobial agent triclosan, when combined with tobramycin, increases biofilm eradication by over 100-fold compared to either treatment alone. This combination also shows activity against Gram-positive biofilm formers. Based on the extensive safety studies of triclosan and an acceptable safety profile, this combination, delivered directly to the lung, has significant clinical potential. Our team of the Waters laboratory at Michigan State University and the TSRL Preclinical Accelerator brings together diverse expertise in biofilm formation, animal models of efficacy, PK/PD studies, and product development to perform the pre-clinical studies necessary to initiate a pre-IND meeting with the FDA.

Public Health Relevance Statement:
Project Narrative TSRL and its collaborators at Michigan State University are developing a novel combination antibiotic drug product for the treatment of, initially, bacterial infections in cystic fibrosis and non-cystic fibrosis bronchiectasis patients. The proposed research will establish the proof-of-concept that effective treatment of pulmonary bacterial infections can be achieved with this novel combination product, without rendering significant treatment limiting toxic effects.

Project Terms:
Adult; Affect; Age; Animal Model; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; antibiotic tolerance; Antibiotics; antimicrobial; antimicrobial drug; Bacteria; Bacterial Infections; Bacteriology; base; Bronchi; Bronchiectasis; Cessation of life; Chronic; chronic infection; Chronic Obstructive Airway Disease; Clinic; Clinical; clinical development; Combined Antibiotics; Combined Modality Therapy; Communicable Diseases; cost; Coughing; Coupled; Cystic Fibrosis; cystic fibrosis infection; cystic fibrosis patients; Data; design; Diagnosis; Disease; Dose; Drug Combinations; Drug Kinetics; Economic Burden; effective therapy; efflux pump; Ensure; Evaluation; Exhibits; experience; experimental study; Formulation; Foundations; Healthcare Systems; high throughput screening; Hospitalization; hospitalization rates; improved; in vitro activity; in vivo; Infection; Inflammation; Inflammatory Response; Inhalation; Inherited; Laboratories; Lead; Length of Stay; Licensing; Lung; lung basal segment; Lung diseases; Lung infections; medication safety; meetings; Michigan; Microbe; Microbial Biofilms; Microbiology; Morbidity - disease rate; mortality; Mus; Nebulizer; Newly Diagnosed; novel; novel therapeutic intervention; Outcome; patient registry; Patients; Persons; Pharmaceutical Preparations; Pharmacodynamics; pharmacokinetics and pharmacodynamics; Phase; Pneumonia; Powder dose form; pre-clinical; preclinical efficacy; preclinical study; Premature Mortality; Prevalence; prevent; product development; Production; Proton-Motive Force; Pseudomonas aeruginosa; pulmonary function; Pulmonary Pathology; Quality of life; Recurrence; Research; Resistance; Respiratory Tract Infections; response; Safety; safety study; Small Business Innovation Research Grant; small molecule; Sputum; survival prediction; Technology; Therapeutic; Tissues; Tobramycin; Toxic effect; Toxicology; Treatment Efficacy; Treatment outcome; Triclosan; United States; Universities; Water