SBIR-STTR Award

Safety of Lung Delivered Tissue Plasminogen Activator
Award last edited on: 4/16/19

Sponsored Program
STTR
Awarding Agency
NIH : NHLBI
Total Award Amount
$932,737
Award Phase
2
Solicitation Topic Code
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Principal Investigator
Kathleen A Stringer

Company Information

HTD Biosystems Inc

1061 Serpentine Lane Suite E
Pleasanton, CA 94566
   (510) 367-0528
   htd@htdcorp.com
   www.htdcorp.com

Research Institution

University of Colorado Health Science Center

Phase I

Contract Number: 1R41HL071439-01A1
Start Date: 00/00/00    Completed: 00/00/00
Phase I year
2003
Phase I Amount
$99,693
Acute respiratory distress syndrome (ARDS) afflicts tens of thousands of individuals annually in the United States and is associated with significant mortality. Presently, there is no effective treatment and little optimism exists for prospective therapies currently under investigation. A unique antiinflammatory agent (protein) that reduces neutrophil reactive oxygen species (ROS)-mediated injury in an animal model of lung inflammation has been identified and represents a potentially viable therapy for ARDS. Therefore, the broad, long-term objectives of this research and drug development program are to develop a unique, localized (lung-targeted) therapy that will be effective in reducing the mortality associated with ARDS. The purpose of this phase I application is to prove the principle of this strategy in man by developing a drug formulation that will sustain the nebulization process and distribute adequately into the human respiratory tract. To this end, the specific aims of this project are to: 1) formulate the agent to make it suitable for local pulmonary delivery via nebulization while retaining activity. Optimal formulation will be derived by the addition of varying concentrations of surfactant. The formulation activities will include an assessment of protein stability, aerodynamic particle size, and biological function. Protein stability will be measured by total protein recovery and structural integrity. Particle size will be determine using a cascade impactor and biological activity will be quantified by the ability of the agent to inhibit neutrophil ROS production; 2) characterize the respiratory deposition of a nebulized formulation of the agent in a human lung replica model. This aim is designed to generate additional supportive evidence to prove the principle of the formulation in man. To accomplish this aim, each viable formulation, as determined by the feasibility criteria of specific aim #1, will be nebulized into a human lung replica. A high-fidelity human lung replica reproduced from a master cast made from a human cadaver which includes five to nine generations of bronchi will be utilized. Deposition in the small airways and alveoli regions of the cast is simulated by material that passes through the upstream airways and is collected on foam filters. The results of the work performed in both specific aims will determine the feasibility of the nebulized formulation of this new and novel agent as well as serve as the basis for a phase II application and the subsequent commercialization of the product

Phase II

Contract Number: 2R42HL071439-02
Start Date: 00/00/00    Completed: 00/00/00
Phase II year
2005
(last award dollars: 2006)
Phase II Amount
$833,044

The acute respiratory distress syndrome (ARDS) represents a significant health hazard that is associated with high morbidity and mortality rates. Unfortunately, little progress has been made in advancing the treatment of ARDS. Phase I STTR funding supported the successful determination of a feasible formulation of tissue plasminogen activator (tPA) for pulmonary delivery. The successful outcome of phase I established the rationale for studies in animals to determine the safety of lung delivered; this is the primary objective of our phase II application. Thus, this application represents the advancement of work for pharmacological innovation in the treatment of ARDS and extends phase I studies to in vivo animal models to test the hypothesis that pulmonary delivery of tPA will be safe and well tolerated. To this end, the specific aims of this proposal are to: 1) Formulate pulmonary tPA for lung delivery. Mouse and human tPA will be formulated for pre-clinical toxicology and pharmacokinetic (PK)/pharmacodynamic (PD) studies; 2) Assess the tolerability of the pulmonary formulated tPA by assessing both acute (dose escalating) and chronic (repeated dose) toxicity as determined by utilization of a mouse model which will be subjected to pulmonary instillation and intravenous (IV) administration of tPA formulated for lung delivery. These experiments are designed to measure indicators of toxicity such as pulmonary injury, disruption in coagulation homeostasis and hemorrhage; and 3) Determine the PK and PD disposition of pulmonary delivered tPA. This aim will be accomplished by measuring lung and systemic therapeutic protein concentrations following pulmonary and IV administration of the pulmonary formulation in a rat model. These experiments are designed to assess disruption in coagulation homeostasis (PD end point) in the context of systemic tPA concentrations that are achieved following high doses of tPA (toxicokinetics). The anticipated outcomes associated with the successful completion of the work proposed in this application are: 1) establishment of the safety profile of a pulmonary formulation; 2) the development of a risk probability model for the clinical situation; and 3) preparation of an IND application that is required for eligibility for an FDA Orphan Products Grant Application. The proposed Phase II project will complement and extend our Phase I work and will facilitate the development of a promising new, greatly needed therapeutic for the treatment of ARDS.

Thesaurus Terms:
adult respiratory distress syndrome, drug design /synthesis /production, drug screening /evaluation, plasminogen activator, respiratory disorder chemotherapy disease /disorder model, dosage, inhalation drug administration, intravenous administration, pharmacokinetics human tissue, laboratory mouse, laboratory rat, tissue /cell culture