The overall objective of this project is to progress NH01, a pure (neat) dry powder of amphotericin B (AMB) combined with our novel, simple to use, DryNeb, dry powder nebulizer, through proof of principle pulmonary delivery, efficacy, pharmacokinetics (PK), and device-formulation characterization. The results of this program will be a decision gate for follow-on Investigational New Drug (IND)-enabling toxicology and device refinement funded through Phase II SBIR and other sources. NH101 (AMB-DryNeb) satisfies an unmet medical need by targeting common and triazole (antifungal classes, e.g., itraconazole) multidrug resistant (MDR) strains of pulmonary-infecting fungi (including aspergillus species) at the site of lung infection. NH101 will initially focus on cystic fibrosis (CF) and asthma-associated allergic bronchopulmonary aspergillosis (ABPA), a rare, orphan, and severe subset of aspergillosis that causes severe allergic exacerbations and bronchiectasis. ABPA is associated with an estimated 2.5% of asthmatics (~5 million) and 15% (~20,000) of CF patients. Exciting proof of principle results have been generated in many "off label" studies of aerosolized IV formulations of AMB targeted at fungal lung disease including ABPA. However, there are currently no regulatory-approved aerosol therapies indicated for fungal infections/ diseases in the lung. For this project AMB will be formulated as a simple, neat, micronized/milled dry powder using standard techniques (i.e. jet mills, ball mills, etc.) with our established partners at Lonza. The latter avoids the need for blending, non-traditional excipients, and advanced technical expertise associated with carrier- based and spray-dried dry powder formulations. AMB will be delivered clinically by the DryNeb (US 9078985) developed by Dr. Hugh D. Smyth ( Consultant) and exclusively licensed to Nob Hill Therapeutics (NHT). The DryNeb combines the high-dose capacity and easy tidal breathing of an on-demand nebulizer with the portability and stability characteristics of a dry powder inhaler. The AMB-DryNeb will be tested with our collaborator Dr. Pavin Mutilli at the University of New Mexico (UNM). NHT facilities are located on the Lovelace Respiratory Research Institute (LRRI) campus in Albuquerque, NM. NHT will utilize this unique location and LRRI's scientific expertise to perform proof of principle efficacy and safety studies in guinea pigs. **We have further recruited clinical and regulatory expertise, Drs. Betty Change and Don Burstyn, to ensure we have considered "next steps" as the project progresses toward the clinical and a Phase II SBIR submission.** At project's end NH101 will be ready to proceed to IND-enabling toxicology studies funded through a Phase II SBIR or alternate sources.
Public Health Relevance Statement: Multidrug Resistant (MDR) pulmonary fungal infections pose an important threat to public health and increase morbidity and mortality in cystic fibrosis and other lung diseases. If successfully developed, the proposed NHT101 (dry powder nebulizer [DryNebï¤]-amphotericin B) product will overcome major limitations of existing antifungal therapies to treat lung diseases in which MDR is emerging.
Project Terms: Aerosols; Amphotericin B; AmB; AmBisome; Amphocil; Amphotec; Amphotercin B; Fungizone; Mysteclin-F; Antifungal Agents; Antifungal Drug; Therapeutic Fungicides; anti-fungal; anti-fungal agents; anti-fungal drug; antifungals; Arts; Aspergillosis; Allergic Bronchopulmonary Aspergillosis; Bronchopulmonary Aspergillosis; pulmonary aspergillosis; Aspergillus; Breathing; Respiratory Aspiration; Respiratory Inspiration; inspiration; Asthma; Bronchial Asthma; Biological Assay; Assay; Bioassay; Biologic Assays; Bronchiectasis; Clinical Research; Clinical Study; Cystic Fibrosis; Mucoviscidosis; Disease; Disorder; Aerosol Drug Therapy; aerosol therapy; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Investigational Drugs; Investigational New Drugs; Excipients; fungus; Future; In Vitro; Infection; Inhalators; Inhaler; Lung; Lung Respiratory System; pulmonary; Lung diseases; Pulmonary Diseases; Pulmonary Disorder; Respiratory Disease; Respiratory System Disease; Respiratory System Disorder; disease of the lung; disorder of the lung; lung disorder; Fungal Lung Diseases; Chronic Obstructive Airway Disease; COPD; Chronic Obstruction Pulmonary Disease; Chronic Obstructive Lung Disease; Chronic Obstructive Pulmonary Disease; Lung Transplantation; Lung Grafting; lung transplant; Morbidity - disease rate; Morbidity; mortality; Mycoses; Fungus Diseases; fungal infection; fungus infection; Nebulizer; New Mexico; Outpatients; Out-patients; Particle Size; Legal patent; Patents; Patients; Drug Kinetics; Pharmacokinetics; Powder dose form; Powders; pressure; Public Health; Research Institute; Respiratory physiology; lung function; respiratory function; Safety; Testing; Toxicology; Triazoles; Universities; Itraconazole; Sporanox; Technical Expertise; technical skills; Immunocompromised Host; Immunocompromised; Immunocompromised Patient; Immunosuppressed Host; immunosuppressed patient; Guinea Pigs; Guinea Pigs Mammals; Cavia; base; Label; Site; Clinical; Phase; Medical; Ensure; Chemicals; Orphan; Multidrug Resistance; Multiple Drug Resistance; Multiple Drug Resistant; Resistance to Multi-drug; Resistance to Multidrug; Resistance to Multiple Drug; Resistant to Multiple Drug; Resistant to multi-drug; Resistant to multidrug; multi-drug resistant; multidrug resistant; Multi-Drug Resistance; Funding; Therapeutic; programs; milligram; Source; Techniques; Location; respiratory; particle; Performance; solid state; Histopathology; anti-fungal therapy; fungal infectious disease treatment; Antifungal Therapy; novel; Devices; Allergic; Position; Positioning Attribute; Modeling; performance tests; portability; Drops; MDI Inhaler; Metered Dose Inhalers; Metered Dose Inhaler Device; Dose; Reproducibility; SBIR; Small Business Innovation Research; Small Business Innovation Research Grant; Preparation; Characteristics; developmental; Development; safety study; scale up; CF patients; individuals with CF; individuals with cystic fibrosis; patients with CF; patients with cystic fibrosis; cystic fibrosis patients; clinical relevance; clinically relevant; chemotherapy; aerosolized; prototype; commercialization; resistance strain; resistant strain; Phase I Study; phase 1 study; asthmatic; Formulation; PM2.5; fine particulate matter; fine particles; efficacy study; recruit; Inhaling; Inhalation; pulmonary infections; Lung infections; Lung retention; off-label application; off-label prescribing; off-label use; Aspergillus resistance; resistance in Aspergillus; resistant Aspergillus
