Lung cancer (LC) with over 2 million cases/year worldwide also remains the leading cause of cancer- related death in the US and Europe. Treating LC remains challenging due to ~60% of patients presenting with Stage IV disease, the heterogeneity of tumors with respect to genetic and epigenetic mechanisms that alter gene expression, and treatment-related resistance. Combining chemotherapy with immunotherapy as the first treatment option for advanced LC has significantly improved response rates and survival; however, median duration for progression free survival (PFS) was still 8.8 versus 4.9 months for Stage IV LC patients receiving chemo/immune versus chemotherapy with 69% and 49% alive at one year, respectively. Second line drugs after relapse provide minimal benefit. Epigenetic deregulation involves cytosine methylation in the promoter region of hundreds of genes to impede transcription leading to loss of expression. Thus, a therapy that could reverse methylation and awaken these genes could produce durable and sustained tumor regression. The cytosine nucleoside analogs 5-azacytidine (5AZA) and 5-aza-2'-deoxycytidine (DAC) inhibit the enzyme responsible for cytosine methylation resulting in re-expression of genes silenced through cytosine promoter hypermethylation. These FDA approved drugs are serving as potent therapy for blood-borne cancers, myelodysplasia and acute leukemia. Epigenetic therapy for solid tumors including LC has been impacted by the poor stability in an aqueous solution of 5AZA and DAC and catabolism by cytidine deaminase in liver and GI. Lovelace Biomedical working with Bend Research/Lonza have overcome these barriers by developing a stable dry powder (DP) formulation of 5AZA (5AZA-DP). The novel dry powder nebulizer (DryNeb) developed by Nob Hill Therapeutics generates optimal aerosol particle sizes for local lung delivery-activity and optimal systemic absorption characteristics while facilitating patients' "easy" tidal breathing inhalation with no forced pulmonary function maneuvers. In studies in which 5AZA-DP was delivered to tidally breathing rats, superior pharmacokinetics were achieved in the liver, and most impressively to the brain with a half-life of 4 hours when compared with injected aqueous solutions of 5AZA. Using a rat lung tumor model developed from instilling cells obtained from human lung tumors, tidally inhaled 5AZA-DP reduced tumor burden by 70-95% for the 4 different non-small cell lung tumors evaluated, far exceeding the 32% reduction seen with systemic injection of 5AZA. A proof-of-concept clinical study showed stable localized lung cancer in 3 of 8 Phase I patients treated with nebulized aqueous 5AZA. This Phase II SBIR through three specific aims builds on these exciting data by focusing on performing formulation scale up and stability optimization of 5AZA-DP, aerosol performance in the DryNeb, and GLP toxicology studies. Completion of these aims will support filing an investigational drug application (IND) to the FDA to allow evaluation of 5AZA-DP using DryNeb in a Phase I dose escalation safety study followed by a Phase IB study in LC patients who have relapsed on standard-of-care therapy.
Public Health Relevance Statement: Project Relevance This Phase II SBIR application builds on exciting preclinical pharmacokinetic and efficacy data for inhaled 5-azacytidine dry powder formulation (5AZA-DP) in rodent lung cancer models by focusing on performing formulation scale up and stability, optimization of 5AZA-DP aerosol performance in the novel dry powder nebulizer DryNeb, and GLP toxicology studies. Completion of work will support filing an investigational drug application (IND) to the FDA to enable first in human safety and proof of concept studies that could ultimately improve progression free survival for lung cancer patients.
Project Terms: Lung; Lung Respiratory System; pulmonary; Lung Neoplasms; Lung Tumor; Pulmonary Neoplasms; Methylation; Dysmyelopoietic Syndromes; Myelodysplastic Disease; Myelodysplastic Syndromes; Refractory Anemia with an Excess of Blasts; Refractory anaemia with excess blasts; Smoldering Leukemia; myelodysplasia; Nebulizer; nebulization; nebulize; Particle Size; Legal patent; Patents; Patients; Drug Kinetics; Pharmacokinetics; Powder dose form; Powders; pressure; Promoter Regions; Promotor Regions; genetic promoter element; genetic promoter sequence; promoter sequence; Rattus; Common Rat Strains; Rat; Rats Mammals; Relapse; Research; Rodent; Rodentia; Rodents Mammals; Safety; Signal Pathway; Technology; Testing; Tissues; Body Tissues; Toxicology; Genetic Transcription; Gene Transcription; RNA Expression; Transcription; Work; Acute leukemia; promotor; promoter; Practice Guidelines; quality assurance; Label; improved; Phase; Chemicals; Evaluation; lung function; pulmonary function; Malignant Tumor of the Lung; Pulmonary Cancer; Pulmonary malignant Neoplasm; lung cancer; Malignant neoplasm of lung; Progression-Free Survivals; Solid Tumor; Solid Neoplasm; Therapeutic; Genetic; programs; Hour; Immune; Immunes; Stream; Clinic; nucleoside analog; Performance; success; Gene Silencing; Gene Inactivation; transcriptional silencing; aqueous; novel; Devices; Catabolism; Reporting; Modeling; response; Documentation; Phase I Clinical Trials; Early-Stage Clinical Trials; Phase 1 Clinical Trials; phase I protocol; Dose; Tumor Burden; Tumor Load; Data; Dryness; Hypermethylation; Inhalation Toxicology; Regulatory Pathway; in vivo; Cancer Etiology; Cancer Cause; Cancer Model; CancerModel; Cancer Patient; research clinical testing; Clinical Evaluation; Clinical Testing; clinical test; Epigenetic Process; Epigenetic; Epigenetic Change; Epigenetic Mechanism; epigenetically; Rodent Model; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Characteristics; Enzyme Inhibition; safety study; pre-clinical; preclinical; scale up; innovate; innovative; innovation; resistant; Resistance; chemotherapy; aerosolized; tumor; FDA approved; standard of care; good laboratory practice; Immune Cell Activation; immune activation; RNA Seq; RNA sequencing; RNAseq; transcriptomic sequencing; transcriptome sequencing; phase 3 trial; phase III trial; global gene expression; global transcription profile; transcriptome; Formulation; Intratumoral heterogeneity; heterogeneity in tumors; intra-tumoral heterogeneity; intratumor heterogeneity; tumor heterogeneity; Injections; epigenetic therapy; Inhaling; Inhalation; first in man; first-in-human; Chronic Obstructive Pulmonary Disease; COPD; Chronic Obstruction Pulmonary Disease; Chronic Obstructive Lung Disease; manufacture; absorption; Aerosols; Air; air flow; airflow; Air Movements; Breathing; Respiratory Aspiration; Respiratory Inspiration; inspiration; Azacitidine; 5 AZC; 5-AC; 5-Aza-cytidine; 5-Azacytidine; AZC; Azacytidine; ladakamycin; Brain; Brain Nervous System; Encephalon; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Cells; Cell Body; Clinical Research; Clinical Study; Cytidine Deaminase; Cytidine Aminohydrolase; Cytosine; Cessation of life; Death; Deoxycytidine; 2'-deoxy-cytidine; Cytosine Deoxyribonucleoside; Cytosine Deoxyriboside; Diagnosis; Disease; Disorder; Combination Drug Therapy; Polychemotherapy; combination chemotherapy; combination pharmacotherapy; combined drug therapy; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Investigational Drugs; Investigational New Drugs; Emulsions; Europe; Forced expiratory volume function; FEVt; Forced Expiratory Volume; Timed Forced Vital Capacity; Timed Vital Capacity; Gene Expression; Genes; Half-Life; Human; Modern Man; Immunotherapy; Immune mediated therapy; Immunologically Directed Therapy; immune therapeutic approach; immune therapeutic interventions; immune therapeutic regimens; immune therapeutic strategy; immune therapy; immune-based therapies; immune-based treatments; immuno therapy; Inhalators; Inhaler; Liver; hepatic body system; hepatic organ system
