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12 OctOber 2022 Inhalation Process targets for an EEG formulation differ from typical inhalation dry powders, instead targeting par- ticles with a distribution centered around approxi- mately 1.5 µm. is smaller particle size allows the API to be delivered deep into the lung tissue, where the powder is exposed to the humid environment of the lung. e hygroscopic excipient absorbs water, causing particle growth. In turn, the particle growth improves particle deposition and prevents exhalation of the smallest particles. [13] In addition to meeting the needs for delivery effi- ciency and reducing potential exposure for clinicians, spray drying also allows for generation of compos- ite materials and enables the EEG platform. e key performance targets for this process are: • Inhalation particle size, with a high fraction of particles less than 1 µm • Low water content • Low water exposure post-manufacturing e spray-dried intermediate includes gemcitabine, the hygroscopic agent and a dispersion enhancer. is formulation was then tested in a pre-clinical, in vivo study in nude rats against the standard-of- care. e study design, a collaboration between Quench Medical and Lovelace Biomedical, is sum- marized in Table 1. Rat participants not in the naïve control population were dosed with human lung adenocarcinoma A549 cancer cells, which were allowed to grow for three weeks. After that point, dosing with gemcitabine occurred once per week for four consecutive weeks. After completion of the study, lungs from the animals were measured for weight, as a proxy for disease bur- den. e data from the study is depicted in Figure 1. e localized dosing of gemcitabine has a pro- nounced effect on lung weight. Rats without cancer have a lung weight of ~1.5 g. Lung weight above this value is attributed to the mass of cancerous tumors. Treatment by IV standard-of-care did not produce a statistically-significant reduction in lung weight (p = 0.0605). In contrast, the EEG half-dose treatment reduced tumor burden in the lungs significantly, compared with both untreated and IV standard- of-care groups (p < 0.0001). e reduction in lung weight for the EEG matched-dose group was also significant (p < 0.0001). is case study emphasizes that local delivery can improve efficacy in a NSCLC rat model at both matched and 50% reduced doses. Case study 2: Inhaled bevacizumab dry powder reduces tumor burden in NSCLC rat model [14] Bevacizumab is a monoclonal antibody vascular endo- thelial growth factor (VEGF) inhibitor approved for the treatment of colon cancer, NSCLC and glioblas- toma. It acts in the body by disrupting angiogenesis, Case study 1: Dry powder gemcitabine with excipient-enhanced growth [12] Gemcitabine is an approved, cytotoxic chemotherapy for the treatment of NSCLC through IV delivery. Dose-limiting toxicity is a problem for gemcitabine, so local delivery to the lung could greatly enhance treatment potential and improve patient comfort. Following previous safety and efficacy studies using a nebulized formulation, Quench Medical and Lonza are partnering to deliver this API directly to the site of action by using a spray-dried powder. is formu- lation is designed to improve delivery efficiency and protect care providers from this highly potent API. e strategy for delivering gemcitabine to the target tissues in the deep lung rests upon excipient-enhanced growth (EEG) technology. Using EEG, a hygro- scopic excipient is included in the spray-dried inter- mediate, which will swell upon exposure to moisture. Figure 1 Efficacy of the Quench inhaled EEG formulation with a matched dose (1 mg/kg) and half dose (0.5 mg/kg) versus IV standard-of-care (1 mg/kg). From reference 12. Reprinted with permission. Lung Weight (grams) 20 15 10 5 0 P < 0.0001 P = 0.0605 P < 0.0001 No Cancer Untreated Standard IV 1 mg/kg Quench EEG 0.5 mg/kg Quench EEG 1 mg/kg Table 1 Efficacy study design for gemcitabine. Adapted from Reference 7. Arm Cancer Cells Treatment Route Dose Naïve Control No NA NA Sham Control Yes NA NA Clinical IV Standard Yes Intravenous 1 mg/kg Inhalation - Same IV Dose Yes Inhalation 1 mg/kg Inhalation - ½ IV Dose Yes Inhalation 0.5 mg/kg