Preclinical Development Of A Novel Precision Olfactory Delivery (Pod (R)) - L-Dopa Drug-Device Combination Product For The Treatment Of Off Episodes In Parkinson'S Disease

Objective: Impel NeuroPharma has developed the POD device to generate rapid, consistent systemic levels of drugs for neurological diseases. This work was to develop a L-dopa powder formulation delivered by the POD device that results in plasma exposure in rats and non-human primates (NHP), that when extrapolated to humans, will be sufficient to reverse OFF episodes in Parkinson’s disease (PD) patients. Background: L-dopa has been the “platinum” standard PD treatment for over 50 years1,2. As PD advances, patient response to pharmacotherapy decreases; the benefits of L-dopa become increasingly sensitive to change in systemic concentrations resulting in motor fluctuations (OFF episodes)3. Previous studies report the L-dopa plasma concentration threshold for switching from OFF to ON is approximately 400 ng/mL4. POD-L-dopa is a drug-device combination product consisting of a novel L-dopa powder formulation delivered to the upper nasal cavity by the POD device. Design/Methods: Powder L-dopa formulations were designed and manufactured for POD device delivery and evaluated by analytical methods including assay, related substances, X-ray diffraction, differential scanning calorimetry, and device compatibility. Lead formulations were evaluated in rat and NHP using species specific POD devices. Results: Over 50 formulations were manufactured, and 30 formulations were assessed in vivo. PK assessment focused on comparing time to achieve 400 ng/mL plasma levodopa, Tmax, and Cmax. Lead formulation candidates resulted in concentrations of 400 ng/mL within 5 – 12 min in NHP, a 3 to 5-fold improvement compared to unformulated L-dopa. Median Tmax occurred between 30–60 min with Cmax values exceeding 1 μg/mL. Conclusions: Impel is developing POD-L-dopa, a powder formulation of L-dopa delivered to the vascular-rich upper nasal cavity with the POD device, allowing self- or care-giver administration, to achieve consistent and rapidly effective treatment to abort OFF episodes. This work has led to the selection and further evaluation of a novel formulation in a Phase 2A clinical study. Disclosure: Dr. Satterly has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Impel NeuroPharma. Dr. Satterly has received compensation for serving on the Board of Directors of Impel NeuroPharma. Dr. Satterly has received research support from Impel NeuroPharma. Dr. Davies has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Impel NeuroPharma. Dr. Davies has received research support from Impel NeuroPharma. Dr. Gajera has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Impel NeuroPharma. Dr. Gajera has received research support from Impel NeuroPharma. Dr. Wright has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Impel NeuroPharma. Dr. Wright has received research support from Impel NeuroPharma. Dr. Lin has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Impel NeuroPharma. Dr. Lin has received research support from Impel NeuroPharma. Dr. Muppaneni has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Impel NeuroPharma. Dr. Muppaneni has received research support from Impel NeuroPharma. Dr. To has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Impel NeuroPharma. Dr. To has received research support from Impel NeuroPharma. Dr. Dashevsky has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Impel NeuroPharma. Dr. Dashevsky has received research support from Impel NeuroPharma. Dr. Shrewsbury has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Impel NeuroPharma. Dr. Hoekman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Impel NeuroPharma. Dr. Hoekman has received compensation for serving on the Board of Directors of Impel NeuroPharma.