Development of a Precision Olfactory Delivery (POD®)-Olanzapine Drug-Device Product for Agitation (2019)

Introduction: Agitation is a cluster of behaviors observed in multiple psychiatric diseases, which can increase the likelihood of violent behavior. Atypical antipsychotics, including oral and intramuscular (IM) olanzapine (OLZ), have been approved for chronic and acute agitation treatment, respectively, for schizophrenia and bipolar I disorder in the U.S. for over 20 years. During acute agitation episodes, IM OLZ is preferred over oral treatments due to a shorter Tmax. However, IM OLZ is invasive, predominantly administered in a hospital setting, and may require restraint if the patient is uncooperative, potentially reducing trust between patient and medical personnel and increasing the likelihood of injuries. When possible, non-injectable routes of administration are preferred during agitation events; however, slower-onset oral products often require labor-intensive observation of the medicated patient until adequate symptom resolution.Impel NeuroPharma is developing INP105, a drug-device combination product consisting of a novel OLZ powder formulation for upper nasal cavity administration using precision olfactory delivery (POD®) technology. This rescue therapy is designed to provide non-invasive, rapid relief of acute agitation comparable to IM injection, without excessively sedating the patient, in a reasonably safe and tolerable manner. POD technology is designed to deliver drug to the upper nasal mucosa with minimal effort or coordination for self or caregiver administration.Methods: OLZ formulations were designed and manufactured to optimize powder characteristics and device compatibility. Formulations were characterized by analytical methods to assess chemical and physical state as well as device compatibility. Lead formulations were evaluated in rat and non-human primate (NHP) pharmacokinetic (PK) studies, where dose was administered by species-specific POD devices, and plasma samples for PK analysis were analyzed by liquid chromatography mass spectrometry. Formulation selection for further evaluation was based on analytical and PK properties, and a single formulation was identified for inclusion in the INP105-101 proof-of-concept, clinical study.Results: Approximately 30 formulations designed for nasal delivery by POD technology were manufactured and then assessed using analytical chemistry techniques and device-compatibility testing. Twenty of the formulations were evaluated in rat and NHP PK models. Short-term stability tests and device compatibility testing were used to further narrow down formulations for additional PK studies. The lead formulation was tested to five months of stability with &gt;99% assay, &lt;1% total impurities, and positive device compatibility over the storage period. All formulations tested in NHP PK studies resulted in a Tmax of less than 53 minutes and a Cmax greater than 26 nanograms per milliliter (ng/mL). The lead formulation, selected for clinical development in the INP105-101 study, exhibited a Tmax of 17 minutes, similar to that reported for IM OLZ, and a Cmax of 71 ng/mL, approximately threefold higher than the reported Cmax in patients receiving 10 milligrams (mg) IM OLZ.Conclusion: Impel NeuroPharma is developing a drug-device combination product that will administer powder OLZ to the vascular-rich, upper nasal space with a novel precision olfactory delivery (POD®) device. It is needle-free, easily administered by self or caregiver, and a potentially rapidly effective OLZ treatment to abort episodes of acute agitation in the low-intensity community clinic or emergency department setting. This series of preclinical development studies has led to the identification of a lead formulation to be tested in the INP105-101 proof-of-concept clinical study for further development.