SNAP 101: Randomized, Crossover, Active and Placebo-Controlled, Safety, Pharmacokinetic, and Pharmacodynamic Study of 3 Ascending Doses of Olanzapine delivered by the Novel Precision Olfactory Delivery (POD®) Device
Authors: Hocevar-Trnka J, Swardstrom M, Satterly KH, Hoekman J, Shrewsbury SB
Objectives: 1) Establish safety and tolerability of 3 doses of INP105 (POD-olanzapine) 2) Compare PK data for olanzapine (OLZ) from 3 INP105 doses to OLZ IM (5 mg and 10 mg) and orally disintegrating tablets (OLZ-ODT, 10 mg) 3) Compare PD effects of INP105 to OLZ IM, OLZ-ODT and placebo.
Background: An estimated 1.7 million acute agitation events occur annually; OLZ IM is a preferred option due to a shorter Tmax than oral, but IM administration, predominantly administered in a hospital setting, can be painful, humiliating, invasive, and requires cooperation or restraint which reduces trust, increases healthcare worker injuries and may be interpreted as an assault. Further, heavily medicated patients may require “boarding” until sedative effects have resolved. Oral administration is preferred but for OLZ, has a slower onset of effect and typically requires isolation and observation of the patient. INP105 is a drug-device combination product in development which delivers OLZ powder by the novel Precision Olfactory Delivery (POD®) device to the vascular rich upper nasal space. It is being developed for rapid control of agitation in a cooperative or uncooperative patient (by a caregiveradministered dose) to potentially provide rapid onset of relief without a needle. INP105 may also be suitable for early use by patients who have insight into their condition and recognize early symptoms of agitation. This may avoid escalating agitation leading to more intensive management, violence, and injury to the patient, their caregivers and/or healthcare workers.
Methods: Randomized, double-blind, active and placebo-controlled, single ascending-dose, 2-way, 2period, crossover Phase 1 trial to compare the safety, tolerability, PK and PD of 3 doses of INP105 (5 mg, 10 mg and 15 mg) or POD-placebo with either OLZ IM (5 mg or 10 mg) or OLZ-ODT (10 mg) in NHVs. Period 1 was open label (the OLZ 10 mg IM dose was discontinued after dosing 2 NHVs); followed by a 14 day washout period and then a double-blind period with INP105 or POD-placebo. Dose escalation was staggered to allow safety monitoring committee assessment of tolerability of INP105 between dose levels. PK draws and PD assessments (VAS, ACES and DSST), were obtained at multiple timepoints. All subjects were observed as in-patients for at least 72 hours post-dosing with follow-up occurring 4, 5 and 14 days after dosing in both periods.
Results: 40 subjects were randomized; 37 dosed in Period 2 (Placebo=10, INP105 5 mg =10, 10 mg=9, 15 mg=8). INP105 was well tolerated with TEAEs reported in 100% IM OLZ 10 mg, 90% IM OLZ 5 mg, 83.3% OLZ ODT 10 mg, and 70% INP105 5 mg, 60% INP105 10 mg and 55.6% INP105 15 mg. INP105 was rapidly absorbed with median Tmax of ~10 min, compared to 20 min for IM (both 5 mg and 10 mg doses) and ~120 min for OLZ ODT. Dose-related, statistically significant PD effects with VAS, ACES and DSST were observed for all three INP105 dose levels compared to placebo.
Conclusions: This study demonstrated that Tmax for nasally administered INP105 was twice as fast as IM and 12 times faster than OLZ ODT with a comparable Cmax and AUC to the corresponding IM dose of OLZ. INP105, OLZ delivered by the POD device to the upper nasal cavity, is a needle-free, rapid and effective potential treatment of acute agitation.