A Phase IIa, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose, Safety and Pharmacokinetic/Pharmacodynamic (PK/PDyn) Study of INP103 (POD® L dopa) Administered in the presence of Benserazide, to L-dopa Responsive Parkinson’s Disease (PD) Patients (THOR 201)
Objectives: Primary: Compare the safety and tolerability of intranasal INP103 to placebo in patients with PD during an OFF episode. Secondary: Characterize the PK of single ascending doses of INP103; Explore the effect of single ascending doses of INP103 versus placebo on motor function and PK/pharmacodynamic relationship of INP103 and motor function.
Background: PD is a degenerative disorder characterised by motor symptoms linked to depleted basal ganglia dopamine. Initial management of PD has been oral L-dopa since 1961, but 4 limitations persist: (1) An enzymatic blood-brain barrier; (2) Peripheral decarboxylation of dopamine requiring co-administration of a decarboxylase inhibitor (DDI: benserazide or carbidopa); (3) Progressive decline in L-dopa responsiveness leading to switches between mobility and immobility (ON and OFF periods, respectively) in >50% of patients; (4) Slow gastric transit. The Precision Olfactory Delivery (POD) device aims to deliver drugs to the vascular rich upper nasal space consistently and efficiently. PD patients suffering OFF episodes would benefit from rapid delivery of L-dopa.
Methods: Subjects must demonstrate 30% dopamine responsiveness by UPDRS Part III to their usual anti-OFF medication. All Parkinson medication from 22:00 hrs the evening before dosing will be stopped. The following morning OFF state confirmed, benserazide 25 mg will be given orally then 60 minutes later they will receive treatment by POD and observed for 4 hours. At 2 hours, subjects will receive their missed morning dose of L-dopa based medication and usual OFF medication if required. Dyskinesia rating and blood draws for PK of L-dopa and benserazide will be conducted and routine safety assessments for 7 days post dosing.
Conclusions: This study, administering L-dopa to the vascular-rich upper nasal space with the novel POD device should guide further clinical development for an easy self or care-giver administered, rapidly effective treatment to abort OFF episodes in PD.