A Phase 1 Study to Evaluate the Safety, Pharmacokinetic (PK) and Effects of CST-2032 in Healthy Volunteers and Subjects with Mild Cognitive Impairment or Parkinson’s Disease

This is a phase 1 open-label single ascending dose, and randomized, double-blind, placebo-controlled, multiple-ascending dose study to evaluate the safety, pharmacokinetic (PK) and pharmacodynamic effects of oral doses of CST-2032 in healthy adult subjects (Parts A, B and D). In addition, an optional cohort of subjects with MCI or PD may be enrolled to evaluate the effects of a single dose of CST-2032 (Part C). The starting oral dose of 1 mg CST-2032 (in Cohort A1, Part A) is predicted to deliver a maximum plasma concentration in humans that is below the exposures at which clinical effects were noted in nonclinical studies. The dose of CST-2032 to be administered to subject in all subsequent cohorts will be determined by a Dose Level Review Meeting (DLRM) based on observed safety, PK and pharmacodynamics (where available) from prior cohorts. CST-2032 will be administered alone or in combination with CST-107 to determine doses of CST-107 that mitigate peripheral effects of CST-2032, e.g. on heart rate, while preserving possible central effects on cerebral perfusion, pupillary light reflex, and cognition. The decision to dose participants in cohorts A7, A8, B5, D2 and D3 with or without CST-107 will be determined by the participating Investigators and study medical monitor based on available safety and PK data. The dose of CST-107 that will be administered to participants in cohorts A7, A8 and B5 will be a dose between 1 and 40 mg. The dose of CST-107 for participants in Cohorts D1-D3 will be defined based on expert review by participating Investigators and study medical monitor of all available safety and PK data from prior cohorts with the aim of identifying the lowest dose of CST-107 that mitigates the peripheral effects of CST-2032 (e.g. on heart rate). The mode of administration of CST-107 is an oral capsule or tablet. A subject can be enrolled into only one cohort. Cohorts in Part A will be enrolled sequentially, and safety data up to Day 3 must be reviewed by the DLRM prior to enrolling the next planned cohort (a minimum of 3 days between each cohort). Enrollment into Parts B and C may not commence until after the DLRM has reviewed data from Cohort A3 in Part A. Cohorts in Part B will also be enrolled sequentially, and safety data up to Day 4 must be reviewed by the DLRM prior to enrolling the next planned Part B cohort (a minimum of 4 days between each cohort). Enrollment of Part C is optional and will be determined in the DLRM based on emerging safety, tolerability, PK and pharmacodynamic data (as available) from Part A. Enrollment into Part D may not commence until after the DLRM has reviewed repeat-dose data from the first cohort in Part B. Interventions in the study include the following: In Part A, up to 8 healthy subjects will be enrolled in each of the following cohorts: - Cohort A1 – single oral dose of 1 mg CST-2032 - Cohort A2 – single oral dose of approximately 3 mg CST-2032 - Cohort A3 – single oral dose of approximately 10 mg CST-2032 - Cohort A4 – single oral dose of approximately 30 mg CST-2032 - Cohort A5 – single oral dose of CST-2032 to be determined - Cohort – Food Effect – single oral dose up to 30 mg CST-2032 to be administered with and without food, 7 days apart - Optional Cohort A7 - single oral dose of CST-2032 with or without oral dose of CST-107 (doses to be determined by the DLRM) - Optional Cohort A8 - single oral dose of CST-2032 with or without oral dose of CST-107 (doses to be determined by the DLRM) In Part B - 8 healthy subjects to be enrolled in each cohort. In the first cohort of Part B, the dose of CST-2032 will be determined at the DLRM based on the safety, PK and pharmacodynamic data from prior cohorts in Part A. The starting dose in Part B will not exceed the maximum dose evaluated in Part A or the maximum dose tolerated in Part A. In all subsequent cohorts in Part B, the dose of CST-2032 will be determined at the DLRM based on safety, PK and pharmacodynamic data from prior cohorts in Parts A and B. At no time in the study will the DLRM select a dose of CST-2032 that exceeds the maximum tolerated dose observed in humans, or that is predicted to give rise to human exposures above the established no-observed-adverse-effect level in completed toxicity studies with CST-2032. - Cohort B1 – once-daily oral dose of CST-2032 (dose to be determined at the DLRM) for 7 days - Cohort B2 – once-daily oral dose of CST-2032 (dose to be determined at the DLRM) for 7 days - Cohort B3 – once-daily oral dose of CST-2032 (dose to be determined at the DLRM) for 7 days - Cohort B4 – once-daily oral dose of CST-2032 (dose to be determined at the DLRM) for 7 days - Optional Cohort B5 - once-daily oral dose of CST-2032 with or without oral dose of CST-107 (doses to be determined by the DLRM) for 7 days In Part C - up to 8 subjects with MCI or PD to be enrolled: - Cohort C1 – single oral dose of CST-2032. The dose of CST-2032 will be determined at the DLRM based on safety, PK and pharmacodynamic data from prior cohorts in Parts A, B and D. At no time in the study will the DLRM select a dose of CST-2032 that exceeds the maximum tolerated dose observed in humans, or that is predicted to give rise to human exposures above the established no-observed-adverse-effect level in completed toxicity studies with CST-2032. In Part D, healthy subjects will undertake within-subject dose titration of CST-2032 and/or CST-107 in order to explore doses/dose combinations that mitigate peripheral effects of CST-2032, e.g. on heart rate, while preserving possible central effects on cerebral perfusion and pupillary light reflex. Up to 8 healthy subjects will be enrolled in each of the following cohorts: - Cohort D1, open-label CST-2032 at one or more dose levels (up to the protocol-defined maximum dose levels) once-daily from Day 1 through Day 7 with oral dose of CST-107 (up to 40 mg) pre-administered or co-administered on one or more of the dosing days. - Cohort D2, open label CST-2032 from Day 1 through Day 3 and open-label CST-107 on one or more of those dosing days. CST-2032 will be administered as escalating doses on Day 1, Day 2 and Day 3 at doses of CST-2032 (up to the maximum protocol-defined dose levels) selected by the DLRM with or without pre-administered or co-administered CST-107 (up to 40 mg) on one or more of the dosing days. - Optional Cohort D3, open label CST-2032 from Day 1 through Day 3 and open-label CST-107 on one or more of those dosing days. CST-2032 will be administered as escalating doses on Day 1, Day 2 and Day 3 at doses of CST-2032 (up to the maximum protocol-defined dose levels) selected by the DLRM with or without pre-administered or co-administered CST-107 (up to 40 mg) on one or more of the dosing days. CST-2032 is an oral solution and will be administered at the clinic in the morning by the research nurse; mouth check will be performed to monitor adherence.