Pharmacokinetics - Pharmacodynamic Study of HT-2157 in Healthy Subjects and in Patients With Major Depressive Disorder

• 7-day plasma PK profile of HT-2157 [ Time Frame: 7-day ] [ Designated as safety issue: No ]
  To assess the multiple dose (7-day) plasma PK profile (including AUC, Cmax, Tmax, T1/2, CL/F, Lambda z, VZ/F) of HT-2157 (and its metabolite) administered in the fed state to healthy male and female subjects
• To assess the brain penetration of HT-2157 [ Time Frame: 21-days ] [ Designated as safety issue: No ]
  To assess the brain penetration (PK [including Cmax, Tmax, AUC if possible] in cerebrospinal fluid [CSF]) of HT-2157 (and its metabolite)
• PD profile (CSF and peripheral biomarkers, exploratory biologic and pharmacodynamic markers of potential efficacy) of multiple (21-day) doses of HT-2157 patients with MDD [ Time Frame: 21-days ] [ Designated as safety issue: No ]
  To assess the PD profile (CSF and peripheral biomarkers, exploratory biologic and pharmacodynamic markers of potential efficacy) of multiple (21-day) doses of HT-2157 administered in the fed state to patients with MDD

• Safety and tolerability of multiple (7-day) doses of HT-2157 [ Time Frame: 7-days ] [ Designated as safety issue: Yes ]
  To assess the safety and tolerability of multiple (7-day) doses of HT-2157 administered in the fed state to healthy male and female subjects. Change from baseline will be assessed for the following measures: Vital signs, 12-lead ECG, laboratory (hematology, chemistry, urinalysis), physical examinations, and adverse events.
• Safety and tolerability of multiple (21-day) ascending-doses of HT 2157 [ Time Frame: 21-days ] [ Designated as safety issue: Yes ]
  To assess the safety and tolerability of multiple (21-day) ascending-doses of HT 2157 administered in the fed state to patients with MDD. Change from baseline will be assessed for the following measures: Vital signs, 12-lead ECG, laboratory (hematology, chemistry, urinalysis), physical examinations, and adverse events.
• 21-day ascending-dose plasma PK profile of HT-2157 [ Time Frame: 21-days ] [ Designated as safety issue: No ]
  To assess the multiple (21-day) ascending-dose plasma PK profile (including AUC, Cmax, Tmax, T1/2, CL/F, Lambda z, VZ/F, RaCmax, RaAUC) of HT-2157 (and its metabolite) administered in the fed state to patients with MDD

This is a two part study. The objective of Part 1 is to evaluate the safety, tolerability, and pharmacokinetics of HT-2157 in healthy normal volunteers

Part 2 is a randomized, double-blind, placebo-controlled, multiple (21-day) ascending-dose evaluation of the safety, tolerability, pharmacokinetics, and pharmacodynamics of HT-2157 in patients with major depressive disorder

This is a two part study. The objective of Part 1 is to evaluate the safety, tolerability, and pharmacokinetics of HT-2157 administered for 7-days in healthy normal volunteers

Part 2 is a randomized, double-blind, placebo-controlled, multiple ascending-dose evaluation of the safety, tolerability, pharmacokinetics of HT-2157 administered for 21-days in patients with major depressive disorder. The primary objective of Part 2 is to assess the CNS penetration of HT-2157 in cerebrospinal fluid. In addition, the potential activity of HT-2157 in this patient population may be assessed using exploratory biologic and pharmacodynamic markers of potential efficacy

• Healthy Volunteers (Part 1)
• Major Depressive Disorder (Part 2)

• Drug: HT-2157
  QD oral dosing
• Drug: Placebo
  QD oral dosing

• Experimental: HT-2157
  Intervention: Drug: HT-2157
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo

Main Inclusion Criteria (Part 1)

• No clinically relevant abnormalities
• Age 18 to 55 years, inclusive
• Body Mass Index (BMI) of 18.5 to 32 kg/m2

Main Inclusion Criteria (Part 2)

• No clinically relevant abnormalities
• Age 18 to 55 years, inclusive
• Body Mass Index (BMI) of 18.5 to 32 kg/m2
• Mild-to-Moderate major depressive disorder

Main Exclusion Criteria (Part 1)

- Any disorder that would interfere with the absorption, distribution, metabolism, or excretion of drugs

Main Exclusion Criteria (Part 2)

• Any disorder that would interfere with the absorption, distribution, metabolism, or excretion of drugs
• Current and primary Axis I disorder other than MDD