A Positron Emission Tomography (PET) Study to Evaluate Dopamine D2 and D3 Receptor Occupancy by SIPI6398

An Open-label Positron Emission Tomography (PET) Study to Evaluate Brain Dopamine D2 and D3 Receptor Occupancy by SIPI6398 in Healthy Volunteers and Patients With Schizophrenia

This is an open label study in 2 cohorts of healthy volunteers and 1 cohort of patients with Schizophrenia, designed to evaluate the Dopamine D2 and D3 Receptor Occupancy by SIPI6398 at various doses and timepoints.

Inclusion Criteria

Healthy Volunteers

1. Participant is aged 18-55 years, inclusive.

2. BMI between 19.0 and 32.0 kg/m2, inclusive.

3. Participant is medically healthy as determined by clinical evaluations including laboratory safety tests, medical history, physical examination, ECG, and vital sign measurements performed at the Screening visit and before administration of the initial dose of study drug.

4. Participant is willing and able to be confined to an inpatient setting for the study duration, follow instructions, and comply with the protocol requirements.

5. Participant is capable of providing informed consent.

   • A signed informed consent form must be provided before any study assessments are performed.
   • Participant must be fluent (oral and written) in English to consent.

Patients with schizophrenia

1. Participant is aged 18-55 years, inclusive.

2. BMI between 19.0 and 35.0 kg/m2, inclusive.

3. Currently meet a diagnosis of schizophrenia as defined by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Diagnosis and differential will be confirmed by using the Mini International Neuropsychiatric Interview (M.I.N.I) for Schizophrenia and Psychotic Disorders Studies version 7.0.2 at Screening Visit.

4. The participant is currently stable: the total Positive and Negative Syndrome Scale (PANSS) score ≤ 60, including P7 (hostile) and G8 (not cooperative) scored ≤ 4.

5. Participant is willing and able to be confined to an inpatient setting for the study duration, follow instructions, and comply with the protocol requirements.

6. Participant is capable of providing informed consent.

   • A signed informed consent form must be provided before any study assessments are performed.
   • Participant must be fluent (oral and written) in English to consent.

Exclusion Criteria

Healthy Volunteers

1. Women of childbearing potential (WOCBP), or fertile men whose sexual partners are WOCBP, who are unwilling or unable to use at least 1 highly effective method of contraception during the study and for 90 days following the last dose of trial medication. A female participant is considered to be a WOCBP after menarche and until she is in a postmenopausal state for 12 months or otherwise permanently sterile (for which acceptable methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy).

2. Females who are pregnant, lactating, or less than 90 days postpartum prior to the Screening Visit.

3. History or presence of any clinically significant illness, such as cardiovascular, neurologic, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, endocrine, or psychiatric disease, considered by the investigator.

4. Risk for suicidal behavior during the study as determined by the investigator's clinical assessment and C-SSRS as confirmed by the following: Answers "Yes" to any of the 5 items (C-SSRS - ideation) within the 3 months before Screening or between the Screening and Baseline Visits, or answers "Yes" to any of the 5 items (C-SSRS behavior) within the 12 months before Screening or between the Screening and Baseline Visits, or has a history of nonsuicidal, self-injurious behavior in the past 12 months.

5. History of current hepatitis or acquired immunodeficiency syndrome or carriers of hepatitis B surface antigen (HBsAg) and/or anti- hepatitis C virus (HCV) or human immunodeficiency virus (HIV) antibodies or treponema pallidum antibody.

6. Participants who had any major surgery, any blood transfusion, donation of blood or plasma within 30 days prior to Screening Visit.

7. Participants with a history of allergy to more than one class of medications or known to be allergic to any components of the study drug or the radioligand.

   Physical and Laboratory Results

8. Clinically significant abnormal findings on the physical examination, vital signs, 12-lead ECG, or clinical laboratory results.

9. The following laboratory tests are exclusionary:

   • Neutrophils, absolute <= 1000/mm3
   • Aspartate Aminotransferase (AST) > 1.5 times upper limit of normal (ULN)
   • Alanine Aminotransferase (ALT) > 1.5 times upper limit of normal
   • Total Bilirubin (TBil) > 1.5 times upper limit of normal
   • Creatinine >1.2 times upper limit of normal

10. Clinically significant abnormal findings on 12-ECG and/or evidence of any of the following cardiac conduction abnormalities:

    • Heart rate < 50 bpm or > 110 bpm (based on the ECG reading)
    • QTcF interval > 450 msec for males and > 470 msec for females
    • Evidence of second- or third-degree atrioventricular block (AVB)

11. Participants who test positive for drugs of abuse at Screening Visit or Baseline Visit are excluded.

12. Use of any prescription medications or over-the-counter (OTC) medications, including health supplements, vitamins or herbal remedies within 7 days or within 5 half-lives of the medication, whichever is longer, prior to Baseline Visit.

13. Participants who would be likely to require prohibited concomitant therapy during the study.

14. Participants who suffer from claustrophobia.

15. Participants with magnetic resonance imaging (MRI)-incompatible implants and other contraindications for MRI, such as pacemakers, artificial joints, nonremovable body piercings, tattoos larger than 1 cm in diameter, metal fragments, etc.

16. Participants who have received a diagnostic or therapeutic radiopharmaceutical within 30 days prior to Screening Visit.

17. Participation in other research trials involving ionizing radiation within 1 year of the PET scans that would cause the participant to exceed the yearly dose limits for participants.

18. Severe motor problems that prevent the participant from lying still for PET and MRI.

19. Within 6 months prior to Screening Visit:

    •> 21 cigarettes per day;

    • consumes more than 300 mg of caffeine per day (5 cups of coffee or equivalent in caffeinated beverages);
    • for alcohol, an average weekly intake of greater than 21 units or an average daily intake of greater than 3 units (males), or an average weekly intake of greater than 14 units or an average daily intake of greater than 2 units (females). One unit is equivalent to a half-pint (220 mL) of beer or 1 measure (25 mL) of spirits or 1 glass (125 mL) of wine.

20. Unwilling or unable to comply with lifestyle considerations.

21. Participants who received any investigational agent or device in a clinical trial within 90 days prior to Screening Visit.

22. Participant does not tolerate venipuncture or has poor venous access that would cause difficulty for administration of the radioisotope and for collecting blood samples.

23. Participant is, in the opinion of the investigator, unsuitable in any other way to participate in this study.

Patients with schizophrenia

1. WOCBP, or fertile men whose sexual partners are WOCBP, who are unwilling or unable to use at least 1 highly effective method of contraception during the study and for 90 days following the last dose of trial medication. A female participant is considered to be a WOCBP after menarche and until she is in a postmenopausal state for 12 months or otherwise permanently sterile (for which acceptable methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy).

2. Females who are pregnant, lactating, or less than 90 days postpartum prior to the Screening Visit.

3. Participant has any of the following psychiatric conditions per DSM-5 criteria, as assessed by the M.I.N.I version 7.0.2. Conditions not assessable by the M.I.N.I should be assessed by clinical judgment.

   • Substance use disorder within the past 12 months (other than nicotine, alcohol or caffeine).
   • Bipolar I or Ⅱ disorder; obsessive-compulsive disorder; post-traumatic stress disorder; neurocognitive disorders; or other psychotic disorders.
   • Intellectual disabilities.
   • Any other psychiatric condition that could interfere with participation in the study.
   • Mild depressive or anxiety symptoms are permitted if, in the opinion of the investigator, they are considered secondary to the diagnosis of schizophrenia and do not require specific pharmacological intervention.

4. Participants who experience clinical deterioration during the drug-free interval prior to Baseline Visit, such that they require prohibited rescue therapy.

5. Participant who is judged to be resistant to antipsychotic treatment by the investigator, based on failure to respond to 2 or more marketed antipsychotic agents, given at adequate dose for at least 6 weeks.

6. Participant have a history of failure to clozapine, or who are responsive only to clozapine treatment.

7. Risk of violent or destructive behavior.

8. Risk for suicidal behavior during the study as determined by the investigator's clinical assessment and C-SSRS as confirmed by the following: Answers "Yes" to item 4 or 5 (C-SSRS ideation) within the 3 months before Screening or between the Screening and Baseline Visits, or answers "Yes" to any of the 5 items (C-SSRS behavior) within the 12 months before Screening or between the Screening and Baseline Visits. Nonsuicidal, self-injurious behavior is not exclusionary.

9. History or presence of clinically significant:

   • Cardiovascular disease: Unstable angina, myocardial infarction, heart failure, severe arrhythmias, or hypertension.
   • Pulmonary disease: Chronic obstructive pulmonary disease, asthma, interstitial lung disease, obstructive sleep apnea or active tuberculosis.
   • Hepatic disease: Cirrhosis, active hepatitis B/C.
   • Renal disease: Acute kidney injury, end-stage renal disease.
   • Hematologic disease: Severe anemia, or coagulopathy.
   • Gastrointestinal disease: Inflammatory bowel disease, gastrointestinal obstruction, or active peptic ulcer.
   • Endocrine disease: Diabetes, or thyroid pathology (unless the condition has been stabilized with medications for at least the past 90 days prior to Screening Visit).
   • Immunologic disease: Active systemic autoimmune disorders or primary immunodeficiency.
   • Dermatologic disease: Severe atopic dermatitis requiring systemic therapy, or active psoriasis.
   • Neurologic disease: Epilepsy, Parkinson's disease, Alzheimer's disease, multiple sclerosis, residual of stroke, transient cerebral ischemic attacks, or cerebral palsy.
   • Oncologic disease: Active malignancy except curatively treated carcinoma in situ or basal cell carcinoma within 5 years.
   • Or any other condition that, in the investigator's judgment, would jeopardize participant safety or study validity.

10. History of current hepatitis or acquired immunodeficiency syndrome or carriers of HBsAg and/or anti-HCV or HIV antibodies or treponema pallidum antibody.

11. History of neuroleptic malignant syndrome.

12. Participants who had any major surgery, any blood transfusion, or donation of blood or plasma within 30 days prior to Screening Visit.

13. Participants with a history of allergy to more than one class of medications, or known to be allergic to any components of the study drug or the radioligand.

14. Clinically significant abnormal findings on the physical examination, vital signs, 12-lead ECG, or clinical laboratory results, in the opinion of the investigator, would jeopardize the safety of the participant or the validity of the study results.

15. The following laboratory tests are exclusionary:

    • Neutrophils, absolute <= 1000/mm3
    • AST > 3 times upper limit of normal
    • ALT > 3 times upper limit of normal
    • TBil > 2 times upper limit of normal
    • Creatinine >1.5 times upper limit of normal

16. Clinically significant abnormal findings on 12-ECG and/or evidence of any of the following cardiac conduction abnormalities:

    • Heart rate < 50 bpm or > 110 bpm (based on the ECG reading)
    • QTcF interval > 450 msec for males and > 470 msec for females
    • Evidence of second- or third-degree AVB

17. Participants who test positive for drugs of abuse at Screening Visit or Baseline Visit are excluded.

18. Use of any oral antipsychotic medications within 14 days or within 5 half-lives of the medication, whichever is longer, prior to Baseline Visit.

19. Participants on intramuscular (IM) depot therapy within 180 days, or within 5 half-lives of the medication, whichever is longer, prior to Baseline Visit.

20. Except for antipsychotic medications, use of any other psychotropic medications (including but not limited to antidepressants, anxiolytics, hypnotics, mood stabilizers, and cognitive enhancers) within 7 days or within 5 half-lives of the medication prior to the Baseline Visit, whichever is longer, is exclusionary. Exceptions are detailed in Section 5.6 of the protocol.

21. Use of any moderate or strong cytochrome P450 (CYP) 3A4 inhibitors or CYP3A4 inducers within 7 days or within 5 half-lives of the medication prior to Baseline Visit (whichever is longer), is exclusionary.

22. Use of electroconvulsive therapy (ECT) within 90 days prior to Screening Visit.

23. Participants who would be likely to require prohibited concomitant therapy during the study.

24. Participants who suffer from claustrophobia.

25. Participants with MRI-incompatible implants and other contraindications for MRI, such as pacemakers, artificial joints, nonremovable body piercings, tattoos larger than 1 cm in diameter, metal fragments, etc.

26. Participants who have received a diagnostic or therapeutic radiopharmaceutical within 30 days prior to Screening Visit.

27. Participation in other research trials involving ionizing radiation within 1 year of the PET scans that would cause the participant to exceed the yearly dose limits for participants.

28. Severe motor problems that prevent the participant from lying still for PET and MRI.

29. Within 6 months prior to Screening Visit:

    •> 21 cigarettes per day;

    • consumes more than 300 mg of caffeine per day (5 cups of coffee or equivalent in caffeinated beverages);
    • for alcohol, an average weekly intake of greater than 21 units or an average daily intake of greater than 3 units (males), or an average weekly intake of greater than 14 units or an average daily intake of greater than 2 units (females). One unit is equivalent to a half-pint (220 mL) of beer or 1 measure (25 mL) of spirits or 1 glass (125 mL) of wine.

30. Unwilling or unable to comply with lifestyle considerations.

31. Participants who received any investigational agent or device in a clinical trial within 90 days prior to Screening Visit.

32. Participant does not tolerate venipuncture or has poor venous access that would cause difficulty for administration of the radioisotope and for collecting blood samples.

33. Participant is, in the opinion of the investigator, unsuitable in any other way to participate in this study.