A Study to Investigate Pharmacokinetics, Safety, and Tolerability of B2227 Extended-Release Injectable Suspension and Vraylar® in Participants With Schizophrenia

Inclusion Criteria:

1. Participant and/or their legally acceptable representative (LAR) must sign an informed consent form (ICF) indicating that the participant understands the purpose of and procedures required for the study as described in Section 10.1.3 and in this protocol and is willing to participate in the study.
2. Male or female participant with age of 18-65 years (both inclusive) at the time of signing the informed consent.
3. Participant has a body mass index (BMI) within the range 18.50 to 30.00 kg/m2 (inclusive).
4. Participant diagnosed with schizophrenia as per Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) (or later) criteria.
5. Participant with a Clinical Global Impression-Severity of Illness (CGI-S) Score of ≤ 4 at screening.
6. Participant with Positive and Negative syndrome-scale (PANSS) total score ≤75 at screening.

7. Schizophrenic participants who are clinically stable on their current antipsychotic medication other than cariprazine, for a duration of at least 8 weeks prior to screening.

   Note: Participants must NOT be taking > 1 antipsychotic medication for their disease.

8. Participant who has previously received and tolerated oral cariprazine 3 mg or higher dose (no discontinuations due to AEs attributable to cariprazine).

9. Contraceptive use by participant or participant's partner(s) should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

   A female participant is eligible to participate if she is not pregnant or breastfeeding and at least one of the following conditions applies:

   • Is not a woman of childbearing potential (WOCBP) as defined in Appendix 4: Contraceptive and Barrier Guidance.

   OR

   • Is a WOCBP and agrees to remain on an acceptable contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency when used consistently and correctly, as described in Appendix 4: Contraceptive and Barrier Guidance during the study period and for at least 12 weeks after the last dose of the study intervention. The investigator should evaluate the effectiveness and the potential for contraceptive method failure (e.g., noncompliance, recently initiated) of the contraceptive method in relation to the first dose of the study intervention.
   • A WOCBP agrees not to donate eggs (ova, oocytes), freeze them for future use for reproduction or retrieve them for their own use during the recommended period of contraception. A WOCBP agrees to seek advice about donation and cryopreservation of germ cells.
   • A WOCBP must have a negative highly sensitive pregnancy test (serum) at screening assessment and a negative highly sensitive pregnancy test (urine) on day 1 prior to the first dose of investigational intervention, but no more than 7 days before the first dose of the study intervention. If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
   • Additional requirements for pregnancy testing during and after study intervention are located in Section 8.3.5.

   The investigator is responsible for reviewing medical history, menstrual history, and recent sexual activity to decrease the risk of inclusion of a woman with early undetected pregnancy.

10. Male participant is eligible to participate if he agrees to the following during the study period and for at least 12 weeks after the last dose of the study intervention.

    • Must agree not to plan to father a child or donate sperm for reproduction;

    PLUS, EITHER:

    • Be abstinent from heterosexual intercourse as his preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent; OR
    • Must agree to use contraception /barrier as detailed below:
    • A male participant must wear a condom when engaging in any activity that allows for the passage of ejaculate to another person.
    • Male participant should also be advised of the benefit for a female partner(s) to use a highly effective method of contraception as the condom may break or leak when having sexual intercourse with a woman of childbearing potential who is not currently pregnant.

11. Participant has adequate hematologic, liver and renal functions at screening assessment.

    a ANC ≥1500 cells/μL b Platelet count ≥100000 cells/μL c Haemoglobin ≥9.0 g/dL d White blood cell count (WBC) ≥ 4000 cells/μL e Creatinine clearance ≥ 60 mL/minute (using the Cockcroft-Gault Equation). f Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2 × upper limit of normal (ULN) g Total Bilirubin < 1.2 mg/dL h Alkaline phosphatase ≤ 2 * ULN

12. Participant willing and able to adhere to the lifestyle restrictions specified in this protocol.
13. Participant who agrees to avoid drinking alcohol during the study.

Exclusion Criteria:

1. Participant has a known clinically significant (≥Grade 3) allergies, hypersensitivity, or intolerance to any of the study interventions (or related class of drugs) or components/ excipients thereof [refer to the investigator's brochure (IB)/US-prescribing information (USPI) 1,2], or drug or other allergies that in the opinion of the investigator or medical monitor, contraindicate participation in the study.
2. Participant has contraindications to the use of B2227, cariprazine per local prescribing information.
3. Participants currently in acute, manic episodes of schizophrenia, as assessed by the Investigator.
4. Participants with history of or a current DSM-5-TR (or later) diagnosis of concurrent mental disorder besides schizophrenia (e.g., schizoaffective-disorder, major depressive disorder, bipolar I disorder, bipolar II disorder, general anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, dementia or mild neurocognitive disorder, and personality disorder).
5. Participants who have attempted suicide within 12 months prior to screening based on history, or who had suicidal ideation within 2 months prior to screening based on C-SSRS (Columbia-Suicide Severity Rating Scale), or who exhibit violent tendencies/behavior, as clinically assessed by the investigator.
6. Participants with history or presence of neuroleptic malignant syndrome (NMS), tardive dyskinesia, Parkinson's disease, epilepsy or other seizure disorders, cognitive and motor impairment, pathological gambling, dysphagia or other compulsive behavior.
7. Participants with a prior personal or family history of dystonic reactions to medications.
8. Participants with clinically significant dyslipidemia as per Investigator's discretion.
9. Participants with a history of syncope or a presence of significant orthostatic hypotension (i.e., a drop in systolic blood pressure of 20 mm Hg or more and/or a drop in diastolic blood pressure of 10 mm Hg or more within 3 minutes of standing from supine) at screening.
10. Participants with known history or presence of any uncontrolled systemic disease (e.g., cardiovascular disease, cerebrovascular disease, diabetes mellitus, etc.) as per clinical judgment of clinical investigator.
11. Participants who are on concurrent treatment with other anti-psychotic Long-acting Injection (LAIs).
12. Participants who have received concomitant medications that are strong CYP3A4 inhibitors or CYP3A4 inducers within 14 days prior to study drug administration (or within five halflives since the last drug administration, whichever is greater), or is expected to require such treatment during the study. Refer Table 6-2.
13. Participants with any other medical condition or serious inter-current illness that, in the opinion of the Investigator, may make it undesirable for the patient to participate in the study including but not limited to cirrhosis or psychiatric illness other than schizophrenia /social situations that would limit adherence to study requirements.
14. Any other condition(s) which could significantly interfere with protocol compliance.
15. Participants found positive for urine screen for drugs of abuse (except for benzodiazepine, which is a permissible medication if supported by prescription).
16. Participants with major surgical procedure (including periodontal) within 28 days of investigational intervention dosing or plan to have major surgical procedure during the study.
17. Participants with current surgical or other non-healing wounds.
18. Participants who have participated in any clinical trial with another investigational drug or other investigational intervention within 90 days of enrolment.
19. Participant has donated blood or blood product or had substantial Loss of blood ≥ 350 mL (1 unit) within 90 days before enrolment in the study.
20. Participants with history of difficulty with donating blood or difficulty in accessibility of veins.
21. Presence of hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to the first dose of investigational intervention.

22. Positive hepatitis C antibody test result at screening or within 3 months prior to starting the investigational intervention.

    NOTE: Participants with positive hepatitis C antibody due to prior resolved disease can be enrolled only if a confirmatory negative hepatitis C RNA test is obtained.

23. Has known human immunodeficiency virus (HIV) seropositive status, or positive HIV antibody test at screening.
24. Alcoholics (alcohol consumption of more than 14 units per week for men and more than 7 units per week for women, each unit equivalent to 360 mL of beer or 150 mL of wine or 45 mL of spirits with 40% alcohol content) and those who have a positive urine alcohol test.
25. Participants who have consumed tobacco-containing products (smoking, tobacco chewing, etc.), xanthine containing food, poppy seeds, and beverages (chocolates, tea, coffee, or cola drinks) or alcohol within 48.00 hours (02 days) prior to dosing.
26. Participants who have consumed grapefruit or its juice and cranberry juice within 96.00 hours (04 days) prior to dosing.
27. Participants currently smoking greater than or equal to 10 cigarettes or equivalent per day.
28. Participant unable to swallow solid, oral dosage forms whole with the aid of water (participants may not chew, divide, dissolve, or crush the investigational intervention).
29. Participant with a documented medical history or current evidence of uncontrolled, clinically significant intercurrent medical condition(s), therapy, laboratory abnormality, or other circumstance for which, in the opinion of the investigator, participation would not be in the best interest of the participant (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.