An Open-label Study to Assess the Long-term Safety, Tolerability, and Efficacy of KarXT in Adult Patients With Schizophrenia (EMERGENT-5)

An SAE is any untoward medical occurrence, in the view of either the investigator or sponsor, that results in death; is life-threatening; results in inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity, and/or; is a congenital anomaly/birth defect using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0.

TEAEs are defined as events with an onset date on or after the first dose of KarXT. An Adverse Event is any symptom, physical sign, syndrome, or disease that either emerges during the study or, if present at baseline, worsens during the study, regardless of the suspected cause of the event using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0.

The PANSS rating form contains 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology symptom scales. Participants are rated from 1 to 7 on each symptom scale. The positive symptoms in schizophrenia are the excess or distortion of normal function and the negative symptoms are the diminution or loss of normal functions. PANSS total score is the sum of all 30 items with a minimum score of 30 and a maximum score of 210. Higher scores indicate more severe symptoms.

PANSS positive score is the sum of all PANSS 7 positive symptom scales with a minimum score of 7 and a maximum score of 49. Higher scores indicate more severe symptoms. Participants are rated from 1 to 7 on each symptom scale. The positive symptoms in schizophrenia are the excess or distortion of normal function such as hallucinations, delusions, grandiosity, and hostility.

PANSS negative score is the sum of all PANSS 7 negative symptom scales with a minimum score of 7 and a maximum score of 49. Higher scores indicate more severe symptoms. Participants are rated from 1 to 7 on each symptom scale. The negative symptoms in schizophrenia are the diminution or loss of normal functions.

PANSS Marder factor score is a subscale of the PANSS; the sum of 5 negative scales and 2 general scales (N1. Blunted affect; N2. Emotional withdrawal; N3. Poor rapport; N4. Passive/apathetic social withdrawal; N6. Lack of spontaneity; G7. Motor retardation; and G16. Active social avoidance).

Participants are rated from 1 to 7 on each symptom subscale. Higher score indicates more severe symptoms. The negative symptoms in schizophrenia are the diminution or loss of normal functions.

Completed independently by a clinician, the CGI-S categorizes the severity of the illness as: 1 = Normal, not at all ill; 2 = Borderline mentally ill; 3 = Mildly ill; 4 = Moderately ill; 5 = Markedly ill; 6 = Severely ill; and 7 = Among the most extremely ill patients, by asking the clinical 1 question and providing a rating based upon observed and reported symptoms, behavior, and function in the past 7 days to reflect the average severity level across the 7 days. Higher score indicates more severe illness.

A PANSS responder is defined as a participant with a reduction from baseline of at least a 30% improvement at Week 52 in the PANSS total score. The PANSS rating form contains 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology symptom scales. Participants are rated from 1 to 7 on each symptom scale. PANSS total score is the sum of all 30 items with a minimum score of 30 and a maximum score of 210. Higher scores indicate more severe symptoms.

LFT elevations, inclusive of drug-induced liver injury (DILI) and symptomatic orthostasis including syncope (a transient loss of consciousness or fainting) is to be captured as an AESI and reported as such. Non symptomatic orthostasis will not be reported as an AESI. Any such AESI due to any cause, whether or not related to KarXT, must be reported within 24 hours of occurrence or when the investigator becomes aware of the event.

The number of participants experiencing adverse events related to procholinergic symptoms (believed to be associated with xanomeline) and anticholinergic symptoms (believed to be associated with trospium) symptoms. Examples of procholinergic symptoms include vomiting, nausea, diarrhea, sweating and hyper-salivation. Examples of anticholinergic include dizziness, confusion, hallucinations, and somnolence.

The Simpson-Angus Rating Scale (SAS) is a clinical tool used to assess the severity of extrapyramidal symptoms (EPS), which are drug-induced movement disorders often associated with antipsychotic medications. The scale consists of 10 items, each rated from 0 (none) to 4 (severe), with a total score range of 0 to 40.

Higher scores indicate more severe symptoms.

The SAS helps clinicians monitor and manage EPS in patients, guiding treatment decisions to minimize these side effects.

The BARS for akathisia is a rating scale used to assess the severity of drug-induced akathisia, or restlessness, involuntary movements and inability to sit still. The range of scores is 0 to 14, with higher scores indicating greater severity.

The Abnormal Involuntary Movement Scale (AIMS) is a tool used to assess the severity of tardive dyskinesia and other involuntary movements, often caused by antipsychotic medications. It includes 12 items, with the first 10 focusing on specific body areas and movement severity, rated from 0 (none) to 4 (severe).

The total score ranges from 0 to 28, with higher scores indicating more severe symptoms.

AIMS helps clinicians monitor and manage these movement disorders, guiding treatment adjustments to reduce side effects.

BMI is a person's weight in kilograms divided by the square of height in meters. Baseline is defined as measurements taken at screening.

The change in waist circumference in centimeters from baseline. Baseline is defined as measurements taken at screening.

The change from baseline in orthostatic diastolic and systolic blood pressure measured while supine and standing after 2 minutes.

Baseline is defined as measurements taken at screening.

The change from baseline in orthostatic heart rate measured while supine and standing after 2 minutes. Baseline is defined as measurements taken at screening.

Laboratory assessments include:

• Hematology
• Serum chemistry
• Urinalysis
• HbA1c
• Prolactin levels
• Coagulation studies
• Viral Serology
• Pregnancy test

An electrocardiogram (ECG) measures electrical activity of the heart to detect cardiac problems.

A complete physical examination (body temperature, general appearance, head/eyes/ears/nose/throat [HEENT], examination of thorax and abdomen, assessment of cardiac, musculoskeletal, and circulatory systems, palpations for lymphadenopathy, and limited neurological examination) will be performed.

A targeted physical examination includes at a minimum body temperature, a check of general appearance, as well as examination of organ systems that are relevant to the investigator based on review of the participant's reported AEs, review of systems, or concomitant medication use. These also include symptom-driven physical examinations which will be performed as clinically indicated at any study visit.

The Columbia Suicide Severity Rating Scale (C-SSRS) is a tool used to assess the severity and immediacy of suicidal ideation and behavior. It covers suicidal thoughts, plans, and actions, including the frequency, intensity, and context of these behaviors. The C-SSRS does not use a numerical scoring system like some other assessment tools. Instead, it categorizes the severity of suicidal ideation and behavior based on specific criteria. The scale helps clinicians identify individuals at risk of suicide and monitor changes over time, guiding treatment decisions and ensuring safety. It is quick and easy to administer, making it useful in various clinical and research settings.