Efficacy, Safety, Tolerability, and Biomarker Effects of GT-02287 in Early Parkinson's Disease

Change from Baseline to Week 48 in the sum of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II score and Part III score assessed in the practically defined OFF state. MDS-UPDRS is a multimodal scale assessing impairment and disability consisting of four parts. Part II assesses motor experiences of daily living (Range 0-52). It contains 13 questions which are to be rated by the patient and/or caregiver. Part III assesses the motor signs of PD and is rated by the investigator (Range 0-132). Part III contains 33 scores based on 18 items. For each question a numeric score is assigned between 0-4, where 0 = Normal, 1 = Slight, 2 = Mild, 3 = Moderate, 4 = Severe. A higher score indicates more severe symptoms of PD.

Incidence, nature, relationship to investigational product (IP), and severity of adverse events (AEs); Incidence of clinically significant findings for clinical laboratory evaluations, physical and neurological examinations, body weight , vital signs measurements, 12-lead o 12-lead electrocardiograms (ECGs), Columbia Suicide Severity Rating Scale (C-SSRS)

Change from Baseline to Week 48 in the MDS-UPDRS Part II score. MDS-UPDRS is a multimodal scale assessing impairment and disability consisting of four parts. Part II assesses motor experiences of daily living (Range 0-52). It contains 13 questions which are to be rated by the patient and/or caregiver. A higher score indicates more severe symptoms of PD.

Change from Baseline to Week 48 in the MDS-UPDRS Part III score assessed in the practically defined OFF state. MDS-UPDRS is a multimodal scale assessing impairment and disability consisting of four parts. Part III assesses the motor signs of PD and is rated by the investigator (Range 0-132). Part III contains 33 scores based on 18 items. For each question a numeric score is assigned between 0-4, where 0 = Normal, 1 = Slight, 2 = Mild, 3 = Moderate, 4 = Severe. A higher score indicates more severe symptoms of PD.

Change from Baseline to Week 48 in the Timed Up and Go (TUG) test performed in the practically defined OFF state. The TUG is a clinical test for assessing functional mobility and balance, where a person times how long it takes to stand up from a chair, walk 3 meters, turn 180 degrees, walk back, and sit down again. A time of less than 14 to 15 seconds indicates good mobility, while longer times suggest an increased risk of falling, poor physical performance, and potentially neurological issues.

Change from Baseline to Week 48 in the Parkinson's Disease Questionnaire 39 (PDQ-39) score. The PDQ-39 is a 39-item self-report questionnaire, which assesses PD-specific health-related quality over the last month. The questionnaire measures 39 items, which assess 8 domains of health: mobility (10 items), activities of daily living (6 items), emotional well being (6 items), stigma (4 items), social support (3 items), cognitions (4 items), communication (3 items), and bodily discomfort (3 items). Each item is scored on the following scale: 0 = never, 1 = occasionally, 2 = sometimes, 3 = often, and 4 = always. Items in each subscale and the total scale can be summarized into an index and transformed linearly to a scale from 0 (perfect health as assessed by the measure) to 100 (worst health as assessed by the measure).

Change from Baseline to Week 48 in the Schwab and England Activities of Daily Living (SEADL) scale. The SEADL Scale assesses the capabilities of people with impaired mobility in a range of life activities. The scale uses a percentage score to rate a person's abilities, with 100% indicating complete independence (able to do all chores without slowness, difficulty, or impairment) and 0% indicating full dependence (bedridden and almost completely comatose).

Change from Baseline to Week 48 in the Patient Global Impression Scale - Severity (PGI-S). The PGI-S is a simple, direct, easy to use scales used to rate the response of a condition to a therapy. It is a transition scale for the participant to rate their condition now as compared with how it was prior to before starting the treatment on a scale from 1 "Very much better" to 7 "Very much worse" with lower scores indicating greater improvement.

Change from Baseline to Week 48 in the Clinical Global Impressions Scale - Severity (CGI-S). The CGI-C scale is a clinician-rated measures of severity of a symptom or condition, using a single item, 6-point-scale. The CGI-S scale ranges from 1 ("None") to 6 ("Very Severe") with lower scores indicating lower severity.

Change from Baseline to Week 48 in the MDS-UPDRS Part I score. The MDS-UPDRS is a multimodal scale consisting of four parts. Part I assesses non-motor experiences of daily living and has 2 components (Range 0-52). Part IA contains 6 questions and are assessed by the examiner (Range 0-24). Part IB contains 7 questions on non-motor experiences of daily living to be completed by the participant (Range 0-28). For each question a numeric score is assigned between 0-4, where 0 = Normal, 1 = Slight, 2 = Mild, 3 = Moderate, 4 = Severe. A higher score indicates more severe symptoms of PD.

Change from Baseline to Week 48 in the Cognitive Summary Score (CSS). The CSS is a composite score that combines results from several detailed neuropsychological tests into a single, more sensitive measure of cognitive ability. It compares the score to norms to identify deficit in cognitive areas like processing speed, working memory, and verbal memory, and tracks cognitive changes over time. CSS scores can range from 0 to 100. A lower score indicates more significant cognitive impairment.

Change from Baseline to Week 48 in the Purdue Pegboard Test (PPT) total score performed in the practically defined OFF state. The PPT is a standardized test to assess fine and gross motor skills and coordination, commonly used to evaluate manual abilities. It measures the ability to move the arms, hands, and fingers quickly and accurately by placing pegs into a board, both with individual hands and with both hands simultaneously, and in an assembly task. The time and the number of pegs inserted is recorded. A faster time is indicative of a better function, i.e., a higher score (more pegs) signifies better performance.

Change from Baseline to Week 48 in the Geriatric Depression Scale 15-item version (GDS-15). The 15-item Geriatric Depression Scale (GDS-15) is a depression screening tool developed for use in older adults. The GDS-15 has a yes-no format. Scores range from 0 to 15; the higher the score the more likely the individual is experiencing depression.

Change from Baseline to Week 48 in the Movement Disorder Society-Non-motor Scale (MDS-NMS) score. The MDS-NMS is a 52-item rater-administered scale to assess a wide range of non-motor symptoms in Parkinson's disease.

It measures both frequency (0/never to 4/ >51% of the time) and severity (0/not present to 4/major distress or disturbance) of 13 domains (depression, anxiety, apathy, psychosis, impulse control/related disorders, cognition, orthostatic hypotension, urinary, sexual, gastrointestinal, sleep/wakefulness, pain, and other). Each question is scored by multiplying frequency x severity. All question scores for each domain are summed, and the scores for each domain are summed to provide the Total Score (range = 0-832) with the higher score indicating greater non-motor symptom burden. The higher the total score, the more progressed (i.e., worse) is the disease state.

Change from Baseline to Week 48 in Neuronal Synuclein Disease (NSD) stage. The NSD41 is a research framework that classifies the stages of diseases like PD by combining biological markers and functional impairment. It uses a 7-stage system, beginning with Stage 0 for a genetic variant and progressing through stages based on the presence of abnormal α synuclein protein, dopaminergic dysfunction, and the increasing severity of functional impairment in later stages. Higher stages are indicative of more severe functional impairment.

Number of participants who require an increase in, or initiation of, dopaminergic treatment by Week 48.

Change from Baseline to Week 48 in in olfaction as measured with the University of Pennsylvania Smell Identification Test (UPSIT) The UPSIT is considered to be an reliable and accurate tool for diagnosing smell loss and screening for conditions like PD. The test is a 40-item, self-administered "scratch-and-sniff" test to quantitatively measure olfactory function. The test involves scratching a strip to release an odor and selecting the correct identification from multiple-choice options. The UPSIT has a minimum score of 0 and maximum score of 40 with lower scores indicating a greater degree of impairment.

Mean concentration of GT-02287 24 hours postdose, immediately before the next dose

Mean concentration of GT-02287 around Cmax/time to maximum concentration (Tmax)

Postdose (approximately 4 hours postdose) concentration of GT-02287 in CSF at Week 48

Change in biomarkers in biofluids (CSF, blood, plasma) from Baseline to Week 48