A Study to Investigate the Effects and Safety of Codabakalner for the Treatment of FXS in Male Participants and Adult Participants With ADS

This Phase 2b/3, randomized, double-blind, placebo-controlled, 2-part study will evaluate the efficacy, safety and tolerability of different dose regimens of codabakalner in adult male participants with Fragile X syndrome. The results from Phase 2b will be hypothesis generating and will inform the Phase 3 design.

Phase 2b, dose-regimen finding, 4-arm parallel design: Eligible participants will be randomized 1:1:1:1 to receive codabakalner at different doses or matched placebo. Participants will receive study intervention over 4 weeks and will be followed up for 4 weeks after last dose of study intervention.

Phase 3, 2-arm parallel design: Eligible participants will be randomized 1:1 to receive codabakalner or matched placebo. The dose of codabakalner administered in the Phase 3 will be defined based on analysis of Phase 2b. Participants will receive study intervention over 12 weeks and will be followed up for 4 weeks after last dose of study intervention.

• Codabakalner (Drug), also known as SPG601: synthetic small molecule
• Placebo (Drug): Placebo

Primary outcomes

• Phase 2b: FXS- Change from baseline in Total Cognition Composite Change Sensitive Score from the NIH-TCB [28 days]: The NIH Toolbox (NIH-TCB) Total Cognition Composite Change-Sensitive Score (CSS) is used to measure cognitive change over time. Higher scores indicate higher level of functioning. The scores typically span across the developmental range, often extending well above and below the 500-point mark depending on the age and cognitive ability of the individual.
• Phase 2b: ASD - Change from Baseline at Day 28 on the Vineland Adaptive Behavior Scales in ASD(Vineland-III) Adaptive Behavior Composite Score [28 days]: Vineland Adaptive Behavior Composite (ABC) have a mean of 100 and a standard deviation of 15, where scores from 85 to 115 reflect expected or average adaptive functioning
• Phase 3: FXS - Change from baseline in Total Cognition Composite score from the NIH-TCB [12 weeks]: The NIH Toolbox (NIH-TCB) Total Cognition Composite Change-Sensitive Score (CSS) is used to measure cognitive change over time. It is calculated by combining the Crystallized Composite (reading/vocabulary) and Fluid Composite (memory/executive function/speed) scores. Higher scores indicate higher level of functioning.

Secondary outcomes

• Phase 2b: FXS- Change from baseline in Fluid Reasoning Composite Change Sensitive Scores from the NIH-TCB [28 days]: The Fluid Cognition Composite (FCC) from the NIH Toolbox Cognition Battery (NIHTB-CB) is designed to measure changes to neurological functioning. It combines scores from five tests (Dimensional Change Card Sort, Flanker, List Sorting, Pattern Comparison, and Picture Sequence Memory) to provide a measure of executive function, memory, and processing speed. Higher scores indicate higher level of functioning. Superior ability is 130, average is approx. 100 and less than 70 is impairment.
• Phase 2b: FXS- Change from baseline in Flanker Scores from the NIH-TCB [28 days]: The Flanker test measures executive attention, inhibitory control, and attention by having participants identify the direction of a central arrow (or fish for young children) while ignoring surrounding flanking stimuli. Yields a standardized score scaled with a mean of 100 and a standard deviation of 15 (up to a maximum score of 130)
• Phase 2b- FXS Change from Baseline at Day 28 on the Vineland Adaptive Behavior Scales (Vineland-III) Adaptive Behavior Composite Score [28 days]: Vineland Adaptive Behavior Composite (ABC) have a mean of 100 and a standard deviation of 15, where scores from 85 to 115 reflect expected or average adaptive functioning
• Phase 2b: FXS and ASD: Change from baseline at Day 28 in Clinical global impression of severity (CGI-S) as assessed by the investigator [28 days]: This is a 7-point clinician-rated tool used to measure how ill a patient is at the time of assessment
• Phase 2b: FXS and ASD: Change from baseline at Day 28 in Clinical global impression of improvement as assessed by the investigator [28 days]: The Clinical Global Impression-Improvement (CGI-I) scale is a clinician rated scale used to assess treatment response. The score ranges from 1 to 7 (with 1 being "very much improved", 4 being "no change" to 7 being "very much worse")
• Phase 2b: FXS and ASD: Change from baseline at Day 28 in Caregiver global impression of change (CGI-C) as assessed by the caregiver [28 days]: The Caregiver Global Impression of Improvement (CGI-C) is a global measure to provide a caregiver's perspective of a subject's overall condition. The caregiver will use a 7-point scale to assess how the condition has changed from baseline. A higher number indicates worsening condition.
• Phase 2b: FXS and ASD: Change from baseline at Day 28 in the Numerical Rating Scale as completed by the caregiver [28 days]: Numerical rating scale (NRS) scores based on patient-specific behaviors within the domains of Daily Function, Language, and Academic Skill. Caregiver will rate individual from 0 to 10, where 0 indicates 'worst problem' and 10 indicates' no problem at all.'
• Phase 2b: FXS and ASD - Incidence, nature, and severity of adverse events (AEs) and serious adverse events (SAEs) [28 days]: Incidence, nature, and severity of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs)
• Phase 2b: FXS and ASD - Change from baseline in Columbia-Suicide Severity Rating Scale (C-SSRS) throughout the study [28 days]: Prospective suicidality assessment is performed using the Columbia-Suicide Severity Rating Scale (C-SSRS), a questionnaire to evaluate suicidal ideation and behavior. Answer "yes" on item 4 or 5 of the Suicidal Ideation section or "yes" on any item of the Suicidal Behavior section is considered positive. Range is 2-25
• Phase 2b: FXS and ASD - The PK parameters of codabakalner concentrations in plasma-Cmax [28 days]: Maximum concentration of drug in plasma following dose
• Phase 2b: FXS and ASD: Change from baseline to Day 28 in EEG resting state relative power in the alpha, theta, and gamma bands during rest [28 days]: EEG power bands categorize brain electrical activity into five primary frequency ranges that reflect different states of arousal, sleep, and cognition
• Phase 3: Change from baseline to week 12 in Total Cognition Composite score from the NIH-TCB [12 weeks]: The NIH Toolbox (NIH-TCB) Total Cognition Composite Change-Sensitive Score (CSS) is used to measure cognitive change over time. It is calculated by combining the Crystallized Composite (reading/vocabulary) and Fluid Composite (memory/executive function/speed) scores. Higher scores indicate higher level of functioning. The scores typically span across the developmental range, often extending well above and below the 500-point mark depending on the age and cognitive ability of the individual.
• Phase 3: Incidence, nature, and severity of adverse events (AEs) and serious adverse events (SAEs) [12 weeks]: Incidence, nature, and severity of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs)
• Phase 3: Change from baseline in Columbia-Suicide Severity Rating Scale (C-SSRS) throughout the study [12 weeks]: Prospective suicidality assessment is performed using the Columbia-Suicide Severity Rating Scale (C-SSRS), a questionnaire to evaluate suicidal ideation and behavior. Answer "yes" on item 4 or 5 of the Suicidal Ideation section or "yes" on any item of the Suicidal Behavior section is considered positive. Range is 2-25
• Phase 3: Change from baseline to Week 4, Week 8, and Week 12 in Flanker from the NIH-TCB [12 weeks]: Flanker Inhibitory control will assess inhibitory control and attention through asking participant to focus on one stimuli will not focusing on any stimuli surrounding it.
• Phase 3: Change from baseline to Week 4, Week 8, and Week 12 in Fluid Reasoning Composite Change Sensitive Scores from the NIH-TCB [12 weeks]: The Fluid Cognition Composite (FCC) from the NIH Toolbox Cognition Battery (NIHTB-CB) is designed to measure changes to neurological functioning. It combines scores from five tests (Dimensional Change Card Sort, Flanker, List Sorting, Pattern Comparison, and Picture Sequence Memory) to provide a measure of executive function, memory, and processing speed. Higher scores indicate higher level of functioning. Superior ability is 130, average is approx. 100 and less than 70 is impairment.
• Phase 3: Change from baseline to week 4 and week 8 in Total Cognition Composite score from the NIH-TCB [8 weeks]: The NIH Toolbox (NIH-TCB) Total Cognition Composite Change-Sensitive Score (CSS) is used to measure cognitive change over time. It is calculated by combining the Crystallized Composite (reading/vocabulary) and Fluid Composite (memory/executive function/speed) scores. Higher scores indicate higher level of functioning. The scores typically span across the developmental range, often extending well above and below the 500-point mark depending on the age and cognitive ability of the individual.
• Phase 3: The PK parameters of codabakalner concentrations in plasma-Cmax [12 weeks]: Maximum concentration of drug in plasma following dose
• Phase 3: Change in from baseline to Week 4, Week 8, and Week 12, in ABC total score and subscale scores (FXS scoring) [12 weeks]: The Aberrant Behavior Checklist-Community edition (ABC-C) is a 58-item, caregiver-rated symptom checklist for assessing problem behaviors of children and adults with mental retardation at home, in residential facilities, and work training centers. The assessment was done by attributing to each item a score from 0 ("not at all a problem") to 3 ("problem is severe in degree") The ABC will be scored using the FXS-specific factoring system (ABC-FX) for which the total score ranks from 0 to 165.
• Phase 3: Change from baseline to Week 4, Week 8, and Week 12 in behaviors and other symptoms on NRS by caregiver [12 weeks]: Numerical rating scale (NRS) scores based on patient-specific behaviors within the domains of Daily Function, Language, and Academic Skill. Caregiver will rate individual from 0 to 10, where 0 indicates 'worst problem' and 10 indicates' no problem at all.'
• Phase 3: Change from baseline to Week 12 in Vineland Adaptive Behavior Scale 3rd Edition [12 weeks]: Vineland-3 Adaptive Behavior Scale (Vineland-3), using the composite score and domain scores from communication, daily living skills, and socialization. The adaptive behavior composite standard score is computed from the sum of standard scores from the domains and converted into the adaptive behavior composite standard score. Higher scores indicate a higher adaptive level of functioning.
• Phase 3: Change from baseline in CGI-S as assessed by investigator [12 weeks]: This is a 7-point clinician-rated tool used to measure how ill a patient is at the time of assessment
• Phase 3: Change from baseline in CGI-I as assessed by investigator [12 weeks]: The Clinical Global Impression-Improvement (CGI-I) scale is a clinician rated scale used to assess treatment response. The score ranges from 1 to 7 (with 1 being "very much improved", 4 being "no change" to 7 being "very much worse")
• Phase 3: Change from baseline in Caregiver Global Impression of Improvement (CGI-C) assessments [12 weeks]: The Caregiver Global Impression of Improvement (CGI-C) is a global measure to provide a caregiver's perspective of a subject's overall condition. The caregiver will use a 7-point scale to assess how the condition has changed from baseline. A higher number indicates worsening condition.
• Phase 3: Change from baseline in the Numerical Rating Scale at Week 4, Week 8, and Week 12 as completed by the caregiver [12 weeks]: Numerical rating scale (NRS) scores based on patient-specific behaviors within the domains of Daily Function, Language, and Academic Skill. Caregiver will rate individual from 0 to 10, where 0 indicates 'worst problem' and 10 indicates' no problem at all.'

Sex: Male, ages: 18 Years to 45 Years

Inclusion Criteria:

* Phase 2b: Adult males aged 18 to 45 years, inclusive Phase 3: Males aged 13-45 years, inclusive Mental age >/= 36mon
* Diagnosis of Fragile X as confirmed with genetic testing and Stanford Binet testing or
* Confirmed diagnosis ASD per DSM5-TR and EEG criteria
* Patient must have caregiver
* Must be in good health with no significant medical history

Exclusion Criteria:

* Any physical or psychological condition that prohibits study completion
* Uncontrolled seizures or history of epilepsy with a seizure in the past 6 months.
* Auditory or visual impairments that cannot be corrected
* History of suicidal behaviour or suicidal ideation
* Screening vital signs that are abnormal per protocol specification
* ECG that are abnormal and clinically significant
* History of substance abuse or dependence within 6 months
* Other investigational products within 30 days
* Unable to swallow capsules