A Randomized Study of BPN14770 in Male Adolescents (Aged 9 to < 18 Years) With Fragile X Syndrome

Inclusion Criteria:

1. Patient is male adolescent aged 9 to < 18 years. 2. Patient has FXS with amolecular genetic confirmation of the full fragile X mental retardation-1 (FMR1) mutation (≥ 200 CGG repetitions).

2. Current treatment with ≤ 3 prescribed psychotropic medications. Anti-epilepticmedications are permitted and are not counted as psychotropic medications ifthey are used for treatment of seizures. Anti-epileptics for other indications,such as the treatment of mood disorders, count towards the limit of permittedmedications. If the subject is on 3 prescribed psychoactive medications and, inaddition, is taking either a psychoactive over-the-counter medication (eg,melatonin, Benadryl, etc.) or CBD products, the investigator is encouraged todiscuss eligibility with the medical monitor.

3. Permitted concomitant psychotropic medications must be at a stable dose anddosing regimen for at least 4 weeks before screening and must remain stableduring the period between screening and the commencement of study drug. Everyeffort should be made to keep dosing stable throughout the study.

4. Anti-epileptic medications must be at a stable dose and dosing regimen for 12weeks before screening and must remain stable during the period betweenscreening and the commencement of study drug. Every effort should be made tokeep dosing stable throughout the study.

5. Patients with a history of seizure disorder who are currently receivingtreatment with anti-epileptics must have been seizure-free for 3 months beforescreening or must be seizure-free for 2 years if not currently receivinganti-epileptics.

6. Behavioral and other non-pharmacological treatments/interventions must bestable for 4 weeks before screening and must remain stable during the periodbetween screening and the commencement of study drug, and throughout the study.Minor changes in hours or times of therapy that are not considered clinicallysignificant will not be exclusionary. Changes in therapies provided through aschool program, due to school vacations, are allowed.

7. Patient must be willing to practice barrier methods of contraception while onstudy, if sexually active. Abstinence is also considered a reasonable form ofbirth control in this study population.

8. Patient has a parent(s), legal authorized guardian(s), or consistentcaregiver(s).

9. Patient and caregiver are able to attend the clinic regularly and reliably. 11.Patient's parent(s), legal authorized guardian(s), or consistent caregiver(s)is able to understand and sign an informed consent form to participate in thestudy.

10. Patient must provide assent for participation in the study if the patient hasthe cognitive ability to provide assent.

11. To participate in the Part 1 PK only: subjects must be able to swallowcapsules.

Exclusion Criteria:

Diagnosis and main criteria for inclusion:

The eligibility criteria are the same for all parts of the study except for Part 1 (PK), where patients must be able to swallow capsules and must weigh at least 75 lbs (34 kg) to receive the 50 mg dose.

Patient Inclusion Criteria

1. Patient is male adolescent aged 12 to < 18 years.

2. Patient has FXS with a molecular genetic confirmation of the full fragile X mentalretardation-1 (FMR1) mutation (≥ 200 CGG repetitions).

3. Current treatment with ≤ 3 prescribed psychotropic medications. Anti-epilepticmedications are permitted and are not counted as psychotropic medications if theyare used for treatment of seizures. Anti-epileptics for other indications, such asthe treatment of mood disorders, count towards the limit of permitted medications.

4. Permitted concomitant psychotropic medications must be at a stable dose and dosingregimen for at least 4 weeks before screening and must remain stable during theperiod between screening and the commencement of study drug.

5. Anti-epileptic medications must be at a stable dose and dosing regimen for 12 weeksbefore screening and must remain stable during the period between screening and thecommencement of study drug.

6. Patients with a history of seizure disorder who are currently receiving treatmentwith anti-epileptics must have been seizure-free for 3 months before screening ormust be seizure-free for 2 years if not currently receiving anti-epileptics.

7. Behavioral and other non-pharmacological treatments/interventions must be stable for 4 weeks before screening and must remain stable during the period between screeningand the commencement of study drug, and throughout the study. Minor changes in hoursor times of therapy that are not considered clinically significant will not beexclusionary. Changes in therapies provided through a school program, due to schoolvacations, are allowed.

8. Patient must be willing to practice barrier methods of contraception while on study,if sexually active. Abstinence is also considered a reasonable form of birth controlin this study population.

9. Patient has a parent(s), legal authorized guardian(s), or consistent caregiver(s).

10. Patient and caregiver are able to attend the clinic regularly and reliably.

11. Patient's parent(s), legal authorized guardian(s), or consistent caregiver(s) isable to understand and sign an informed consent form to participate in the study.

12. Patient must provide assent for participation in the study if the patient has thecognitive ability to provide assent.

13. To participate in the Part 1 PK only: patients must be able to swallow capsules.

Patient Exclusion Criteria

1. Inability to successfully complete the NIH-TCB picture vocabulary and oral readingassessments at screening and baseline for Part 2 (DB). Patient must be able tocomplete these assessments at baseline to be randomized into Part 2; care should betaken that a patient enrolled into Part 1 (PK) possesses this ability if theirdesire is to continue to Part 2. The ability to complete the NIH-TBC oral readingand picture vocabulary subtest at baseline is defined as the ability to completeboth subtests, with (1) confirmation from the clinician administering that the testadministrations are valid (noted on the administration form), and (2) generation ofvalid test scores for each test.

2. History of, or current cardiovascular, renal, hepatic, respiratory,gastrointestinal, psychiatric, neurologic, cerebrovascular, or other systemicdisease that would place the patient at risk or potentially interfere with theinterpretation of the safety, tolerability, or efficacy of the study drug.

• Common conditions such as mild hypertension, etc. are allowed per the PI'sjudgment as long as they are stable and controlled by medical therapy that isconstant for at least 4 weeks before randomization.

3. Renal impairment, defined as serum creatinine > 1.25 × ULN at screening.

4. Cirrhosis, unstable chronic liver disease or acute liver disease. Hepaticimpairment, defined as alanine aminotransferase or aspartate aminotransferaseelevation > 2 × ULN at screening. Note: liver function tests may be repeated after 1week to evaluate return to acceptable limits; if liver function tests remainelevated, patient is ineligible to participate. Subjects with stable chronichepatitis B on oral anti-viral therapy and subjects cured of chronic hepatitis C maybe allowed. Subjects with Gilbert syndrome are allowed.

5. Clinically significant abnormalities, in the PI's judgment, in safety laboratorytests, vital signs, or 12-lead ECG, as measured during screening.

6. History of alcohol abuse at any time in life or history of other substance abusewithin the past year, according to PI's assessment.

7. Significant hearing or visual impairment that may affect the patient's ability tocomplete the test procedures.

8. Concurrent major psychiatric condition (eg, major depressive disorder,schizophrenia, or bipolar disorder) as confirmed by the PI. Patients with additionaldiagnosis of autism spectrum disorder or anxiety disorder will be allowed.

9. Subject has active diseases that would interfere with participation, such asacquired immunodeficiency disorder, hepatitis C, hepatitis B, or tuberculosis.

10. Subject is planning to commence psychotherapy or CBT within 4 weeks prior toscreening.

11. Patient is an immediate family member of anyone employed by the sponsor, PI, orstudy staff.

12. Patient has weight < 25 kg or a BMI greater than the 97th percentile for his ageaccording to the Centers for Disease Control and Prevention (refer to Appendix 1).To participate in the Part 1 cohort receiving 50 mg dose, patient must weigh ≥ 75lbs (34 kg).

13. Patient has participated in another clinical trial within the 30 days beforescreening.