A 6-week, Study of MG01CI Low Dose and High Dose Compared With Placebo in Adults and Adolescents With Fragile X Syndrome

This study is a multisite, randomized, double-blind, placebo-controlled, phase 2 study of
MG01CI (low and high doses of metadoxine once daily) for 6 weeks compared with placebo in a
1:1 ratio of 60 adolescent and adult subjects with FXS. Following Screening, subjects will
be randomized to MG01CI or matching placebo at Baseline (Day 0) and the 6 week Double-blind
Treatment Period will begin on Day 1.

The first 4 weeks of the treatment period will be a dose-optimization period, during which
the subject's dose of MG01CI or placebo will be optimized. Investigators and subjects will
be blinded with regard to whether the subject is taking active drug or placebo. Subjects
will be blinded to anticipated dose (low vs high dose), while Investigators will not be
blinded to anticipated dose, low dose vs high dose. Every two weeks subjects will receive
2-week supply treatment. A phone follow-up assessment of safety and tolerability will occur
during titration after 1 and 3 weeks of treatment; if the investigator has any significant
concerns regarding safety and tolerability, the subject will be assessed at the site at an
unscheduled visit. All subjects will be assessed at the site after 2 weeks and 4 weeks of
treatment.

All subjects will start with either low dose or matching blinded placebo (2 tablets daily).
At weekly visits/phone assessments, the investigator will evaluate the dose based upon the
investigator's assessment of safety and tolerability. If the subject demonstrates safety or
tolerability concerns with the low dose after 1 or 2 weeks of treatment, then the subject
will be discontinued. If there are no concerns about safety and tolerability after 2 weeks
of treatment, then the dose will be increased to 2 tablets of either high dose of active
treatment or placebo. If at high dose there are concerns about safety and tolerability, then
the dose will be either kept the same or reduced to low dose for the remainder of the
treatment period.

The last 2 weeks of the treatment period will be a dose-maintenance period. During the
dose-maintenance period, the subject will maintain his or her optimal dose as determined at
the end of the dose-optimization period. A phone follow-up assessment of safety and
tolerability will occur after 5 weeks of treatment (after 1 week of dose maintenance). If
the investigator has any significant concerns regarding safety and tolerability, the subject
will be assessed at the site at an unscheduled visit. The subject will be assessed at the
site after 6 weeks of treatment (after 2 weeks of dose maintenance).

There will be a 2-week Follow-up Period after the last dose of study treatment or early
termination.

Inclusion Criteria:

1. Subject is a man or a non-pregnant, non-lactating woman aged 15 to 55 years,
inclusive, at the Randomization Visit.

2. Subject has Fragile X Syndrome with a molecular genetic confirmation of the full
Fragile X Mental Retardation (FMR1) mutation (≥200 CGG repetitions).

3. Subject has a score of 12 or greater on the inattentive subscale of the ADHD RS IV
(as rated by the investigator in a clinical interview of the parent/legal authorized
guardian/consistent caregiver).

4. Current treatment with no more than 3 prescribed psychotropic medications. Anti
epileptic medications are permitted and are not counted as psychotropic medications
if they are used for treatment of seizures. Anti-epileptics for other indications,
such as the treatment of mood disorders, count towards the limit of permitted
medications.

1. Permitted concomitant psychotropic medications (except anti-epileptic
medications and stimulants; see 4b and 4d) must be at a stable dose and dosing
regimen for at least 4 weeks prior to Screening and must remain stable during
the period between Screening and the commencement of study medication.

2. Anti-epileptic medications must be at a stable dose and dosing regimen for 12
weeks prior to Screening and must remain stable during the period between
Screening and the commencement of study medication.

3. Subjects with a history of seizure disorder who are currently receiving
treatment with anti-epileptics must have been seizure-free for 3 months
preceding Screening, or must be seizure-free for 3 years if not currently
receiving anti-epileptics.

4. Stimulant medications must be at a stable dose and dosing regimen for 12 weeks
prior to Screening and must remain stable during the period between Screening
and the end of the treatment period (Week 6/early termination), unless the
subject is washing out; see Exclusion Criterion 4.

5. Behavioral treatments (excluding psychotherapy; see exclusion criteria) must be
stable for 4 weeks prior to Screening and must remain stable during the period
between Screening and the commencement of study medication.

6. Subject has a parent, legal authorized guardian or consistent caregiver who interacts
with the subject for at least 10 hours per week and is able to provide weekly rating
forms of the subject's behavior.

7. Male and Female subjects of childbearing potential must agree to use an effective
contraceptive throughout the study (eg, oral contraceptives or Norplant®; a reliable
double barrier method of birth control [diaphragms with contraceptive jelly; cervical
caps with contraceptive jelly; condoms with contraceptive foam]; intrauterine
devices; vasectomy; or abstinence) and for at least a month after the study, and
females must have a negative serum pregnancy test at the Screening Visit and a
negative urine pregnancy test at the Baseline Visit. Females of childbearing
potential are defined as women who are between menarche and 2 years post-menopause
and who are not surgically sterilized. Male and female subjects who are not sexually
active, and who agree to be abstinent throughout the study, will not be required to
use birth control.

8. Subject and caregiver are able to attend the clinic regularly and reliably.

9. Subject is able to swallow tablets and capsules.

10. For subjects who are not their own legal guardian, subject's parent/legal authorized
guardian is able to understand, read, write, and speak English fluently to complete
the study-related materials (or Hebrew for Israeli subjects).

11. For subjects who are not their own legal guardian, subject's parent/legal authorized
guardian is able to understand and sign an informed consent form to participate in
the study.

12. If subject is his/her own legal guardian, he/she can understand and sign informed
consent to participate in the study.

13. If subject is not their own legal guardian, the subject provides assent for
participation in the study, if the subject has the cognitive ability to provide
assent

Exclusion Criteria:

1. Treatment within the 2 weeks prior to randomization (and throughout the clinical
trial) with lithium, acamprosate, racemic baclofen, investigational metabotropic
glutamate receptor subtype 5 (mGluR5) medications, d-cycloserine, oxytocin,
carbetocin, modafinil, armodafinil, benzodiazepines (unless used for seizure
control), memantine, amantadine, bupropion, or any medication in the statin class.

2. Treatment within the 2 weeks prior to Screening with monoamine oxidase (MAO)
inhibitors, tricyclic antidepressants, l-dopa, cisplatin, phenobarbital or phenytoin.

3. Current treatment with an N-methyl-D-aspartate (NMDA) antagonist.

4. While stimulants will not be excluded from the trial, the subject and the
parent/legal authorized guardian may decide to stop stimulant medication prior to the
study upon discussion with the investigator at the Screening visit. If stimulant
medication is stopped at screening, a two-week washout is required. A subject that
decides to washout from stimulants will be excluded from the trial if a stimulant is
administered after the Screening visit or during the course of the trial.

5. Subject is planning to commence psychotherapy or cognitive behavior therapy (CBT)
during the period of the study or had begun psychotherapy or CBT within 6 weeks prior
to Screening.

1. A subject who started psychotherapy or CBT for the first time within 6 weeks
prior to Screening is excluded.

2. If a subject was previously receiving psychotherapy or CBT, and is resuming the
therapy (such as return from summer vacation), then the subject is eligible for
the study if the same therapy was resumed at least 2 weeks before screening.

6. History of or current cardiovascular, renal, hepatic, respiratory, or
gastrointestinal disease that may interfere with the absorption, distribution,
metabolism, or excretion of the study medication, or that may interfere with the
interpretation of the safety, tolerability, or efficacy of the study medication.

7. History of or current cerebrovascular disease or clinically significant brain trauma.

8. Current major depressive disorder (subject must be free of the most recent episode
for 3 months prior to randomization).

9. History of a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
(DSM-5)-defined substance use disorder in the 3 months prior to Screening.

10. Clinically significant abnormalities, in the investigator's judgment, in safety
laboratory tests, vital signs, or ECG, as measured at Screening.

11. Significant hearing or visual impairment that may affect the subject's ability to
complete the test procedures.

12. Enrollment in another clinical trial within the 30 days preceding Screening.

13. Any psychiatric condition (eg, schizophrenia or personality disorder as diagnosed by
DSM-IV) or clinically significant or unstable medical or surgical condition that may
preclude safe and complete study participation as determined by the investigator
using medical history, physical examination, neurological examination, laboratory
tests, and electrocardiograms. Common diseases such as mild hypertension,
well-controlled type 2 diabetes mellitus (hemoglobin A1C [Hgb A1C] <6.5%), etc. are
allowed per the investigator's judgment as long as they are stable and controlled by
medical therapy that is constant for at least 8 weeks before randomization and
subsequently throughout the study. If there are any concerns about the suitability of
the subject's medical or surgical condition, the investigator should review the
subject's history with the medical monitor. Subjects with autism spectrum disorder or
anxiety disorder will be allowed.

14. Subject has known or suspected human immune deficiency virus-positive status or has
diseases such as acquired immunodeficiency disorder, hepatitis C, hepatitis B, or
tuberculosis.

15. Subject has a history of an allergy or sensitivity to B-complex vitamins.

16. Subject has used mega-dose vitamin B6/pyridoxine during the 28 days before the
Randomization Visit. Subjects will be allowed to have a 28-day washout of mega-dose
vitamin B6/pyridoxine after the Screening visit. Routine multivitamin supplements
will be allowed.

17. Subject has used high-dose supplements of omega-3 fatty acids ≥ 500 mg (such as
softgels, capsules, or fish oils; regular daily dietary consumption of fish is
allowed) or folic acid supplements (other than routine multivitamin supplements) at
any time during the 2 weeks before the Randomization Visit.

18. Subject is related to anyone employed by the sponsor, investigator, or study staff.

19. Subject has any condition that, in the principal investigator's opinion, would place
the subject at risk or influence the conduct of the study or interpretation of
results.

20. Subject is pregnant, lactating, or using an inadequate contraceptive method. -