A Safety Study of NNZ-2566 in Patients With Fragile X Syndrome

Fragile X Syndrome is a genetically determined neurological disorder in which affected
individuals are intellectually handicapped to varying degrees and display a variety of
associated psychiatric symptoms. Clinically, Fragile X Syndrome is characterized by
intellectual handicap, hyperactivity and attentional problems, autism spectrum symptoms,
emotional lability and epilepsy. The epilepsy seen in Fragile X Syndrome is most commonly
present in childhood, but then gradually remits towards adulthood. Physical features such as
prominent ears and jaw, and hyper-extensibility of joints are frequently present but are not
diagnostic. Intellectual handicap is the most common feature defining the phenotype.
Treatment for the disorder is symptomatic - focusing on the management of symptoms - and
supportive, requiring a multidisciplinary approach.

This study will investigate the safety and tolerability of treatment with oral
administration of NNZ-2566 at 35 mg/kg or 70 mg/kg BID in adolescent or adult males with
Fragile X Syndrome. The study also will also investigate measures of efficacy during
treatment.

Inclusion Criteria:

1. Fragile X Syndrome with a molecular genetic confirmation of the full FMR1 mutation.

- Results from previously completed testing are acceptable with written
documentation of the genetic results.

- Results from PCR or Southern blot tests are acceptable

- Results from cytogenetic testing are not acceptable but subject may be eligible
if molecular genetic testing is redone.

- A full mutation with mosaicism is allowed if:

- Subject manifests full phenotypic profile of Fragile X syndrome

- CGG Repeats >200 are detected

- Southern blot prevails over PCR, if Southern blot shows >200 repeats and
PCR results show <200 repeats.

- The following results would not meet criteria:

- Deletions

- Point mutations

- Mosaicism without detection of >200 CGG repeats or absence of full
phenotypic profile in an individual with mosaicism

2. Males, aged 12-45 years

3. Subjects with a Clinical Global Impression - Severity (CGI-S) score of 4 or greater
at Screening

4. Subjects with a total score of 30 or greater on the Aberrant Behavior Checklist (ABC)
at Screening.

5. Current treatment with no more than 3 psychotropic medications. This includes
medications used to treat problems with sleep onset and sleep continuity. Melatonin
for difficulties with sleep onset is permissible and is excepted from the count of
psychotropic medications. Similarly, anti-epileptic medications are permitted and are
not denoted as "psychotropic medications" if they are used for treatment of seizures.
Use of anti-epileptics for other indications such as the treatment of mood disorders
counts towards the limit of permitted medications. Concurrent use of omega-3 fatty
acids is also permissible and does not count towards the allowed number of
concomitant psychotropic medications. A complete list of permitted concomitant
psychotropic medications can be found in Appendix A.

6. Concomitant medications for chronic medical conditions are permissible. Examples of
chronic medical conditions include gastroesophageal reflux disease (GERD) and asthma.
Every effort should be made to keep the doses and dosing regimens of these
medications stable in the 4 weeks preceding Screening and during the period between
Screening and the commencement of study medication.

1. Permitted psychotropic concomitant medications (except for anti-epileptic
medications-see below) must be stable, in terms of 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

7. 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

a. For each enrollee, every effort should be made to maintain stable regimens of
allowed concomitant medications and allowed behavioral therapies from the time of
commencement of single-blind study medication until the last study assessment.

8. Sufficient expressive language capabilities to complete the Expressive Language
Sampling Task.

9. Individuals with a history of seizures should have a stable pattern of seizure
activity in the 3 months preceding Screening.

Exclusion Criteria:

1. Treatment within the two weeks prior to Screening with monoamine (MAO) inhibitors,
lithium, minocycline, acamprosate, racemic baclofen, investigational metabotropic
glutamate receptor subtype 5 (mGluR5) medications, d-cycloserine, oxytocin,
carbetocin, tricyclic antidepressants and bupropion.

2. Patients planning to commence psychotherapy, including cognitive behavior therapy
(CBT), during the period of the study or those who had begun psychotherapy, including
CBT, within 6 weeks prior to Screening.

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

4. History of, or current cerebrovascular disease or clinically significant brain
trauma.

5. History of, or current clinically significant endocrine disorder, e.g. hypo or
hyperthyroidism, or diabetes.

6. History of, or current malignancy.

7. Current major depressive disorder (patients have to be free of the most recent
episode for 3 months prior to enrollment).

8. History of a DSM-5-defined substance use disorder in the 3 months prior to Screening.

9. Clinically significant abnormalities in safety laboratory tests, vital signs or ECG,
as measured at Screening.

10. QT/QTcF Exclusions (any of the following):

- QTcF > 450 msec. Three ECGs should be obtained at the time of Screening, 5
minutes apart from each other, and the results should be averaged.

- History of risk factors for torsade de pointes (e.g. heart failure, clinically
significant hypokalemia or hypomagnesemia, or a family of long QT syndrome).

- A serum potassium at screening <3.0 mmol/L.

- QT/QTcF prolongation previously or currently controlled with medication, in
which normal QT/QTcF intervals could or can only be achieved with medication

- Current treatment with other medications that have demonstrated QT/QTc
prolongation and have this risk described in the Warnings and Precautions
section of their Prescribing Information

11. Patients with significant hearing and/or visual impairments that may affect their
ability to complete the test procedures.

12. Current treatment with insulin

13. Hgb A1C values outside of the normal reference range at Screening

14. Current or past treatment with insulin like growth factor IGF-1

15. Current or past treatment with growth hormone

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

17. Previously randomized in this clinical trial

18. Allergy to strawberry