AFQ056 for Language Learning in Children With FXS

The trial will use a double blind placebo-controlled parallel-group flexible-dose forced
titration design in which 100 subjects with FXS, age 32 months to 6 years of age will enter a
12-month blinded treatment phase during which they are randomized 1:1 to AFQ056 or placebo
followed by an 8-month (open label) extension phase in which all participants will be treated
with active drug. The flexible dose design will mimic practice, take into account
differential responsiveness and the known inter-child variability in drug levels with AFQ056,
and allow use of maximum tolerated dose (MTD) which is likely to be most effective.

Inclusion Criteria

1. Age 32 months to 6 years inclusive at Screening (visit 1).

2. Has an FMR1 full mutation.

3. DQ<75 calculated from the Mullen Scales of Early Learning at time of screening.

4. Parent or legal guardian is available and able to communicate well with the
investigator, comply with study requirements and provide written informed consent.

**Note**The Parent or legal guardian who will be signing consent form, should be the
individual administering the language intervention

5. English is the primary language spoken in the home and the subject's first language is
English.

6. Meet criteria indicating evidence of intentional communication based on parent
interview via a communication eligibility screening tool.

**Note** On the Eligibility Screening Tool - Communication, the child must have at
time of screening:

1. Section 1: Answer of YES; the child uses at least 5 spoken words to label items
on a daily basis.

OR

2. Section 2: At least 3 YES answers to items 1-10 if child does not have at least 5
spoken words.

7. Produces 3 or more intentional acts of communication on the structured portion of the
Weighted Communication play sample at time of screening.

8. Stable behavioral and other therapy regimen for 30 days prior to screening.

9. Stable dosing of all concurrent psychotropic medications except stimulants for at
least 60 days prior to screening. Due to the very short half-life of stimulants
(specifically methylphenidate and amphetamine variants), a stable regimen of these
medications is required for 2 weeks only.

- Note** Medications impacting GABA, glutamate and/or mGluR5 pathway receptors are
exclusionary and not permitted during study participation. Additionally,
stimulant regimens may include combinations of short- and long-acting forms and
may be taken with different timing or dosing on different days of the week (e.g.
Doses may be skipped on weekends or days off school and extra doses may be given
some days for therapy sessions later in the day). The intent is to keep the doses
and regimen being used at the time of screening consistent during the trial even
if there is some variation in how the medication is taken on different days.

Exclusion Criteria

1. Use of medications impacting GABA, glutamate and/or mGluR5 pathway receptors or
transmission.

**Note** Treatment with acamprosate, amantadine, budipine, carbetocin, cycloserine,
dextromethorphan, felbamate, ketamine, lithium, minocycline, memantine, oxytocin,
remacemide, racemic baclofen, riluzole, fycampa, investigational mGluR5 medications,
and/or statins are exclusionary.

2. Unstable seizure disorder as defined by any seizure in the 6 months prior to the
screening visit, and/or any change in anti-convulsant drug dosing in the 60 days prior
to screening.

**Note** Use of levetiracetam and oxcarbazepine are among permitted anticonvulsants.

3. Use of any other investigational drug at the time of enrollment or within 30 days or 5
half-lives (whichever is longer) of the investigational drug prior to screening until
end of study visits (or longer if required by local regulations).

4. History of hypersensitivity to AFQ056 or any mGluR antagonist.

5. History or presence of any clinically significant disease of any major system organ
class, within the past 2 years prior to screening including but not limited to
neurological, cardiovascular, endocrine, metabolic, renal, or gastrointestinal
disorders. This does not include typical features of FXS such as psychological
symptoms or history of epileptic seizures.

6. Significant acute illness that did not completely resolve at least four weeks prior to
the Screening visit.

7. Abnormal laboratory values at screening that are in the opinion of the investigator
are clinically significant and may jeopardize the safety of the study subject.

8. Use of (or use within at least 5 half-lives before dosing) concomitant medications
that are strong/moderate inhibitors or inducers of CYP1A1/2, CYP2C9/19 or CYP3A4 (see
Appendix B).

9. Subjects who are, in the opinion of the investigator, unable to comply with the
requirements of the study.

10. History or Ppresence of immunodeficiency diseases at the time of screening, based on
medical history, including a positive HIV test result.

11. History of a positive Hepatitis B surface antigen (HBsAg) or Hepatitis C result at
time of screening.

12. History or presence of suicidal thoughts and/or suicide attempts.