AFQ056 for Language Learning in Children With FXS

This study will enroll 100 participants with Fragile X syndrome (FXS) between the ages of 32 months and 6 years.

After being informed about the study and its potential risks, patients with Fragile X Syndrome will be screened for eligibility. Participants who meet entry criteria and agree to participate will then enter a single-blind 4-month placebo lead-in during which study participants will continue therapy treatments as usual to allow for placebo effects to stabilize. At the end of the 4-month placebo lead-in, all participants will have a repeat battery of AFQ056 baseline assessments and will enter the placebo-controlled phase, where they will be randomized in a 1:1 ratio to AFQ056 or placebo. All subjects will begin at a dose of 25 mg of AFQ056 or placebo, taken orally twice per day. Over 7 weeks, they will titrate up to their maximum tolerated dose (MTD), up to 100 mg. Once they have reached their MTD, both participant groups will initiate an intensive language intervention designed to maximize the extent to which parents engage in types of verbally responsive interactions that have been well documented as facilitating language learning. The entire language intervention will be delivered to the parent in the home or at scheduled study visits through the use of a laptop computer equipped with distance video-teleconferencing software and will include coaching, homework, and feedback sessions. Subjects will be treated with their MTD in combination with the language intervention for 6 months.

After 8 months of treatment in the placebo-controlled phase (including 6 months of language intervention), all participants will have final assessments and will be given the opportunity to enter the open label extension (OLE) period. In the OLE, all participants will be treated with active drug according to the same schedule as in the placebo-controlled phase with 2 months of flexible dose titration to the MTD followed by a period of stable treatment, and will continue the language intervention throughout. A post-intervention follow-up visit will be conducted one month after the final assessment visit of the trial.

Researchers will compare overall weighted communication score in the AFQ056 and placebo groups, after 6 months of treatment in combination with an intensive standardized parent-implemented language learning intervention. This is meant to serve as a marker of drug effect on neural plasticity, the core problem in the disorder. Further assessments will also be compared between groups to determine changes in language, cognitive, and adaptive functioning.

Inclusion criteria

• Age 32 months to 6 years inclusive at Screening (visit 1).
• Has an FMR1 full mutation.

**Note Presence of mosaicism is allowed

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

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

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

OR

• Section 2: At least 3 YES answers to items 1-10 if child does not have at least 5 spoken words.
• Produces 3 or more intentional acts of communication on the structured portion of the Weighted Communication play sample at time of screening.

**Note: subjects are permitted to use augmentative communication devices throughout the study if the device is the subject's primary form of communication and the device has been prescribed for the subject by an SLP.

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

**Note: Patients will be allowed to continue their standard of care therapies throughout the trial but these will not be changed during the placebo lead in or placebo controlled portion of the trial, outside of the standard changes occurring from school schedules.

• 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.Use of CBD oil or hemp based substances legal for sale over the internet are allowed provided that the dosing regimen has been consistent for at least 60 days prior to screening and will remain the same throughout the trial.

Exclusion criteria

• 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.
• Note** Lithium taken as a dietary supplement is permitted if the dose is less than 5mg/day. A 5mg/day dose is the recommended dietary intake level, and therefore is not considered to be therapeutic. Lithium dosage must remain the same throughout the duration of the trial and documented in the concomitant medication log.
• 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.

• 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).
• History of hypersensitivity to AFQ056 or any mGluR antagonist.
• 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.
• Significant acute illness that did not completely resolve at least four weeks prior to the Screening visit.
• 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.
• 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).
• Subjects who are, in the opinion of the investigator, unable to comply with the requirements of the study.
• Presence of immunodeficiency diseases at the time of screening, based on medical history, including a positive HIV test result.
• History of a positive Hepatitis B surface antigen (HBsAg) or Hepatitis C result at time of screening.
• History or presence of suicidal thoughts and/or suicide attempts.