Current Clinical Trials in Rett Syndrome

November 13, 2014


In this blog I will cover the current status and progress of all drug intervention related Rett syndrome trials found on

Summer has closed and we look back on time with family and friends and smile a private smile of fond memories. Many of us involved with Rett syndrome that were fortunate enough to attend the Rett Science Symposium and Family Conference in Chantilly, Virginia in June smile about the new friends we made and the old friends we reunited with for those few days.

Since many were not able to attend the gathering, I thought it might be a good time to review the ongoing clinical trials studying various drug interventions in Rett syndrome. At the conference a brief session describing some of these clinical trials was held, and many that attended asked good questions directed to the physician scientists conducting these trials.

I will cover each of the trials found on the web site that involve a drug intervention. All of these trials are important and I will include all of them not just those that is involved with.

Trials are crucial to our understanding of Rett syndrome and how to treat it with the compounds that are available to clinical research hospitals that study Rett syndrome. Each one is attempting to change the biology associated with Rett syndrome and thus improve the quality of life for all with Rett syndrome. So they are all critical to our understanding of how we might treat children and adults with Rett syndrome.

As of October 2014, there were seven active drug trials in Rett syndrome. The fact that there are seven drugs being tested in Rett syndrome is exciting, and we hope for success in each of them.

Demonstrating efficacy in a Phase 3 trial is our goal with the hope that one of these drugs is approved for Rett syndrome and brings a quality of life improvement for those with Rett syndrome.

Drugs in active trial:

  1. IGF-1
  2. NNZ-2566
  3. Desipramine
  4. Fingolimod
  5. Dextromethorphan
  6. Copaxone
  7. EPI-743

IGF-1 and NNZ-2566 has partnered in two of these trials; the Boston Children’s Hospital trial investigating Insulin-like Growth Factor-1 under Dr. Walter Kaufmann, and the Baylor College of Medicine trial (along with University of Alabama at Birmingham and the Gillette Clinic) with the Neuren Pharmaceutical drug called NNZ-2566.

Both of these compounds fall into the category of “growth factors” which may help in Rett syndrome by providing a more robust environment for neuronal cells to grow and form synapses. More synapse formation is the goal of these trials in the hope that this treatment can lead to a greater number of neuronal connections within the central nervous system.

The IGF-1 trial is a Phase 2 double blind placebo controlled cross over study of 48 children with Rett syndrome.

The NNZ-2566 trial is Phase1/2 study with a placebo group, low dose group and a high dose group studying 60 adult women with Rett syndrome.  This trial closed in September, and the data was analyzed and results were just announced.  The next steps for Neuren are to meet with the FDA and to apply for Orphan Drug Status and Breakthrough Therapy Status.


  • NNZ-2566 was shown to be well tolerated at the dose levels tested after 28 days of treatment, and no significant safety concerns were identified. 
  • The data indicate dose-response and improvement over time in the study. 
  • The high dose used in this study showed benefit vs placebo both in the group-level analysis as well as in the individual subject analysis. 

For the details of the results please refer to Neuren’s announcement.

So what does this mean? Growth factors have the potential to create more connections, and this is key to communication between nerve cells.

By increasing the possible number of connections, we have hope that this will lead to new neural networks that can help with everyday Central Nervous System (CNS) controlled activities like:

  • breathing
  • locomotion
  • controlled movement
  • general stability of the neuronal environment

You can read more detail about these trials by going to our website


Another drug that is in a clinical trial is desipramine (a selective inhibitor of norepinephrine reuptake, which has been shown to reduce respiration alterations in Mecp2 deficient mice) which is being tested in France. This is a Phase 2 trial with a placebo group (12 individuals), low dose group (12 individuals) and a high dose group (12 individuals) and will run for 24 months.

Being a Phase 2 trial, it is designed as a safety and efficacy study with the primary outcome measure in this trial being of a change in the respiratory disturbances in Rett syndrome.

This trial was started in October of 2008 and is due to end in December 2014; we anxiously await the completion.


A study that is being carried out in Switzerland is with a drug called fingolimod (Novartis Pharmaceuticals). This trial revolves around the fact that fingolimod stimulates the production of Brain derived neurotrophic factor (BDNF). BDNF is a neurotropic factor which plays a role in:

  • neurogenesis
  • neuronal survival
  • neuronal differentiation
  • maturation during early development
  • synaptic function
  • neuroplasticity

Abnormally low levels of BDNF have been demonstrated in Mecp2 deficient mice, and the administration of fingolimod has reversed the symptoms in Mecp2 deficient mice, thus the rationale for this clinical trial.

Based on these results this Phase 1 clinical study will assess the safety and efficacy of oral fingolimod in children with Rett syndrome. Since this is a safety study, fingolimod will be given orally to each of 6 Rett syndrome patients for 12 months and the outcome measure will be a study of the levels of BDNF in blood and cerebrospinal fluid before and after treatment. The BDNF levels will be measured before the start of treatment, at the first dose, at 6 months and at 12 months.

This study was started in August of 2013 and is expected to run until July of 2017.


A third trial that is being conducted in the U.S. is a Phase 2 trial with dextromethorphan. This trial is being conducted at Johns Hopkins University/Kennedy Krieger Institute. The premise of this study is that receptors for a certain brain chemical called glutamate, in particular the NMDA type receptors, are increased in the brain of young Rett syndrome children.

Glutamate and its receptors, when in excess, cause harmful over-stimulation of nerve cells in the brain contributing in part to:

  • seizures
  • behavioral problems
  • learning disabilities

In this study the dextromethorphan is being studied to investigate whether it counters or blocks glutamate and the NMDA receptors.

This is a phase 2 trial because dextromethorphan has been on the market for years as a cough suppressant for children with respiratory infections. This phase 2 trial is a placebo controlled trial looking to enroll 60 Rett syndrome children from 1-10 years of age. The clinical team will use outcome measure to determine the benefits of dextromethorphan on cognition, behavior and seizures (if present).

This study was started in March of 2012 and its estimated date of completion is June 2015.

Copaxone (Glatiramer Acetate)

Another clinical trial that began this year in Israel and New York is with glatiramer acetate which some of you may know by its trade name, Copaxone.

The trial in Israel is a Phase 1 safety trial and will be conducted in up to 10 girls with Rett syndrome. In the Israel study the primary safety objective being is the drug safe and tolerable after 6 months of treatment with Copaxone.
There are secondary objectives looking at:

  • respiration
  • general behavior
  • communication
  • hand stereopathies
  • feeding
  • seizure activities
  • sleeping

In the New York trial, a Phase 2 trial, the primary outcome measure is gait speed to be assessed using a computerized walkway.

Additional secondary outcome measures will monitor respiratory function.
Other outcome measures will include:

  • eye-tracking
  • visual attention
  • memory
  • visual pursuit

The New York study will enroll 20 girls with Rett syndrome. So why glatiramer acetate?  Glatiramer acetate is a potent inducer of Th2-cells (a subset of white blood cells call T helper cells) and it modulates these T helper cells to secrete high levels of neurotrophic factors, particularly BDNF. The induced cells cross the blood brain barrier, accumulate in the CNS and express BDNF and other regulatory substances. Like fingolimod (discussed above) the goal is to increase the levels of BDNF in the central nervous system.

These trials were scheduled to start in early 2014 and are anticipated to end next year, but again the timing depends on patient enrolment.


The final clinical trial I will address in this blog was just completed with a compound known as EPI-743 (Edison Pharmaceuticals). One characteristic of Rett syndrome is that there is a significant elevation in blood markers of oxidative stress. So many may ask what is oxidative stress?  Oxidative stress is an imbalance between the reactive oxygen species and the body’s ability to readily detoxify the reactive intermediates or to repair the resulting damage. EPI-743 is a novel therapeutic with demonstrated efficacy and safety in the treatment of disorders characterized by oxidative stress.

The purpose of this study is to examine the safety and efficacy of EPI-743 in a population of children with Rett syndrome. This was a randomized/placebo controlled Phase 2 study looking at safety and efficacy. The primary outcome measure in this study was the clinical severity score with secondary outcome measures being changes in oxidative stress markers and head circumference. Recent reports concerning this trial outlined that the primary outcome measures were not changes but the secondary outcome measures did show significant changes.

The Natural History Study under Dr. Alan Percy has published that head circumference falls off the normal growth curves in the first year of life. The observation here with EPI-743 in regard to head circumference may hold hope for Rett syndrome in that, if head circumference can be normalized, the brain size and cellular make up may be moving toward normal. These observations stimulate more research in regard to the general state of oxidative stress and controlling it may have positive outcomes in Rett syndrome.

I hope this short review has helped with an understanding of the current clinical trials and those that have recently closed.

These trials are all Phase 1 or Phase 2 trials and as such they are small in size. If any of them show efficacy in Phase 2 then the FDA will be petitioned for a Phase 3 trial.

We all hope that one or more might move to a phase 3 trial.

The real heroines here are our girls involved in these trials. They are the trail blazers who are leading the way for all of those with Rett syndrome. We cannot thank them and their families enough for all they are doing to help ease the burden for all.

Other Resources?

“How Clinical Trials Happen, Updates on the IGF-1 and NNZ-2566 Clinical Trials“  Virginia 2014


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