Therapeutic Focus - Turning point ahead for Fragile X syndrome


This year could hold some interesting developments for Fragile X syndrome, the most common cause of inherited learning disabilities. With clinical data due in the most promising therapies tested to date and Novartis hoping to file a candidate for approval in 2013, the first disease modifying treatment for the condition could be just around the corner.

Following the discovery of the associated gene back in 1991 pre-clinical research is continuing to determine the underlying pathways that drive Fragile X. The ultimate goal is to arrest or even reverse mental retardation, turning the syndrome into a manageable condition. “Previously we haven’t had a disease modifying agent to study in Fragile X and with major clinical trials underway we can learn a lot from the results,” says Dr Michael Tranfaglia, medical director of FRAXA Research Foundation.

Genetic understanding

Fragile X is caused by a mutation that leads to transcriptional silencing of the X chromosome-linked FMRI gene, preventing expression of the Fragile X mental retardation protein (FMRP).

FMRP has a role in repressing translation of mRNA at nerve synapses; in its absence protein synthesis remains unchecked and overactive, causing immature synapses and elongated dendritic spines. This results in weaker connections between brain cells and the clinical features of Fragile X, which include moderate to severe mental retardation, behavioural problems and seizures. Between 2-6% of children with autism are diagnosed with Fragile X.

In the US it is estimated that 1 in 5,000 males and 1 in 6,000-8,000 females are born with the disorder. There are also approximately 1 million carriers of the mutation; women carriers are usually unaffected although men can show some symptoms later in life.

Medications such as antidepressants, psychostimulants and mood stabilisers are used to control symptoms of the disease. However, medication used for one symptom can often worsen others and none improve cognitive impairment.

Fragile X syndrome pipeline

In the search for therapeutic agents that might specifically treat Fragile X, neurotransmitter pathways have become a target for research (see table below).

Much attention has turned to the metabotropic glutamate receptor 5 (mGluR5) pathway, the receptor for glutamate. At nerve synapses mGluR5 activation initiates local protein synthesis while FMRP suppresses it; in Fragile X where the FMRP brake is absent excessive protein synthesis occurs, leading to the morphological changes in dendritic spines and subsequent impaired brain function.

Researchers have shown that by blocking the mGluR5 signalling pathway excessive protein synthesis can be checked. This mechanism of action is now being tested in man, to see if it will translate into tangible benefits for patients.

“mGluR5 antagonists would be tremendously useful, and they are almost certainly disease modifying," says Dr Tranfaglia. “However, we do think mGluR5 antagonists are potentially most useful in patients with full blown Fragile X. If… you have a lot of normal cells in your brain it is possible that mGluR5 antagonists might actually cause some impairment in those normal cells.”

Most advanced

The most advanced oral mGluR5 antagonist is AFQ056 from Novartis, currently in a phase II/III study. Read outs from two 160-patient trials in adults and adolescents are expected in August this year, according to; and Novartis has said it hopes to file for approval in 2013.

A previous trial using AFQ056 in 30 male patients aged 18 to 35 years showed no significant effects of treatment across the whole group. However, after subsequent analysis significant improvement in behaviour was detected in seven patients who had a fully non-functioning FMRI gene.

“It is important to keep in mind the relatively small numbers in the trial, and treatment duration was relatively brief,” says Dr Tranfaglia. “In the current study Novartis are…. using more patients and treating them for a longer period of time and there is a good chance it will work across the whole spectrum, but we will just have to see.”

Also in the clinic

Another mGluR5 antagonist, RO4917523 from Roche, has completed a 40-patient phase II trial, the results of which have not been published. A larger 180-patient phase II was set to commence in early 2012, according to, although this does not appear to have started. 

Seaside Therapeutics’ meanwhile is testing STX209, an oral GABA-B receptor agonist which inhibits glutamate signalling in the brain, indirectly inhibiting excessive mGluR mediated protein synthesis.

Two phase III studies are ongoing testing the drug’s impact on social withdrawal in Fragile X patients. Seeking to recruit 200 children and 120 adolescents and adults, the completion dates in are December 2011 and July 2012 respectively, although both are said to be still enrolling.

In 2010 a randomised, placebo-controlled phase II study the drug failed to hit the primary endpoint, a significant improvement on a measure called the Irritability subscale of the Aberrant Behaviour Checklist. However the company did report a positive trend on all measures and “clinically meaningful improvements” on global and specific neurobehavioral outcomes, which hit statistical significance in paediatric patients with more severe impairments in sociability. Several patients in an ongoing label-extension study have withdrawn from other medications such as mood stabilisers and anti-psychotics.

“There is lots of evidence of the possibility of disease modifying potential in Fragile X in a number of different compounds,” says Dr Tranfaglia. “The exact parameters of treatment are unknown at this point with regards to exactly how long you would have to treat and at what ages, but there has always been the idea that you want to treat as early as possible.

“Interestingly, recent studies … showed that you can basically rescue the phenotype if you turn the gene on in adulthood.”

Fragile X pipeline
Product Company Pharmacological Class Proprietary Level 2 Trial IDs
Phase III AFQ056 Novartis Metabotropic glutamate receptor 5 (mGluR5) antagonist NME NCT01253629, NCT01357239
STX209 Seaside Therapeutics GABA B agonist NDA NCT01282268, NCT01013480
Phase II RO4917523/EVT 101 Roche mGluR5 antagonist NME NCT01015430, NCT01517698
STX107 Seaside Therapeutics mGluR5 antagonist NME NCT01325740
Pre-clinical PAK inhibitor program Afraxis PAK inhibitor NME
NX201 NexGenix Pharmaceuticals PAK1 inhibitor NME 
Ganaxolone Marinus Pharmaceuticals GABA A receptor modulator NME + Proprietary Drug Delivery
STX110 Seaside Therapeutics mGluR5 antagonist NME

New targets

There are a large backlog of targets that have been validated in Fragile X but still have to be explored. Glycogen synthase kinase 3 (GSK3) has been implicated in the disease, while excessive matrix metalloproteinase-9 (MMP-9) activity is thought to maintain the immature morphology of dendritric spines. Meanwhile inhibitors of other protein kinases including ERK/MEK and PI3K could potentially be useful in Fragile X, pre-clinical evidence suggests.

Many companies are waiting to see how Novartis fares with AFQ056 before pushing on with more research, Dr Tranfaglia believes, in terms of assessing the clinical benefit, but also to learn lessons about trial design and outcome measures.

One novel target that is progressing towards the clinic is PAK, a protein kinase that regulates dendritic spine remodelling. Research is ongoing at both California-based Afraxis and New York’s NexGenix Pharmaceuticals.Initially researched by Susumu Tonegawa with funding from FRAXA, Dr Tonegawa, who went on to establish Afraxis, demonstrated proof of concept by using genetic modifications in animal models. Blocking PAK expression later in life rescued multiple Fragile X phenotypes.

Afraxis hopes to start clinical trials in the near future.

“As PAK is relatively ubiquitous and mGluR5 primarily a CNS target, it remains to be seen how safe PAK inhibitors are,” Dr Tranfaglia says.

Looking to the future

As the disease pathway continues to be revealed and more targets emerge, the opportunities for drug companies are growing.

As a single gene disorder a gene therapy approach could be an option, however as a drug that ultimately needs to be delivered to the brain, current approaches are limited.

“It could be feasible if the technologies for delivery to the CNS were improved, getting the gene to every signal cell in the brain is a daunting task,” Dr Tranfaglia says. Protein replacement therapy however has been largely ruled out.

“FMRP needs to be expressed temporarily and spatially in a very tightly regulated way. Just dumping the protein into the whole brain doesn’t help and may even be a little toxic,” he says.

Meanwhile Fragile X target pathways have implications for other neurological disorders. Researchers have found that in conditions such as psychotic depression, schizophrenia, Alzheimer’s and autism there can be low levels of FMRP, which may be a cause of their disorder. Sufferers do not have Fragile X mutations but are for some reason not expressing the protein. As the most common single gene cause of autism, any advances made in Fragile X should also benefit this poorly understood broad spectrum disorder.

The search for an effective disease modifying treatment for Fragile X has certainly made progress since the discovery of the causative gene.

“The current small molecule approach does have the potential to enormously improve people’s functional capacity and normalise it to some extent,” says Dr Tranfaglia. “We are not talking about a cure just yet. Similar to the development of HIV drugs we are looking at developing a Fragile X treatment cocktail that will modify the course of the disease and make it a manageable condition.

“I think that in the near term that is an achievable goal.”

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