Seaside setbacks in autism and Fragile X leave few therapeutic hopes


The news that Seaside Therapeutics has terminated two open-label extension studies of STX209 in autism and Fragile X syndrome comes as a blow to patients with these complex neurological disorders, with so few treatment options available. The move was perhaps inevitable following the drug's failure in two late-stage studies, which prompted the project's potential partner Roche to walk away earlier this month.

Later this year Novartis’s AFQ056 should report pivotal phase II results; the mGluR5 antagonist is the most advanced project in Fragile X syndrome. Meanwhile, Curemark is beginning to file its enzyme-replacement therapy CM-AT for autism, an approach which has been surrounded by scepticism. It remains to be seen whether these drugs can reinstate patient confidence that improved therapy options are on the horizon.

Clinical setback

Autism and Fragile X syndrome are developmental brain disorders. While Fragile X is caused by a genetic mutation, there is no known single cause for autism, with both genetic and environmental factors thought to play a part. People with Fragile X have degrees of mental retardation, behavioural problems and seizures. Autism is associated with social deficits, language impairment and repetitive behaviours.

Seaside’s STX209, a GABA B agonist known generically as arbaclofen, is the Massachusetts-based company’s lead pipeline project and one of the most advanced compounds being tested in both of these disorders (Therapeutic Focus – research into autism gains momentum, April 18, 2012).

At the beginning of May Seaside said a phase IIb study in 150 patients with autism spectrum disorder had not met its primary endpoint of improving social withdrawal but did demonstrate significant improvement in the clinical global impression of severity scale.

However, this week the company said the open-label extension study in autism would be terminated owing to "resource limitations". Also terminated was the Fragile X extension study, the phase III trial of which also failed to meet its primary endpoint.

The company says that a Fragile X trial in children aged 5-11 will continue, with results available in late summer. The remainder of Seaside’s pipeline is made up of two mGluR5 antagonists – a preclinical candidate called STX110 and STX107, the phase II trial of which is suspended pending further evaluation, according to

Last June Roche bought an option to commercialise STX209, and licensed patents covering mGluR5 antagonists for the treatment of neurodevelopmental disorders (Roche adds to pipeline with side bet on CNS, June 19, 2012). The Swiss pharma giant told EP Vantage today that the trial failure had prompted the decision over STX209, but said it would still retain exclusive patent licences covering the use of mGluR5 antagonists.

With Seaside seemingly struggling to finance any more work on STX209, the future of both the company and the compound is in doubt.

Big pharma

In terms of the big pharma involvement in Fragile-X and autism, Roche remains the main contender. Its mGluR5 antagonist RG7090 is in phase II for Fragile X, testing its ability to improve functional deficits. Meanwhile RG7314, a V1A vasopressin receptor antagonist, is in phase I investigating its potential to modulate emotional processing and key social deficits in autism spectrum disorders.

Two phase II trials with RG7090 are recruiting a total of 225 patients, and are due to complete later this year, according to A previous phase II trial was completed in 2011, but no results have been reported. RG7090 is also in phase II for depression.

In Fragile X the most advanced compound left is Novartis’s mGluR5 antagonist AFQ056, in phase II/III. Results from a pivotal phase II trial should emerge in the second half of the year, according to analysts at JP Morgan. They note a potential launch in 2015 with peak sales of $800m. EvaluatePharma forecasts 2018 sales of $91m.

Limited results have emerged so far – a small trial in 30 patients aged 18 to 35 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 (Therapeutic Focus – Turning point ahead for Fragile X syndrome, February 28, 2012).


The most advanced project in autism is Curemark’s enzyme replacement therapy CM-AT. The New York-based company said in April that it would begin filing for approval. Positive phase III results were reported at the end of 2011, showing improvements in core and non-core symptoms.

Also trying to exploit the possibility of enzyme deficiency in autism is Kuvan, Biomarin's treatment for phenylketonuria. A phase II study in autism, involving 46 children, failed to meet its primary endpoint although it did show improvements on secondary measures including social interaction and language. Results from a phase II/III open-label extension study are due in mid-2013.

Meanwhile, Autism Therapeutics is developing AT001, a selective serotonin reuptake inhibitor. Last October the company said it was discussing the design of a phase III study with the FDA under a SPA, although there has been no update on this. The trial would be in the treatment of repetitive behaviours.

While the termination of Seaside’s two most advanced clinical trials in Fragile X and autism is clearly a setback, the presence of big pharma provides some comfort. The results of Novartis’s AFQ056 later in the year are eagerly awaited.

Drug Company Trial ID Details
STX209 Seaside Therapeutics NCT01706523 Phase III open-label extension study, terminated
CM-AT Curemark NCT00912691 Phase III open-label extension study, recruiting
Kuvan Biomarin NCT00943579 Phase II/III open-label extension study, completed
Fragile X
STX209 Seaside Therapeutics NCT01555333 Phase III open-label extension study, terminated
STX209 Seaside Therapeutics NCT01325220 Phase III trial in children aged 5-11, results late summer
RG7090 Roche NCT01517698
Two Phase II trials, primary completion end of 2013
RG7314 Roche NCT01793441 Phase II trial not yet open for recruitment

To contact the writer of this story email Joanne Fagg in London at or follow @JoEPVantage on Twitter

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