BioWorld Today Contributing Writer

Seaside Therapeutics Inc. will begin a landmark Phase III trial to evaluate the efficacy of a drug candidate against the core symptoms of Fragile X syndrome.

"Our company's really leading a paradigm shift in drug discovery by taking a scientific approach to neuropsychiatric diseases, particularly autism and disorders of brain development," Seaside CEO Randall L. Carpenter told BioWorld Today.

Seaside, of Cambridge, Mass., executives believe that the pathologies of Fragile X and some autism spectrum disorders are caused by excessive activation of glutamate receptors and an imbalance of excitatory to inhibitory neurotransmission in the brain.

In order to regulate neurotransmission, Seaside targeted gamma-amino butyric acid type B (GABA-B) receptor with its investigational compound STX209. Modulating the GABA-B pathway may normalize that deficiency, while also providing additional benefits by reducing activation of another pathway of interest to Seaside, mGluR5.

Fragile X is the most common inherited form of intellectual disability and the largest known cause of autism. At this time, there are no approved therapies on the market for Fragile X, and it has been declared an orphan disease by the FDA.

Previous attempts to treat autism generally have involved using existing compounds that have shown activity in autism patients and trying for clinical data that would support an expanded label, but results have been unsatisfactory.

Fragile X alone would be a market sizable enough for drug success, but STX209 and the pathways it regulates may have relevance for other forms of autism.

"We think that though this was discovered by focusing on a single gene disorder, the pathway could be disregulated by a number of other causes . . . with broader applicability in a subset of individuals with what's currently considered idiopathic autism," Carpenter explained.

In a Phase II study reported in September 2010, Seaside saw significant improvements in the symptoms of autism spectrum disorder. The open-label study was carried out in 28 individuals between 6 and 17 with autism spectrum disorder. The primary endpoint of the study was an improvement on the irritability subscale of the aberrant behavior checklist. The study also tracked improvements in other neurobehavioral symptoms, particularly social withdrawal.

The company reported similar results from a Phase IIa study in Fragile X in July 2010.

Seaside is virtually alone in the field of Fragile X and autism. The reason for that, Carpenter said, is a high level of perceived risk around the indication. In fact, Seaside has raised funds for research and development of its products on the strength of the science and the large unmet need, not on any calculable return on investment.

Seaside's initial investor was an individual who wanted to support the development of new treatments for autism. The company also had support from the National Institutes of Health and other foundations. Its $30 million Series B was funded by a private family investment firm. (See BioWorld Today, Sept. 18, 2009.)

At that time, in 2001 the targets Seaside was investigating were not validated, and there was no regulatory path for approval of drugs in autism and Fragile X.

"What you're seeing now is much greater interest," Carpenter said. "People are starting to explore and think about drug discovery programs for autism and neurodevelopmental disorders. We're thrilled by that."

The new Phase III study of STX209 will enroll 120 patients, randomized to placebo or STX209 for an eight-week period. A titration period of up to 28 days will precede stable dosing, and there will be a withdrawal period and a follow-up period for those in active treatment.

As with the previous Phase II studies, there will be an open-label extension study following the trial. Trial endpoints include safety, tolerability and efficacy as measured by improvements in social withdrawal.