Tackling Fragile X

At the annual fragile X conference in Dearborn, Mich., in July, executives from Seaside Therapeutics found themselves confronted by a desperate mother. Her son was enrolled in a clinical study of STX209, a drug the small biotech firm is developing to treat the neurological disorder fragile X, and she had driven across several states to make a direct plea to the company: Please extend the trial, or at least provide medication to kids who participated.

“She didn’t know what she would do if it stopped,” recalls Seaside’s chief executive officer, Randy Carpenter. Indeed, preliminary results from the Phase II trial suggest the drug is having a positive effect on the behavior of kids with fragile X, which is caused by a mutation in a single gene and is also the most common known genetic cause of autism.

Seaside was able to convince the Food & Drug Administration to approve an open-label extension of the trial so that children could continue taking the drug. Nearly all of them have stayed on it. Like the mother at the conference, parents are in despair over the lack of treatments for fragile X, symptoms of which range from learning impairment to mental retardation.

Until recent interest by big pharma, Seaside was pretty much the only company developing drugs for fragile X and autism. Other small start-ups focusing on the diseases have one by one run out of money and closed up shop. Venture capitalists simply haven’t had an appetite to fund such risky drug development.

But Cambridge, Mass.-based Seaside has a secret weapon: an anonymous wealthy family that is committed to finding new treatments for fragile X and autism. With funds from the family and grants from the National Institutes of Health and patient advocacy organizations, Seaside has been able to explore the basic science of the brain disorders in tandem with its drug development efforts. Although unusual, that balanced approach to building up a scientific and clinical rationale looks like it’s working. In just five years, the firm’s two drug candidates have made it to mid-stage trials as a treatment for fragile X, where they show promise, and to early-stage tests on autism.

The unique funding stream puts Seaside in a league of its own in the biotech world: The company’s fate isn’t tied to the whims of shareholders or a venture board. The relative financial freedom means Seaside isn’t in a race to get to the next milestone; corners aren’t being cut on basic research or early tests; and if a drug candidate fails, it isn’t a death knell. Furthermore, if competitors emerge—and slowly, as Seaside carves out a clinical path, they are—it is viewed as a good thing rather than a threat.

“We’re very fortunate that our investor’s primary goal is to bring new treatments forward to help children and their families,” Carpenter says.

The lack of financial pressure doesn’t mean Seaside isn’t in a hurry. Managers are keenly aware of the urgency for new medicines. According to the patient advocacy organization Autism Speaks, some 1.5 million people are affected by autism, yet there are no dedicated drugs to alter the course of the disease.

At the same time, industry historically has had little incentive to research drugs that treat fragile X or autism. In the case of fragile X, the disease’s connection to a single gene malfunction has led to some obvious starting points for drug discovery, but the patient population is quite small. For autism, a lack of understanding of the root cause of the disease has deprived drug developers of easy targets.

Thus when Carpenter and Massachusetts Institute of Technology neurologist Mark Bear started Seaside in 2005, “we felt a moral imperative to get treatments out as soon as possible to this population,” Carpenter says.

Early results from trials of STX209, a single-isomer version of the already-approved muscle-relaxant baclofen, suggest that the company is making headway. Data from a Phase II trial of the drug, a selective γ-amino butyric acid type B receptor agonist, point to an improvement in the behavior of kids with severe social impairments, a core symptom of fragile X. Meanwhile, stories from parents whose children participated in the trial, including the mother who drove to Dearborn, suggest the drug noticeably eases children’s anxiety and reduces social challenges.

Seaside’s pipeline includes a second fragile X treatment, STX107, which works by dampening the activity of a neurotransmitter receptor called mGluR5. MIT’s Bear had discovered that the receptor, which prompts new proteins to be synthesized, was overstimulated in fragile X. Turning down its activity in mice with fragile X alleviated the symptoms of the disease.

Armed with this knowledge, Seaside licensed a family of mGluR5 antagonists from Merck & Co., which hadn’t looked at their effect in fragile X. A $6 million grant from NIH and additional support from patient advocacy organizations enabled the studies necessary to bring STX107 to the clinic. The compound is currently in Phase I trials, and Carpenter says a pilot Phase II study is planned to begin by the end of the year.

The discovery of the role of mGluR5 in fragile X has prompted several big pharma companies to test the usefulness of mGluR5 antagonists that had been collecting dust on lab shelves. Roche and Novartis both have molecules in Phase II trials for fragile X. Last year, Pfizer started a small autism research unit that will initially focus on fragile X.

Capturing big pharma’s interest in fragile X and autism has been a major feat, one Carpenter attributes to progress in understanding the basic science of the disorders and to Seaside’s efforts to create a framework for testing drugs in humans.

Designing clinical trials has been tough. In autism, for example, “there’s so much heterogeneity in both the severity of the symptoms and the nature of the symptoms,” says Geraldine Dawson, chief scientific officer at Autism Speaks. Not only do patients display a wide range of IQs and abilities, but even the core symptoms manifest themselves in different ways. For example, impaired social behavior might mean trouble making eye contact for one person but difficulty developing peer relations for another.

At the time Seaside began considering human tests for its fragile X drug, Carpenter says, only a handful of research centers had the expertise with such patients, and they lacked validated measures, or “end points,” to confirm that a drug worked. The only measurements were IQ tests and the like, which aren’t designed to be given frequently. “We worked for years with the medical community, including participating in NIH symposia, on how you would develop clinical end points for a trial,” Carpenter adds.

Going forward, Seaside is trying to determine whether other single-gene disorders might open doors to treating autism. About 20 genes in a signaling pathway related to autism have been discovered, and the company and its collaborators are now sequencing them to see whether autistic patients have mutations in that pathway, says Aileen M. Healy, Seaside’s vice president of research.

“Seaside has really been at the forefront of a new era of autism clinical research,” says Dawson of Autism Speaks. If one of its drug candidates for fragile X reaches the market, she adds, it would be a landmark for those affected by two debilitating neurological disorders.