Personalized medicine and Fragile X: complexity, disease and economics

Fragile X is a genetic disorder that typically causes distinct facial features as well as moderate to severe mental impairment and social withdrawal, and as such it is considered to be the most common single-gene cause of autism.  The disorder was determined some time ago to be  "caused by the unstable expansion of a CGG repeat in the FMR1 gene and abnormal methylation, which results in suppression of FMR1 transcription and decreased protein levels in the brain" (Lutz et al., 1998, cited in OMIM).  That this repeat expansion is causal, for whatever reason, it well established by a strong association between the genetic variant and the trait. As with nearly all genetic disorders, even when 'the' cause has been identified as a variant or variants in a single gene, the manifestation of this disorder is a spectrum of severity.

There is currently no drug treatment for the "core symptoms" of fragile X, though several drugs that treat various behavioral symptoms are available.  A recent story in the New York Times describes the experiences of several families with a drug that was developed to reduce social withdrawal in children with fragile X or autism, manufactured by Seaside Therapeutics, but was still undergoing clinical trial.  Why autism should have any physiological connection with fragile X is not known, but there is an overlap of symptoms.  The drug, arbaclofen, or STX209, affects neurotransmitter signaling and hence, brain function and its behavioral implications.

A Phase 2 clinical trial was carried out over three years ago, and the results announced in 2011.  Seaside said

...clinically meaningful improvements on global and specific neurobehavioral outcomes were observed in the general study population. The improvements were statistically significant in pediatric patients with more severe impairments in sociability -- a core symptom of fragile X syndrome.

Following the trial, Seaside Therapeutics continued to supply the drug to some children for whom the drug was considered to be beneficial.  According to the NYT, the drug made an enormous difference in the lives of a number of children.  Some were able to speak for the first time, others halted aggressive behaviors, and so forth.  This seemed at least statistically, as well as subjectively, to be a cause-effect relationship.  There were parents, of children with autism as well as fragile X, who considered arbaclofen a miracle drug.

In 2012 Seaside initiated a Phase 3 trial, to further test the drug.  In announcing this trial, the president of Seaside said,

“In our Phase 2 study, we were very excited to observe clinically meaningful improvements in social impairment in patients receiving STX209—marking the first time a drug candidate has positively impacted a core symptom of fragile X syndrome. The Phase 3 study is the most comprehensive study ever undertaken in patients with fragile X syndrome and represents the first time that a drug candidate will be evaluated for a core symptom of fragile X syndrome as the primary endpoint.”

But, production is now being halted because the drug has not proven to be a successful enough treatment for social withdrawal in children with autism in the Phase 3 study.  This seems to be a bureaucratic and financial issue rather than a scientific one.  According to a Seaside vice president, quoted on the "Age of Autism" website,

The FDA requires companies to pick one, and only one, assessment as the “primary endpoint” of the study. In their eyes, the result on that one pre-selected endpoint makes or breaks the study. In our recent autism study, STX209 did not show an advantage over placebo (see above) on the primary endpoint of social withdrawal, so the FDA and some news reporters regard it as a negative study. In fact, STX209 did show advantages over placebo on a number of other assessments. Some of these secondary endpoints are just as meaningful as the social withdrawal assessment, or even more so, but in the FDA’s eyes, they don’t make the study a positive study, because they were not pre-selected as the “primary endpoint.”

The pharmaceutical giant, Roche, had been backing development of the drug, but they've recently pulled their support as they cut back on research and development in general, and it seems that Seaside cannot afford to continue manufacturing the drug alone.

Seaside released this statement:

"The study termination is due to resource limitations at seaside, and is not due to any safety issue associated with STX209. We know that this termination will be disruptive and disappointing for many. We are planning to complete phase 3 and the results of this study should be available late summer. If the results are positive, seaside will discuss with FDA the required next steps for approval of STX209. 

"This means the drug could potentially become available in the future but there is still nothing guaranteed."

Parents who saw tremendous improvement in their children on this medication are devastated.

Well, we started this post after reading the piece in the New York Times, thinking that we knew where we were going with it -- like most other genetic disorders, fragile X is a complex disorder, and only a subset of children in the studies would respond favorably to the drug because of the heterogeneity of the phenotype and variation in genetic background, and so of course it's understandable that it's difficult to ascertain the drug's efficacy.  By implication, genetic background determines whether a child responds poorly or well to STX209, and which children respond well and which respond poorly hasn't been determined.

While that may well be true, that's not the real story here.  Instead it's economics.  And that's heartbreaking.  So here is a case when 'personalized genomic medicine' might be a correct way to identify cause or predict effect, and here, where the association actually works (regardless of why), we have other issues interfering with effective care.  Life is complex, but our culture often advances things that don't do good, and impedes ones that actually do.