16 January 2009. Fragile X mutations are the most common cause of inherited mental retardation, and often cause autistic symptoms and epilepsy. The syndrome, which affects one in 4,000 males and one in 6,000 females, inactivates the FMR1 gene on the X chromosome, and recent work traced many of the symptoms to overactivity of metabotropic glutamate receptors in the absence of FMR protein. Even as researchers were showing that reducing mGluR5 activity in a mouse model of Fragile X reversed much of the mutant phenotype (see ARF related news story), the push was already on to bring mGluR5 antagonists to the clinic.
The first step on that road has now yielded results, with a report in the Journal of Medical Genetics of a pilot open-label, single-dose trial of the drug fenobam in 12 young adults with Fragile X Syndrome. Headed by Elizabeth Berry-Kravis of Rush University Medical Center in Chicago, Illinois, and Randi Hagerman of the University of California, Davis, the trial found no significant adverse effects of fenobam dosing. Six of the 12 patients showed improvement in a neurological measure of sensory gating, which is often impaired in the syndrome. In nine patients, the treatment appeared to calm behavior and reduced hyperactivity and anxiety.
Fenobam was investigated first in the early 1980s as an anti-anxiety drug, but research halted after Phase 2 clinical trials because of conflicting efficacy results and CNS side effects including hallucinations. Its target, the mGLuR5 receptor, was identified much later (Porter et al., 2005), and this renewed interest in the compound. The compound received orphan drug designation from the U.S. Food and Drug Administration in 2006, and is being developed by Neuropharm LTD, Sussex, United Kingdom.
The FDA’s Orphan Drug Act covers some rare neurologic diseases such as Huntington’s and ALS, but recently, it has come up in discussions about Alzheimer disease drug development as well. By the law’s original intent, AD is far too common to qualify as an orphan disease. Even so, calls are being heard to consider extending parts of this law to include AD. The argument is based on the special difficulties in developing drugs for this indication, where most clinical trials fail (see, for example, ARF story on the Alzheimer Study Group; Reiman comment; Hook comment.
Additional fenobam trials are in the planning stages, according to Katie Clapp of the FRAXA Research Foundation, a private nonprofit organization that has supported some of the mGluR5 research and is advising Neuropharm on clinical trials. Clapp said that there are about 190,000 Fragile X patients in the United States, which makes the disease one of the more common orphan disorders, but still officially a rare disease.
The results, while preliminary, fit with the emerging notion that some neurodevelopmental disorders may respond to pharmacological treatment even in adults, if the underlying biochemical defect can be identified. This is counter to a view that assumes that irreversible abnormalities of brain development are the culprits in diseases like Fragile X and other neurodevelopmental disorders and so holds out hope for a new approach to treating these diseases (see ARF related news story; ARF related news story; for a recent review of this topic, see Ehninger et al., 2008).—Pat McCaffrey.
Berry-Kravis EM, Hessl D, Coffey S, Hervey C, Schneider A, Yuhas J, Hutchison J, Snape M, Tranfaglia M, Nguyen DV, Hagerman R. A pilot open-label single-dose trial of fenobam in adults with fragile X syndrome. J Med Genet. 2009 Jan 6. Abstract