Fragile X syndrome (FXS) is a rare, serious, life-long genetic disorder caused by alterations in the Fragile X gene (FMR1). It is the leading single gene cause of intellectual disability. FXS affects about one in 2,500–4,000 males and about one in 7,000–8,000 females. Females are typically less severely affected than males. Most boys and approximately 30 per cent of girls with FXS will have significant intellectual disability across their lifespan.
FXS is characterised by a range of developmental problems, including learning disabilities, behavioural issues including autism features, cognitive impairment, speech and language deficits, sleep problems, anxiety, and severe difficulties with regulating stress and emotions 1. These core symptoms have a substantial impact on day-to-day functioning of patients and their carers.
Following diagnosis, which typically occurs around three to five years of age, a patient may require treatment to help alleviate the behavioural challenges they experience. Currently, medications prescribed experimentally (not formally approved by regulators) and behavioural interventions developed for other conditions are used to help improve some of the symptoms, with no FXS specific treatments available.
FXS is caused by a mutation to the FMR1 gene located on the X chromosome. This gene controls the production of the FMR protein (FRMP), which is required for the normal development of neural connections. A mutation of the FMR1 gene prevents normal development of neural networks in the brain, disrupts nervous system functions, and leads to the symptoms of FXS.2
The protein produced by the FMR1 gene, known as FMRP, is essential for normal brain development
Anxiety occurs in about 90% of individuals with FXS and represents a substantial unmet clinical challenge. Elevated levels of the stress hormone, cortisol, is also reported in FXS There has been significant clinical interest in evaluating Actinogen’s lead drug candidate, Xanamem, for medical conditions associated with raised levels of cortisol. Thus, Actinogen recognises the potential for anxiety and stress regulation in FXS to be pursued as a clinical development opportunity with Xanamem.
Xanamem may be eligible for orphan drug designation in FXS in key markets. Orphan drug designation provides significant potential regulatory, development and commercial advantages for Actinogen.
FXS is caused by a mutation to the FMR1 gene located on the X chromosome
There are currently no approved drugs to treat FXS.
The current standard of care for FXS includes speech and language therapy, special educational support, occupational therapy, and behavioural therapy. Care may also include the use of off-label pharmaceuticals such as stimulants, anti-depressants, anti-psychotics and anti-convulsants. Selective serotonin reuptake inhibitors (SSRIs) are effective approximately 50 per cent of the time in managing anxiety in FXS patients. However, FXS patients tend to be more sensitive to these drugs and side effects are common even at low doses. This reflects a substantial unmet medical need.
Currently, treatment options that focus specifically on the behavioural aspects of FXS are limited. Drugs registered for other indications and not approved for use in FXS are commonly used. However, these only minimise symptoms of the disorder.
Actinogen plans to initially target patients between 12-18 years of age who need help with the treatment of behavioural issues and who can potentially benefit from Xanamem. Once the safety of Xanamem has been confirmed in this population, longer term plans will see trials run in younger patient cohorts when the brain is more ‘plastic’ and subject to change.
Please note, Xanamem is still an investigational product.
In children with FXS, raised cortisol levels are significantly associated with cognitive impairment and behaviour problems including social anxiety, hyperactivity, and social withdrawal3, 4. High levels of stress hormone may also impair neural circuits important for the regulation of these behaviours.
Treatment options for behavioural problems represent a significant unmet clinical and medical need in FXS. Xanamem’s mechanism of action supports its use in the reduction of cortisol and as a potential treatment for the cognitive and behavioural symptoms associated with FXS.
Xanamem is a novel therapeutic product specifically designed to inhibit the production of excess cortisol in the brain. Xanamem is considered a potential therapy to decrease elevated cortisol and alleviate associated symptoms such as anxiety in FXS. Xanamem works by inhibiting the 11β-HSD1 enzyme in the brain, which blocks the production of the stress hormone, cortisol.
The hypothalamic-pituitary-adrenal axis (HPA-axis) is responsible for maintaining normal levels of circulating cortisol. In FXS, the HPA-axis is impaired, cortisol is abnormally high, and this is thought to result in problems with stress regulation, anxiety as well as other debilitating symptoms including behavioural issues and cognitive impairment. By normalising HPA-axis function, Xanamem provides a targeted strategy that may alleviate the stress regulation difficulties that underlie some of the most debilitating symptoms in FXS.
Fragile X Association of Australia
‘Stuart X’ A short film about a Fragile X sufferer
US National Fragile X Foundation
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