Fragile X Syndrome | Executive Insights | US/EU5/China | 2021

Fragile X syndrome (FXS) is a genetic disorder causing intellectual disability indicated by developmental delays, with symptoms overlapping with autism spectrum disorder, including hand flapping and poor eye contact. Prevalence of FXS among pediatric and adolescent patients (<18 years) is estimated to be 10,030 patients in the United States, 6,770 patients in the EU5, and 35,579 patients in China in 2021. FXS is most commonly caused by expansions of a CGG repeat in the 5′-untranslated (UTR) region of the FMR1 gene, with 200 or more repeats considered a full mutation. Incomplete methylation of the gene, resulting in an incomplete activation of FMR1, can lead to less-severe symptoms within the FXS spectrum. Patients carrying a premutation (55-200 repeats) may be at risk for various symptoms. FXS’s most significant impact is intellectual disability, which persists into adulthood and has lifetime impacts. Psychological abnormalities, including ASD, ADHD, anxiety, and depression, impact patients’ emotional health and their ability to form peer-to-peer relationships. No disease-modifying therapies are yet available, and treatment consists of therapies approved for various behavioral phenotypes, along with supportive psychological care and behavioral intervention, as required. Although various biochemical pathways have been investigated with the hope of developing a DMT, no therapies in the clinical pipeline are expected to fulfill this key unmet need. KOLs expect that approval of a potential DMT would expand diagnosis, potentially motivating inclusion of FXS screening in neonatal panels, expanding the treatable population and improving outcomes for patients and caregivers. The high lifetime costs of managing FXS symptoms will likely allow developers of a true DMT to demand a high price point, although negotiating with both private and public insurance systems will require a robust cost-benefit analysis to justify the cost.