Fragile X: The Quest to Treat a Complex, Little-Understood Condition

We worked on a Phase II study of a drug to treat Fragile X syndrome that, like most rare work we do, was a challenge from the start. Fragile X is a rare and not fully understood genetic disorder, typically resulting from an expansion of the CGG triplet repeat within the Fragile X mental retardation 1 (FMR1) gene on the X chromosome. The study’s primary objective was to evaluate the efficacy of the investigational product, administered once daily, compared to placebo in treating FXS symptoms in adolescents and adults.

This was a challenging trial on many fronts:

  • Three protocol amendments were implemented during the study’s duration of only six
  • Multiple scales and questionnaires were required for endpoint assessments — so many that they became too time-consuming to complete, causing some scales and questionnaires to be removed in one of the amendments.
  • Patients required carefully planned and organized visits due to their underlying condition. This called for streamlined questionnaires and scales for endpoint assessments.
  • Rater and caregiver consistency was a major issue that required multiple protocol deviations.
  • Patients traveled long distances to the sites, reflecting the rarity of FXS and the fact that few doctors study the indication. That was challenging for patients and required the sponsor to budget for travel cost assistance.

Sound familiar? Given these and other complications, it’s no great surprise that this double-blind study — involving 62 adult and adolescent patients across 12 sites — fell short of its goal of showing the drug effective. The outcome also reflects the lack of consensus on what study endpoints are most relevant when researching drugs for Fragile X.

Similarly, it points to the lack of a single scale for measuring the condition’s severity. Instead, a range of scales covers a wide range of behavioral issues.

When designing an FXS study protocol, it’s vital to consider that symptom severity can fluctuate widely and can be complicated by the presence of parallel conditions, such as depression and ADHD, and use of concomitant medications related to Fragile X Syndrome.

Like most rare diseases, FXS is a tough and complex field of study and is still often overlooked or misunderstood as a diagnosis. Learn more by visiting Fragilex.org.uk or following recent discussions on social media.

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