On January 11, Zynerba Pharmaceuticals announced its publication in the Journal of Neurodevelopmental Disorders describing the role of the endocannabinoid system (ECS) and cannabidiol therapy in fragile X syndrome (FXS). The review suggests that the ECS has an essential role in neuronal development, cognitive function, and the pathogenesis of FXS. Furthermore, it supports the potential of Zynerba’s Phase III pipeline agent, Zygel, a transdermal cannabidiol gel to modulate the ECS for treating FXS. GlobalData forecasts that Zygel will launch in the US in Q3 2025 and generate US sales of $17.9 million by 2030.

There are currently no approved therapies available for FXS. The prescribed treatment for FXS consists exclusively of off-label drugs that target individual symptoms of the disease. Examples of such interventions include selective serotonin reuptake inhibitors for depressive symptoms and anxiety; stimulants like methylphenidate for hyperactivity, inattention, and impulsivity; antipsychotic medications for aggression; and anticonvulsant agents for seizures. Many patients with FXS require treatment with several different products to help alleviate their unique set of symptoms. However, as these therapies do not target the pathogenesis underlying FXS, they have a modest effect on a subset of patients. Key opinion leaders (KOLs) previously interviewed by GlobalData agreed that behavioural symptoms of irritability and aggression are not adequately treated with the current off-label therapy options. Furthermore, despite combining pharmacological treatments with interventional services such as speech-language therapy, occupational therapy, and special educational services to address developmental impairments, patients with FXS continue to present with significant impairments in their daily functioning throughout their life.

This has led to a call for an FXS-specific pharmacological treatment that targets the underlying brain deficits of FXS, which could be addressed by Zygel. FXS is caused by the expansion of cytosine, guanine, and guanine (CGG) trinucleotide repeat in the 5’ untranslated region of the fragile X mental retardation 1 (FMR1) gene. Methylation of the CGG repeats leads to transcriptional silencing of the FMR1 gene with a subsequent reduction or absence of fragile X mental retardation protein (FMRP) expression. The absence of FMRP is suggested to disrupt ECS signalling, which has been implicated in the pathogenesis of FXS. Zygel’s proposed mechanisms of action are supported by the results from the Phase III CONNECT-FX (NCT03614663) trial in patients with FXS with greater than or equal to 90% methylation of the FMR1 gene, with the Zygel treatment group demonstrating improvements in social interactions, irritability, and behaviour. As the severity of symptoms is correlated with the amount of FMRP protein produced and the degree of methylation in the FMR1 gene, Zygel could be beneficial to the most severely impacted patients with FXS.

However, KOLs noted that the use of cannabinoid treatments is yet to be widely accepted. Furthermore, when Zygel’s annual cost of therapy was compared with Jazz Pharmaceuticals’s Epidiolex, the first marketed cannabidiol treatment, KOLs were concerned that Zygel would also be associated with a high cost of treatment, which could be a barrier for its uptake. As a result, payers and physicians may prefer to offer cheaper alternatives when possible.

KOLs agreed that products that target the pathogenesis of FXS could have a superior efficacy and safety profile over current off-label symptomatic treatments. However, Zygel will need to demonstrate significant improvements in daily function, quality of life, and drug safety profile to displace the widely available generic therapies used in treating FXS. There is an ongoing Phase III trial (RECONNECT, NCT04977986) to assess the efficacy and safety of Zygel in children and adolescents with complete methylation of the FMR1 gene. The trial’s primary completion date is in September 2023. Completing a head-to-head study investigating functional improvements of daily activities with Zygel could also help differentiate it from the marketed treatments.

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