Harmony Biosciences’ transdermal cannabidiol ZYN002 suffered a setback as a Phase III trial failed to meet the primary endpoint in a Fragile X Syndrome trial, with the biotech blaming a higher-than-expected placebo response.
The Phase III registrational clinical trial (NCT04977986), called RECONNECT, evaluated Harmony’s gel in FSX patients between the ages of three and 30 years. The primary endpoint for the study was change from baseline to week 18 in the ABC-CFXS Social Avoidance subscale score in patients with complete methylation. This scale is a tool used to measure behaviours in individuals with FXS. Harmony did not reveal the data from the trial.
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The pivotal failure was met with investor concern that led to a 16.6% plumet in the US company’s stock. Share price dropped from $29.92 at market open to $26.67 at market close on 24 September. This wiped off a considerable amount of Harmony’s valuation given it has a market cap of $1.5bn.
Harmony Biosciences snagged ZYN002, at the time called Zygel, during its acquisition of Zynerba Pharmaceuticals in a deal worth up to $200m back in 2023. By this point, ZYN002 had already seen failure in the Phase III CONNECT-FX trial (NCT03614663) but redeeming post-hoc analysis indicated significant benefit in a subset of FXS patients with high FMR1 methylation, leading to further study in this population.
Fragile X is a leading cause of inherited intellectual disabilities such as autism spectrum disorder and effects males to a greater extent due to associated X chromosome mutations. There are currently no approved therapies for an Fragile X indication, with treatment constrained to symptom management.
Prior to the Phase III flop, the future appeared bright for ZYN002. A February 2025 report by GlobalData had identified ZYN002 as a catalyst for high growth rates in Fragile X market. GlobalData is the parent company of Pharmaceutical Technology.
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By GlobalDataIn a press release, Harmony avoided comment on the future of the transdermal cannabidiol, instead citing their “late-stage, catalyst-rich pipeline with multiple Phase III programmes.”
“While these results are not what we anticipated, we remain confident in our ability to bring innovative therapies to patients while creating long-term value for shareholders,” said Jeffrey Dayno, President and CEO of Harmony Biosciences. “We will conduct a comprehensive analysis of the full dataset to better understand the results as part of our continued commitment to the Fragile X community,” the company’s chief medical and scientific officer Kumar Budur added.
Sill hope for Fragile X Syndrome pipeline
While Harmony’s FXS pipeline may be thwarted, other pharma companies are gearing up for completion of pivotal trials and new drug application (NDA) filing. Shionogi has recently completed a Phase II/III trial for the cannabidiol zatolmilast in male adults, aged 18 to 45, with FXS (NCT05358886). A further trial in adolescents is due to complete by 30 September 2025 (NCT05163808), as per ClinicalTrials.gov.
Novel BK channel modulator KER-0193 received Rare Pediatric Disease Designation from the US Food and Drug Administration (FDA) back in May 2025, which itself followed Orphan Drug Designation in November 2024. KER-0193 was recently acquired by Servier from Kaerus in a deal that could be worth up to $450m. A Phase II trial in patients with FSX is due to launch in 2026.
In addition, Spinogenix’s SPG60, also a BK channel modulator, received Fast Track Designation from the FDA in January 2025, having completed a Phase II trial (NCT06413537) back in December 2024. Plans for a Phase III trial are yet to be announced.
However, GlobalData has identified several barriers to the market’s growth. This includes the high anticipated annual cost of therapy, clinical heterogeneity in Fragile X and caution of public markets and investors to therapies based on cannabidiols.
