Harmony Biosciences has halted development of its cannabidiol gel candidate, ZYN002, for 22q11.2 deletion syndrome after the treatment failed to meet key efficacy goals in a late-stage study for fragile X syndrome.
Trial Setback and Paused Development
The Pennsylvania-based biotech announced that the phase 3 RECONNECT trial of ZYN002 in fragile X syndrome did not achieve its primary endpoint of improving social avoidance, citing a higher-than-expected placebo response as a potential factor. Following this outcome, Harmony has paused its mid-stage program in 22q11.2 deletion syndrome, also known as DiGeorge syndrome, while it reviews all data from the fragile X trial.
“We are conducting an in-depth review of all Reconnect study data,” Harmony said in a statement. “Once all datasets are available, we expect to share updates early next year on the Fragile X syndrome study and implications for potentially embarking on a phase 3 study in 22q deletion syndrome.”
Background of ZYN002
ZYN002 is a synthetic cannabidiol gel designed to be absorbed through the skin to target disorders linked to disrupted endocannabinoid signaling. The asset was originally developed by Zynerba Pharmaceuticals and acquired by Harmony in 2023. Zynerba’s earlier phase 2/3 trial of ZYN002 in fragile X syndrome had also failed, though it showed possible efficacy in a subset of patients with complete methylation of the FMR1 gene. Mutations in this gene cause excessive methylation that silences protein production, contributing to fragile X syndrome. Based on those findings, Harmony focused the phase 3 RECONNECT trial on patients with complete methylation. However, the gel again failed to demonstrate a statistically significant benefit.
Implications for 22q11.2 Deletion Syndrome
In parallel, Harmony has suspended development of ZYN002 in 22q11.2 deletion syndrome while analyzing data from RECONNECT. The genetic condition, which affects about one in 4,000 people in the U.S., results from the deletion of a portion of chromosome 22. It can lead to a range of symptoms, including developmental delays, cognitive challenges, and congenital heart disease.
Prior to Harmony’s acquisition, Zynerba had completed a phase 1/2 study of ZYN002, then known as Zygel, in children with 22q11.2 deletion syndrome in 2022. That trial reported improvements in anxiety, depression, and aberrant behavior, with only mild side effects from the gel. The company confirmed to Fierce that it isn’t currently running any active trials of ZYN002 in 22q11.2 deletion syndrome.
Harmony’s Broader Pipeline and Financials
Beyond ZYN002, Harmony’s development pipeline includes seven additional programs. Its lead product, pitolisant, marketed as Wakix for excessive daytime sleepiness in narcolepsy, is being evaluated in a phase 3 trial for Prader-Willi syndrome and recently completed a phase 2 study for myotonic dystrophy type 1. Another late-stage candidate, EPX-100 (clemizole hydrochloride), is in phase 3 trials for Dravet syndrome and Lennox-Gastaut syndrome, two rare forms of epilepsy. Harmony obtained EPX-100 through its $35 million acquisition of Epygenix in 2024.
In its third-quarter business update, Harmony reported $239.5 million in revenue, a 29% increase compared to the same period last year. All sales were generated by Wakix, which accounted for the entirety of Harmony’s quarterly earnings.
Outlook
The decision by Harmony to pause the ZYN002 programme reflects both the high hurdles facing therapies for rare neurobehavioural conditions and the volatility of development in this domain. With the RECONNECT trial failing to reach its key endpoint, the company must now reassess not only the clinical validity of ZYN002’s mechanism of action but also its potential path to market in other indications such as 22q11.2 deletion syndrome.
For patients and physicians in both Fragile X and 22q11.2 deletion syndromes, the setback underscores the challenge of addressing complex neurodevelopmental disorders with behavioural endpoints. High placebo response rates, variability in symptom presentation, and the progressive nature of these disorders make trial design difficult.
