Harmony Biosciences Holdings announced disappointing topline results from its Phase 3 RECONNECT study of ZYN002 in Fragile X syndrome (FXS), with the trial failing to meet its primary endpoint of improvement in social avoidance primarily due to a higher than expected placebo response rate. The news sent the company's stock down 7.08% in pre-market trading.
Trial Design and Results
The RECONNECT Study was a randomized, double-blind, placebo-controlled, multiple-center trial designed to assess the efficacy and safety of ZYN002, a pharmaceutically manufactured cannabidiol administered as a transdermal gel. The study enrolled 215 male and female patients, ages 3 to under 30 years, who were randomized 1:1 to receive study drug or placebo during an 18-week treatment period with weight-based dosing.
The primary endpoint measured change from baseline to week 18 in the ABC-CFXS Social Avoidance subscale score in patients with complete methylation (≥90%) in the FMR1 gene. Key secondary endpoints included change from baseline to week 18 in the ABC-CFXS Irritability subscale score in patients with complete methylation (≥90%) in the FMR1 gene.
Company Response and Future Plans
Kumar Budur, M.D., M.S., Chief Medical and Scientific Officer at Harmony Biosciences, acknowledged the disappointment while emphasizing the insights gained: "Although the study did not achieve its primary endpoint, the findings from this study provide valuable insights into Fragile X syndrome, a rare neurobehavioral condition with significant unmet medical need and no FDA-approved therapies."
Despite the setback, CEO Jeffrey M. Dayno, M.D., expressed confidence in the company's broader pipeline: "We have a late-stage, catalyst-rich pipeline with multiple Phase 3 programs in the clinic and continue to be on track to initiate our Phase 3 trials for pitolisant HD in narcolepsy and idiopathic hypersomnia in the fourth quarter of this year."
About ZYN002 and Fragile X Syndrome
ZYN002 represents the first-and-only pharmaceutically manufactured synthetic cannabidiol devoid of THC, formulated as a patent-protected permeation-enhanced gel for transdermal delivery. The product is manufactured through a synthetic process in a cGMP facility rather than being extracted from the cannabis plant. Cannabidiol has received orphan drug designation from both the FDA and EMA for FXS treatment, and ZYN002 has received FDA Fast Track designation for treating behavioral symptoms in FXS patients.
Fragile X syndrome is a rare genetic disorder representing the leading known cause of both inherited intellectual disability and autism spectrum disorder. The condition affects synaptic function, plasticity and neuronal connections, resulting in intellectual disabilities and behavioral symptoms including social avoidance and irritability. Based on prevalence estimates of approximately 1 in 4,000 to 7,000 in males and 1 in 8,000 to 11,000 in females, upwards of 80,000 patients in the US and 121,000 patients in the European Union and UK are believed to have FXS.
The disorder is caused by a mutation in FMR1, a gene that codes for FMRP protein and modulates various systems including the endocannabinoid system. In approximately 70%-75% of FXS patients who have complete methylation of the FMR1 gene, no FMRP is produced, resulting in dysregulation of the endocannabinoid system and severe neurobehavioral symptoms.
Market Impact
The failed trial represents a significant setback for addressing the substantial unmet medical need in FXS, as there are currently no FDA-approved treatments for this disorder. Harmony Biosciences stock has declined 6.8% year-to-date and 14% over the past 12 months. Despite the recent disappointment, Wall Street analysts maintain a Strong Buy consensus rating with an average price target of $50.71, representing potential 58.12% upside from current levels.
